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Esófago de Barrett: contributos para a definição do conceito e para o conhecimento do risco de progressão neoplásica numa população portuguesa
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O esófago de Barrett resulta da substituição metaplásica do epitélio pavimentoso que normalmente recobre o esófago distal por epitélio colunar, associada ao refluxo gastroesofágico. É uma condição pré-maligna através da sequência metaplasia displasia adenocarcinoma, sendo recomendada a vigilância endoscópica. Contudo a definição de esófