Cáncer de esófago generalidades
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Cáncer de esófago generalidades
- 1. CÁNCER DE ESÓFAGO Generalidades José Pinto Llerena Residente de Oncología Médica MAYO 2016
- 2. TEMAS A TRATAR 1. Introducción 2. Epidemiología 3. Factores etiológicos 4. Factores predisponentes 5. Fisiopatología 6. Historia natural y patrones de Falla 7. Anatomía 8. Histología 9. Presentación Clínica 10.Estudios Diagnósticos 11.Estadiaje
- 3. INTRODUCCIÓN Predominio de 2 histologías •Adenocarcinoma y Escamoso •Depende de los factores asociados Incidencia Anual •456.000 casos nuevos por año en el mundo Supervivencia •15 a 25 % sobrevive a 5 años Gastroenterology 2015;149:1700–1715 Cancer Epidemiology 41 (2016) 88–95
- 4. EPIDEMIOLOGÍA Centro-norte de China, Asia central, Norte de Irán, Este de África del Sur Cancer Epidemiology 41 (2016) 88–95
- 5. EPIDEMIOLOGÍA Área de alta incidencia (100 casos /100.000 hab) Turquía, Norte de Irán, naciones del sur de la antigua Unión Soviética, China Alta incidencia en hombres (15 casos /100.00 hab) Clavados, Francia Miyagi, Japón Hong Kong Alta incidencia en mujeres (5 casos /100.000 hab) Mumbai, India Shanghai, China Escocia Riesgo de CE por sexo, durante toda la vida 0.5 % hombres y 0.3 % mujeres DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. Cancer Epidemiology 41 (2016) 88–95
- 6. EPIDEMIOLOGÍA Estados Unidos Infrecuente 1 % de riesgo de desarrollarlo Incidencia + alta Afroamericanos 9/100.000 personas-año (va en ↓) Hombres blancos 8/100.000 personas-año H > M Ecamoso > Adenocarcinoma Adenocarcinoma ↑incidencia en 400 % en WM y 300 % WF > obesidad y ERGE Mejoría en mortalidad Supervivencia 5 % en1970’s vs 17 % en 2000’s 4.8 muertes por 100.000 hab DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. Cancer Epidemiology 41 (2016) 88–95
- 7. EPIDEMIOLOGÍA EN USA (MODELO OCCIDENTAL) Cancer Epidemiology 41 (2016) 88–95 Adenocarcinoma
- 8. EPIDEMIOLOGÍA EN USA (MODELO OCCIDENTAL) Cancer Epidemiology 41 (2016) 88–95
- 9. INCIDENCIA Y SUPERVIVENCIA SEGÚN ETAPA ETAPA INCIDENCIA (%) SUPERVIVENCIA/5AÑOS (%) LOCAL 21 39.6 REGIONA L 30 21.1 DISTANT E 37 3.8 Cancer Epidemiology 41 (2016) 88–95
- 10. FACTORES ETIOLÓGICOS Tabaquismo 65-75 % casos > 6 meses Dosis-respuesta 50 % de reducción de riesgo al dejar de fumar ↑ dos veces el riesgo de Adenocarcinoma en Fumadores pesados Riesgo no reduce por dejar de fumar carcinogénesis en etapa temprana Nitrosaminas, hidrocarbonos policíclicos aromáticos y aminas aromáticas Polimorfismo de TRANSFERASAS DE GLUTATIÓN CYP1A1, GSTM1 y GSTP1 DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. Gastroenterology 2015;149:1700–1715 Cancer Epidemiology 41 (2016) 88–95
- 11. FACTOR DE RIESGO-ETILISMO Etilismo 80 % casos en países occidentales y subdesarrollados Efecto directo, nutricional, irritativo mecánico, susceptibilidad a otros carcinógenos. No factor de riesgo para adenocarcinoma Acetaldehído Carcinógeno tipo 1 para Cáncer Escamoso Polimorfismo de ALDH2 Glu504Lys Forma aductos de DNA Induce mutaciones en gen supresor de tumor TP53 G:C A:T y G:C T:A DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th Gastroenterology 2015;149:1700–1715 Cancer Epidemiology 41 (2016) 88–95
- 12. RELACIÓN ENTRE FUMADOR PESADO Y ALCOHOLISMO Cancer Letters 275 (2009) 240–246 N = 44970 Casos de ESCC = 215
- 13. REFLUJO GASTRO ESOFÁGICO N Engl J Med 1999;340:825-31
- 14. OBESIDAD International Journal of Epidemiology 2012;41:1706–1718
- 15. FACTORES PREDISPONENTES Factor Predisponente Relación Dieta y nutrición Frutas y vegetales factor protector (vitaminas A, C, E, carotenos, selenio) Bebidas muy calientes y dieta baja en selenio predisposición. Estatus socioeconómico Bajo estado socieconómico ↑ riesgo de Cáncer escamoso y adenocarcinoma (menor grado). 39 y 69 % para WM y BM. Exposición a percloretileno, asbesto, sílice, polvo metálico, virus Obesidad > IMC ↑ adenocarcinoma hasta 7 veces más. (adenocarcinoma) Reflujo Gastroesofágico Frecuencia, severidad y cronicidad ↑ 2 a 16 veces adenocarcinoma 10-15 % desarrollará Esófago de Barrett Infección por H. pylori Cepas cagA+ relación inversa con riesgo de adenocarcinoma Incremento de riesgo de escamoso por aumento de nitrosaminas Vía de la Anemia de Fanconi Desorden autosómico recesivo. Inestabilidad genómica, falla de MO, cánceres hematológicos, tumores escamosos de cérvix, CyC y esófago. Mutación en FANCD1 DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. Gastroenterology 2015;149:1700–1715 Cancer Epidemiology 41 (2016) 88–95
- 16. ESÓFAGO DE BARRETT Metaplasia intestinal que reemplaza el epitelio escamoso del esófago distal ↑ riesgo de 40 a 125 veces 1.5 % de todas las endoscopías ERGE sintomático 6-12 % ERGE asintomático 1.2 % Progresión 0.22 % por año (0.12-0.40 % /AÑO) 1-2 % de la población general < 5 % de los ptes con AdenoCa operados tienen esófago de Barrett 1.5-2 Millones de personas con EB en USA INTERNATIONAL JOURNAL OF ONCOLOGY 41: 414-424, 2012 15 % de personas con ERGE N Engl J Med 2014;371:836-45.
- 17. ESÓFAGO DE BARRETTEndoscopía anual para bajo grado ↑producción de COX-2 INTERNATIONAL JOURNAL OF ONCOLOGY 41: 414-424, 2012 LESIÓN PREMALIGNA PARA ADENOCARCINOMA 1 % 5 % N Engl J Med 2014;371:836-45.
- 18. ESÓFAGO DE BARRETT- FACTORES DE RIESGO N Engl J Med 2014;371:836-45.
- 19. ESÓFAGO DE BARRETT N Engl J Med 2014;371:836-45.
- 20. ESÓFAGO DE BARRETT- TRATAMIENTO Gastroenterology Report, 3(4), 2015, 303–315
- 21. DISPLASIA ESCAMOSA N Engl J Med 2014;371:836-45. Cancer Epidemiol Biomarkers Prev. 2013 Apr; 22(4): 540–552. • 3-38 % prevalencia • Alteración de P53 96 % • Alteración de p16INK4a 68% RR 2.2 (0.7- 7.5) RR 15.8(5.9- 42.2) 72.6 (29.8- 176.9) 24 % 50% 74% 8% Lesión premaligna para Cáncer Escamoso de Esófago
- 22. FACTORES PREDISPONENTES FACTOR PREDISPONENTE RELACIÓN Tilosis o Howell-Evans Queratoderma palmoplantar no epidermolítica focal. Hiperqueratosis de palmas y plantas con papilomas esofágicos. 17q25. mutación de RHBDF2. ESCC HEREDITARIO. Síndrome de Plummer Vinson Patterson-Kelly Queilitis, glositis, uñas quebradizas, esplenomegalia, anemia ferropénica y membranas esofágicas. 10 % CE Lesión cáustica 40 a 50 años luego de lesión inicial. CE de 1/3 medio Acalasia Secundario a aumento de presión en EEI. 16 a 30 veces riesgo de ESCC. 17 años después de inicio. VPH Asia y Sudáfrica. Regiones de alta incidencia. 17 % ptes en China con ESCC. E6 y E7 pRb y p53. No confirmado en países de baja incidencia. Maliginidad previa en tracto aerodigestivo Riesgo 4 % por año. 10 % CE (primario en CyC o Pulmón) DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. Gastroenterology 2015;149:1700–1715 Cancer Epidemiology 41 (2016) 88–95
- 23. AINES-FACTOR PROTECTOR Gastroenterology. 2012 March ; 142(3): 442–e23
- 24. PROTECTORES N Engl J Med 2014;371:836-45.
- 25. BIOLOGÍA MOLECULAR SOBREEXPRESIÓN DE EGFR Predice pobre respuesta a QT/RT Factor pronóstico desfavorable Disminución de OS a pesar de esofagectomía en ESCC DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. • Sobre expresado en 59.6 a 76 % de ESCC • Amplificado en 11-24 % • Mutado 0-1.8 % • 78.6 % mutaciones y/o amplificaciones en vías de señalización (RAS Y AKT) Gastroenterology 2015;149:1700–1715
- 26. BIOLOGÍA MOLECULAR: CICLINA D1 Sobreexpresión de Ciclina D1 Pérdida del alelo del locus 13q 50 % DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. 2-10 % de ESCC Genes amplificados: 1. CCND1 46.4% 2. CDK4/CDK6 23.6% 3. MDM2 5.7% Gastroenterology 2015;149:1700–1715 Factor predictivo y pronóstico
- 27. BIOLOGÍA MOLECULAR: P16INK4A 90 % displasia de Barrett 80 % Adenocarcinoma Pérdida de p16INK4a y P53 Locus 9p21 Factor predictivo y pronóstico DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012.Gastroenterology 2015;149:1700–1715
- 28. BIOLOGÍA MOLECULAR P53 80 % de mutación es por Pérdida de sensibilidad Principal sitio de mutación 83 % ESCC 90 % Adenocarcinoma DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012.
- 29. BIOLOGÍA MOLECULAR ACTIVACIÓN DE TELOMERASA Activada en casi 100 % de los Adenocarcinomas y Esófago de Barrett DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012.
- 30. OTRAS MUTACIONES Mutación MSR-1 11 % de ptes con EB y Adenocarcinoma Sobre-expresión de Ciclina D1 CRTC1 Codifica el factor de transcripción CREB BARX1 Codifica una proteína para la especificación esofágica FOXP1 Codifica una proteína para el desarrollo del esófago Alteraciones Genéticas y EB/AdenoCa 5 genes relevantes en desarrollo de AdenoCa N Engl J Med 2014;371:2499-509. Genes relacionados con ESCC (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, and NFE2L2) (ADAM29 and FAM135B)
- 31. HISTORIA NATURAL DE LA ENFERMEDAD Gastroenterology 2015;149:1700–1715 Evolución en el tiempo Tinciones con Lugol Cromoendoscopía SE: 92 % ES: 94 %
- 32. HISTORIA NATURAL Y PATRONES DE FALLA Localmente o regionalmente avanzados Falta de envoltura serosa mucha infiltración e invasión linfática Pulmón, hígado y hueso Principales sitios de metástasis a distancia Mediana de supervivencia luego de esofagectomía 15-18 meses Supevivencia a 5 años 20-25 % Patrones de falla Localización y tipo histológico se relaciona a mejor tasa de recaída a distancia y control locorregional mejor control local que RT sola y a distancia ofrece control local pero no a distancia ↓falla local 45 32 % DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012.
- 33. ANATOMÍA ESCAMOSO UNIÓN GASTROESOFÁGICA Clasificación De Siewert DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012. 1cm y 5 cm 1 cm y 2 cm 2 cm y 5 cm
- 34. ANATOMÍA-DRENAJE LINFÁTICO ESÓFAGO UNIÓN GASTROESOFÁGICA DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012.
- 35. ANATOMÍA G. capa de epitelio estratificado F. membrana mucosa E. muscular de la mucosa D. submucosa C. capa muscular transversal B. capa muscular longitudinal A. capa fibrosa o Adventicia DeVita Principles and Practice of Oncology. Esophageal Cancer. 9th edition 2012.
- 36. HISTOLOGÍA Distribución por histología 40 % ESCAMOSO – USA y 70 % MUNDIAL 57 % ADENOCARCINOMA – USA y 30 % MUNDIAL Distribución 60 % TERCIO MEDIO 30 % TERCIO DISTAL 10 % TERCIO PROXIMAL Abeloff M. Abeloff’s Clinical Oncology. 4th edition
- 37. HISTOLOGÍA Células pequeñas Escamoso adenocarcinoma Transición escomoso-células pequeñas 30-40 % Leiomiosarcoma Abeloff M. Abeloff’s Clinical Oncology. 4th edition
- 38. HISTOLOGÍA INVOLUCRINA • Atipia nuclear • Actividad mitótica • Grado de diferenciación escamosa Gastroenterology 2015;149:1700–1715
- 39. PRESENTACIÓN CLÍNICA SÍNTOMA DESCRIPCIÓN Disfagia Progresiva. Enfermedad localmente avanzada. Pérdida de peso 90 % Dolor Odinofagia 20 %. Retroestornal, óseo. Tos, estridor Irritación local, aspiración, comida no digerida, o infiltración directa del árbol respiratorio (irresecable). Disfonía Afección del N. Laríngeo Recurrente (irresecable) Neumonía Fístula traqueoesofágica o invasión de estructuras vasculares. Otras Hipercalcemia, compresión medular Abeloff M. Abeloff’s Clinical Oncology. 4th edition
- 40. ABORDAJE DIAGNÓSTICO Escoger los estudios correctos dependerá de la historia clínica y probabilidad preclínica de extensión de la enfermedad EXÁMENES COMPLEMENTARIOS NCCN Guidelines. Esophageal Cancer. Version 1, 2016.
- 41. ESTUDIOS DIAGNÓSTICOS Abeloff M. Abeloff’s Clinical Oncology. 4th edition
- 42. ENDOSCOPÍA DIGESTIVA ALTA Adenocarcinoma de UGE Esófago de Barrett Gastroenterology 2015;149:1700–1715 Diagnóstica y terapéutica
- 43. ULTRASONIDO ENDOSCÓPICO (EUS) DETECCIÓN DE T3N1MX SUPERIOR A TC para T y N Gastroenterology 2015;149:1700–1715 No óptimo para evaluar respuesta a inducción o en lesiones estenósticas
- 44. TOMOGRAFÍA TOMOGRAFÍA NORMAL CÁNCER DE ESÓFAGOGastroenterology 2015;149:1700–1715 Permite evaluar respuesta a terapia de inducción
- 45. PET-CT Tomografía Gastroenterology 2015;149:1700–1715 Permite evaluar respuesta a terapia de inducción
- 46. DETECCIÓN DE GANGLIOS Y METÁSTASIS Gastroenterology 2015;149:1700–1715
- 47. ESTADIAJE
- 48. ESTADIAJE American Joint Committee on Cancer, Cancer Staging Manual 7th edition • 2010
- 49. ESTADIAJE American Joint Committee on Cancer, Cancer Staging Manual 7th edition • 2010
- 50. SUPERVIVENCIA A 5 AÑOS POR ETAPA Survival by Stage NCDB National Data 2003- 2006. SEER.
- 51. SUPERVIVENCIA- ESCAMOSO Years American Joint Committee on Cancer, Cancer Staging Manual 7th edition • 2010
- 52. SUPERVIVENCIA- ADENOCARCINOMA American Joint Committee on Cancer, Cancer Staging Manual 7th edition • 2010
- 53. VIGILANCIA NCCN Guidelines. Esophageal Cancer. Version 1, 2016.
- 54. VIGILANCIA NCCN Guidelines. Esophageal Cancer. Version 1, 2016.
- 55. VIGILANCIA NCCN Guidelines. Esophageal Cancer. Version 1, 2016.
- 56. PUNTOS CLAVE 8VA CAUSA DE CÁNCER Y 6TA CAUSA DE MUERTE POR CÁNCER EN EL MUNDO HISTOLOGÍA ESCAMOSA ES LA MÁS FRECUENTE (70-80 %) ADENOCARCINOMA SE HA VUELTO MÁS FRECUENTE POR OBESIDAD Y ERGE MUTACIÓN DE P53 MECANISMO MOLECULAR MÁS IMPORTANTE EN ESCC TABAQUISMO, ETILISMO, OBESIDAD, ERGE, CAUSAS CONSTRICTIVAS EN ESÓFAGO SON PRINCIPALES FACTORES DE RIESGO ESÓFAGO DE BARRETT CON DISPLASIA DE BAJO GRADO (10%) Y ALTO GRADO (40%) MAYOR RIESGO DE PROGRESIÓN A CÁNCER DE ESÓFAGO DISFAGIA, TOS Y DOLOR SON LOS PRINCIPALES SÍNTOMAS SOBREEXPRESIÓN DE EGFR, CICLINA D1 factores pronósticos y predictivos. ALTA MORTALIDAD AÚN CON ESOFAGECTOMÍA
Notas del editor
- one from north central China through the central Asian republics to northern Iran, and one from eastern to southern Africa
- 5-year survival rates for oesophageal adenocarcinoma in US SEER 18 registries, overall (black), and among whites (stripes) and blacks (grey).
- We examined the effect of alcohol consumption, cigarette smoking and flushing response on esophageal squamous cell carcinoma (ESCC) in a large-scale population-based cohort study. 44,970 middle-aged and older Japanese men were followed. A total of 215 cases of ESCC were newly diagnosed. Alcohol consumption and cigarette smoking are strongly associated with the incidence of ESCC. Heavy alcohol consumption increased the risk of ESCC especially among heavy smokers with the flushing response (HR = 3.41, 95% CI = 2.10–5.51). Strong effect modification was detected in heavy smokers. Our results suggest that heavy alcohol consumption together with heavy smoking may increase the risk of ESCC particularly in individuals with the flushing response.
- Background The causes of adenocarcinomas of the esophagus and gastric cardia are poorly understood. We conducted an epidemiologic investigation of the possible association between gastroesophageal reflux and these tumors. Methods We performed a nationwide, populationbased, case–control study in Sweden. Case ascertainment was rapid, and all cases were classified uniformly. Information on the subjects’ history of gastroesophageal reflux was collected in personal interviews. The odds ratios were calculated by logistic regression, with multivariate adjustment for potentially confounding variables. Results Of the patients interviewed, the 189 with esophageal adenocarcinoma and the 262 with adenocarcinoma of the cardia constituted 85 percent of the 529 patients in Sweden who were eligible for the study during the period from 1995 through 1997. For comparison, we interviewed 820 control subjects from the general population and 167 patients with esophageal squamous-cell carcinoma. Among persons with recurrent symptoms of reflux, as compared with persons without such symptoms, the odds ratios were 7.7 (95 percent confidence interval, 5.3 to 11.4) for esophageal adenocarcinoma and 2.0 (95 percent confidence interval, 1.4 to 2.9) for adenocarcinoma of the cardia. The more frequent, more severe, and longerlasting the symptoms of reflux, the greater the risk. Among persons with long-standing and severe symptoms of reflux, the odds ratios were 43.5 (95 percent confidence interval, 18.3 to 103.5) for esophageal adenocarcinoma and 4.4 (95 percent confidence interval, 1.7 to 11.0) for adenocarcinoma of the cardia. The risk of esophageal squamous-cell carcinoma was not associated with reflux (odds ratio, 1.1; 95 percent confidence interval, 0.7 to 1.9). Conclusions There is a strong and probably causal relation between gastroesophageal reflux and esophageal adenocarcinoma. The relation between reflux and adenocarcinoma of the gastric cardia is relatively
- Background Previous studies suggest an association between obesity and oesophageal (OA) and oesophagogastric junction adenocarcinomas (OGJA). However, these studies have been limited in their ability to assess whether the effects of obesity vary by gender or by the presence of gastro-oesophageal reflux (GERD) symptoms. Methods Individual participant data from 12 epidemiological studies (8 North American, 3 European and 1 Australian) comprising 1997 OA cases, 1900 OGJA cases and 11 159 control subjects were pooled. Logistic regression was used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between body mass index (BMI, kg/m2) and the risk of OA and OGJA. Random-effects meta-analysis was used to combine these ORs. We also investigated effect modification and synergistic interaction of BMI with GERD symptoms and gender. Results The association of OA and OGJA increased directly with increasing BMI (P for trend <0.001). Compared with individuals with a BMI <25, BMI 540 was associated with both OA (OR 4.76, 95% CI 2.96– 7.66) and OGJA (OR 3.07, 95% CI 1.89–4.99). These associations were similar when stratified by gender and GERD symptoms. There was This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc/3.0/), which permits non-commercial reuse, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com Published by Oxford University Press on behalf of the International Epidemiological Association The Author 2012; all rights reserved. Advance Access publication 12 November 2012 International Journal of Epidemiology 2012;41:1706–1718 doi:10.1093/ije/dys176 1706 Downloaded from http://ije.oxfordjournals.org/ by guest on May 2, 2016 evidence for synergistic interaction between BMI and GERD symptoms in relation to OA/OGJA risk. Conclusions These data indicate that BMI is directly associated with OA and OGJA risk in both men and women and in those with and without GERD symptoms. Disentangling the relationship between BMI and GERD will be important for understanding preventive efforts for OA and OGJA.
- A comparison of initial biopsy diagnoses with the occurrence of ESCC over the subsequent 3.5 years showed that only dysplasia predicted development of ESCC, and that increasing grades of dysplasia predicted increased risk: compared to normal, relative risks (95% confidence intervals) were 2.2 (0.7–7.5) for mild dysplasia, 15.8 (5.9–42.2) for moderate dysplasia, 72.6 (29.8–176.9) NIH Public Access Author Manuscript Cancer Epidemiol Biomarkers Prev. Author manuscript; available in PMC 2014 April 01. Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2013 April ; 22(4): 540–552. doi:10.1158/1055-9965.EPI-12-1347. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript for severe dysplasia, 22.9 (6.7–78.0) for dysplasia not otherwise specified, and 62.5 (24.1– 161.9) for carcinoma-in-situ. Of note, dysplasia not otherwise specified (NOS) and moderate dysplasia risks were similar, as were risks for carcinoma-in-situ and severe dysplasia. Further follow-up of this same endoscopic cohort for a total of 13.5 years corroborated the previous risk estimates and provided more precise quantification. Over the full follow-up period ESCC developed in 8% of participants with normal histology, but 24% with mild dysplasia, 50% with moderate dysplasia, 74% with severe dysplasia, 58% with dysplasia NOS, and 75% with carcinoma-in-situ (Fig 2) (5).
- RHBDF2 = Missense mutation of romboid family member gene 2, está involucrado en la activación de la señalización de EGFR
- a Adjusted for any use of non-aspirin NSAID, age, sex, body mass index (kg/m2), gastroesophageal reflux, education, smoking intensity (pack-years), alcohol intake (drinks per day) and study center (when applicable) b Number of studies included in a specific analysis varies based on the number of studies with contributing data (e.g. studies with no participants in that category or not enough cases or controls in that category to provide a study-specific estimate would not be included in the random-effects meta-analysis model). c Trend tests used the category of intake as an ordinal variable (e.g. 0-3) and were calculated from meta-analytic pooling of study-specific odds ratios estimated from logistic regression models Background & Aims—Regular use of aspirin and other non-steroidal anti-inflammatory drugs (NSAID) has been reported to reduce risks for esophageal adenocarcinoma (EAC) and esophagogastric junctional adenocarcinoma (EGJA). However, individual studies have been too small to accurately assess the effects of medication type, frequency, or duration of use. We performed a pooled analysis to investigate these associations. Methods—We performed a pooled analysis of 6 population-based studies within the Barrett's and Esophageal Adenocarcinoma Consortium to evaluate the association between NSAID use and the risk of EAC and EGJA, using uniform exposure definitions. We collected information from 6 studies (5 case-control and 1 cohort), with a total of 1226 EAC and 1140 EGJA cases, on aspirin and/or NSAID use. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariate adjusted logistic regression models and then pooled using a random effects meta-analysis model. Results—Compared to non-users, individuals who have used NSAIDs had a statistically significant, reduced risk of EAC (OR=0.68; 95% CI, 0.56–0.82); they also appeared to have a reduced risk of EGJA (OR=0.84; 95% CI, 0.68–1.03). Similar reductions in risk were observed among individuals who took aspirin or non-aspirin NSAIDs. The highest levels of frequency (≥daily) and duration (≥10 years) of NSAID use were associated with an approximately 40% reduction in risk for EAC: OR=0.56 (95% CI, 0.43–0.73; P-trend, <.001) and OR=0.63 (95% CI, 0.45–0.90; P-trend, 0.04), respectively. Conclusions—Although reverse causation could, in part, explain the inverse association observed between NSAID use and EAC risk, pooled analysis indicates a role for NSAIDs in prevention of adenocarcinomas of the esophagus and esophagogastric junction.
- The mammalian cell cycle is regulated exquisitely by cyclins, cyclin-dependent kinases ( CDK), and cyclin-dependent kinase inhibitors ( CDKi such as p 1 5 , p 1 6, p2 1 , and p27) . During Gl phase, the cyclin Dl oncogene complexes with either CDK4 or CDK6 to phosphorylate the retinoblastoma (pRb) tumor suppressor protein and, in so doing, relieves the negative regulatory effect of pRb, allowing the E2F family of transcription factors to propel the cell cycle toward the G1/S phase transition. 16 Toward the late G1 phase, cyclin E complexes with CDKs to phosphorylate p 1 07, which is related to pRb, and liberate more E2F members to navigate the cell cycle into S phase. As with EGFR, cyclin Dl overexpression is found in premalignant lesions, such as esophageal squamous dysplasia or Barrett's esophagus, and the maj ority of early-stage ESCC or EAD. 17·1 8 Additionally, cyclin D l overexpression correlates with poor outcomes and survival as well as poor response to chemotherapy. 1 9·2o Although cyclin D l overexpression accounts for cyclin D l dysregulation, other mechanisms include mutations i n cyclin Dl and mutations in Fbx4, which is the E3 ligase for cyclin D l , thereby preventing degradation of cyclin Dl in the cytoplasm and reimportation into the nucleus, where it exerts its oncogenic effects.
- In a similar vein, p l 6INK4a is an early genetic alteration, via promoter hypermethylation, point mutation, or allelic deletion, in Barrett's esophagus and EAD, but interestingly, a late event in ESCC. Loss of heterozygosity of 9p2 1 , the locus for both p 1 6 and p 1 5 , has been demonstrated with high frequency in both dysplastic Barrett's epithelium and Barrett's adenocarcinoma ( 9 0 % and more than 8 0 % of cases, respectively) . 22•23 Promoter hypermethylation, which prevents tumor suppressor function by blocking transcription, has been documented and correlates with the degree of dysplasia in Barrett's esophagus. It is present in up to 75 % of specimens with high-grade dysplasia and is found in almost 5 0 % of patients with adenocarcinoma of the esophagus.24 Point mutations of p 1 6 in ESCC have been found and promoter hypermethylation has been noted in up to 5 0 % of these tumors.25·26 Rb gene mutation is not found in either type of esophageal neoplasm, but allelic loss of 1 3 q where the locus of the Rb gene resides is found in up to 5 0 % of patients with Barrett's adenocarcinoma and squamous cell carcinoma .18·27 This can correlate with diminished or loss of pRb protein in Barrett's esophagus with dysplasia, EAD, and ESCC.
- p53 is one of the most commonly mutated genes in human cancer.22-24 p53 (molecular weight approximately 53 kDa) is a tumor suppressor that interrupts the G1 phase to evaluate and permit repair of damaged DNA, which may arise from environmental exposure (e.g., irradiation, ultraviolet light) or cellular stress.30 In the face of irreparable damage, p53 induces apoptosis. The p53 transcription factor binds DNA to activate or suppress a large repertoire of target genes.31 p53 mutations induce loss of cell-cycle checkpoints and promote genomic instability. The maj ority of p53 mutations occur in the DNA-binding region, and more than 8 0 % of them are missense mutations resulting in loss of wild type p53 function.32 Wild type p53 has a short half-life and is difficult to detect by immunohistochemistry; mutation in p53 results in stabilization of the protein and allows for easier detection by immunohistochemistry. Detection of mutated p53 protein by immunohistochemistry has been demonstrated with increasing frequency during histologic progression from Barrett's esophagus ( 5 % ) through dysplasia ( 6 5 % to 75 % ) to frank adenocarcinoma ( up to 9 0 % ) .33-36 Thus, p53 mutation or loss of heterozygosity appears early in Barrett's esophagus and EAD. Both mutant p5 3 protein detected by immunohistochemistry and specific p53 gene mutations detected by genomic sequencing have been identified in 4 0 % to 75 % of patients with ESCCY-4° The presence of a p53 point mutation correlates with response to induction chemoradiotherapy and predicted survival after esophagectomy in patients with either ESCC or EAD.41
- Maintenance of telomere length allows DNA replication to be sustained indefinitely. Aberrant expression of telomerase has been observed in most esophageal cancers examined to date.42 Morales et al.43 observed increased telomerase expression in 1 0 0 % of adenocarcinoma and Barrett's esophagus cases with high-grade dysplasia. Telomerase activation is important, but alternative mechanisms to maintain the length of telomeres may operate in these cancers as well.44
- 5 of which (TP53, CDKN2A, SMAD4, ARID1A, and PIK3CA) are relevant to the pathogenesis of adenocarcinoma.34 Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org, lists genes and molecular pathways that have been found to have alterations reported as prevalent among patients with esophageal adenocarcinoma. Lineage-specific factors, especially transcription factors, appear to be important in the development of esophageal cancers.34 Likewise, whole-genome and wholeexome sequencing in Chinese patients with esophageal squamous-cell carcinoma revealed eight mutated genes — six known tumor-associated genes (TP53, RB1, CDKN2A, PIK3CA, NOTCH1, and NFE2L2) and two novel genes (ADAM29 and FAM135B).35
- Lymph node maps for esophageal cancer. Regional lymph node stations for staging esophageal cancer, from front ( A ) and side ( B ). 1, Supraclavicular nodes; above suprasternal notch and clavicles. 2R, Right upper paratracheal nodes; between intersection of caudal margin of innominate artery with trachea and the apex of the lung. 2L, Left upper paratracheal nodes; between the top of aortic arch and apex of the lung. 3P, Posterior mediastinal nodes; upper paraesophageal nodes, above tracheal bifurcation. 4R, Right lower paratracheal nodes; between intersection of caudal margin of innominate artery with trachea and cephalic border of azygos vein. 4L, Left lower paratracheal nodes; between top of aortic arch and carina. 5, Aortopulmonary nodes; subaortic and para-aortic nodes lateral to the ligamentum arteriosum. 6, Anterior mediastinal nodes; anterior to ascending aorta or innominate artery. 7, Subcarinal nodes; caudal to the carina of the trachea. 8M, Middle paraesophageal lymph nodes; from the tracheal bifurcation to the caudal margin of the inferior pulmonary vein. 8L, Lower paraesophageal lymph nodes; from the caudal margin of the inferior pulmonary vein to the esophagogastric junction. 8R, 9, Pulmonary ligament nodes; within the inferior pulmonary ligament. 10R, Right tracheobronchial nodes; from cephalic border of azygos vein to origin of RUL bronchus. 10L, Left tracheobronchial nodes; between carina and LUL bronchus. 15, Diaphragmatic nodes; lying on the dome of the diaphragm and adjacent to or behind its crura. 16, Paracardial nodes; immediately adjacent to the gastroesophageal junction. 17, Left gastric nodes; along the course of the left gastric artery. 18, Common hepatic nodes; along the course of the common hepatic artery. 19, Splenic nodes; along the course of the splenic artery. 20, Celiac nodes; at the base of the celiac artery. ( D ) The IASLC lymph node map. (D, © Memorial Sloan-Kettering Cancer Center, 2009.) The pattern of lymphatic drainage of the esophagus influences the choice of surgical approach, based on tumor location in the esophagus (Fig. 79 . 5 ) . Tumors of the cervical and upper third of the thoracic esophagus drain to cervical and superior mediastinal lymph nodes. Tumors of the middle third of the esophagus drain both cephalad and caudad with lymph nodes at risk in the para tracheal, hilar, subcarinal, periesophageal, and pericardia! nodal basins. Lesions in the distal esophagus primarily drain to lymph nodes in the lower mediastinum and celiac axis region. Because of the extensive lymphatic network within the wall of the esophagus, skip metastases for upper third lesions have been noted in celiac axis nodal basins, and likewise, cervical lymph node metastases have been noted in as many as 3 0 % of patients with distal esophageal lesions. Some surgeons recommend a more radical oncologic procedure, a combined transthoracic and abdominal approach for lesions of the middle and distal esophagus, 8l,83 and others recommend a three-field (cervical, mediastinal, and abdominal) lymphadenectomy for all tumors of the middle through distal esophagus. 84·85 However, lymph node metastases are initially limited in an overwhelming maj ority of patients to regional lymph nodes . Lymph node involvement in lymphatic basins distant from the primary tumor are rarely identified unless metastases to regional lymph nodes have already occurred,86 which suggests the potential of sentinel lymph node sampling to direct surgical dissection. 87
- Small cell carcinomas account for approximately 1 % of esophageal malignancies and arise from argyrophilic cells in the basal layer of the squamous epithelium. These neoplasms are usually located in the middle or lower third of the esophagus and may be associated with ectopic production of a variety of hormones, including parathormone, secretin, granulocyte colony-stimulation factor, and gastrin-releasing peptide; individuals with these cancers often present with systemic disease.89-91 Recent series have reported patients with locally advanced disease treated with systemic chemotherapy in combination with either radiation therapy, surgery, or both, with some patients achieving long-term disease-free survival.92
- Leiomyosarcoma is the most common mesenchymal tumor that affects the esophagus, still accounting for less than 1 % of esophageal malignancies . These neoplasms are lower-third tumors presenting as bulky masses with hemorrhage and necrosis. Malignant lymphoma and Hodgkin's lymphoma rarely involve the esophagus and is usually secondary to extension from other sites. Patients with acquired immunodeficiency syndrome may exhibit Kaposi's sarcoma involving the esophagus. Malignant melanoma involving the esophagus is exceedingly rare and presents as a bulky polypoid intraesophageal tumor of varying color depending on melanin production.
- Figure 4. Representative histopathologic images of ESCC. ESCC is graded based on mitotic activity, nuclear atypia, and degree of squamous differentiation. (Left panel) Welldifferentiated SCC. (Middle panel) Moderately differentiated SCC. (Right panel) Poorly differentiated SCC.
- A focused history taking should elicit information on predisposing factors for esophageal cancer, including tobacco use, alcohol use, symptomatic reflux, diagnosis of Barrett's esophagus, and history of head and neck or thoracic malignancy. Prior surgery on the stomach or colon may influence the choice of reconstructive conduit to restore alimentary continuity at the time of esophagectomy. Findings on history and physical examination that would prompt further diagnostic testing include hoarseness, cervical or supraclavicular lymphadenopathy, pleural effusion, or new onset of bone pain.
- Patients with symptoms of dysphagia should undergo upper endoscopy and biopsy to establish a tissue diagnosis. Biopsies or cytologic brushings have a diagnostic accuracy approaching 1 0 0 % , 107,108 Targeted biopsy can be enhanced by the use of chromoendoscopy techniques using vital dyes, including indigo carmine, Lugol's iodine solution, methylene blue, and toluidine blue. 109·1 10 Autofluorescence imaging and narrow band imaging are emerging endoscopic techniques that allow for detailed inspection of mucosa Chest radiography and liquid oral contrast examination of the esophagus and stomach have been replaced by computed tomography ( CT) and flexible endoscopy. Esophagogastroscopy allows precise evaluation of the extent of esophageal and gastric involvement and can precisely measure the distance of the tumor from the incisors to appropriately categorize the tumor's location. Upper endoscopy also allows identification of " skip " lesions or second primaries as well as indicates the presence and extent of Barrett's esophagus. Bronchoscopy should be reserved for those patients with tumors of the middle and upper esophagus to rule out invasion of the membranous trachea and possible tracheoesophageal fistula.
- The accuracy of endoscopic ultrasonography (EUS) in determining both T and N stage is a function of its ability to clearly delineate the multiple layers of the esophageal wall124·125 and its use of multiple criteria, including shape, border pattern, echogenicity, and size, to determine lymph node involvement. 126,127 EUS is superior to CT in both T and N staging of esophageal cancer. 128,129 The overall accuracy for T staging is approximately 8 5 % and for N staging it is approximately 75 % . 130 The accuracy of determining lymph node involvement has been increased to 8 5 % to 1 0 0 % with the use of linear-array EUS with a channel that allows passage of a needle to perform tissue aspiration for cytology. l23,131·132 EUS is highly operator dependent
- A recent single institution review of 201 CT scans in 99 patients undergoing staging for esophageal cancer indicated that imaging of the pelvis did not contribute added staging information, and it may not need to be routinely performed. 1 15 CT scans are highly accurate ( approaching 1 00 % ) in detecting liver or lung metastases and suggesting peritoneal carcinomatosis (e.g., ascites, omental infiltration, peritoneal tumor studding ) . 1 16-1 1 8 Accuracy for detecting aortic involvement or tracheobronchial invasion exceeds 9 0 % . 1 17·119·12° CT is inaccurate in determining T stage and N stage
- FDG-PET is superior to CT, with a sensitivity, specificity, and accuracy all in the range of 8 0 % to 9 0 % . 142·143 PET in combination with CT (PET-CT fusion or hybrid FDG-PET/CT) further improves specificity and accuracy of noninvasive staging. 144 This leads to detection of unsuspected metastatic disease ( up-staging ) in 1 5 % of patients, which leads to alteration of the intended treatment plan in at least 2 0 % of patients . FD G-PET may also have value in evaluating response to chemotherapy and radiotherapy. Weber et al.l45 demonstrated that decreased FDG uptake significantly correlated with pathologically confirmed response in p atients treated with induction chemotherapy before esophagectomy for esophageal adenocarcinoma.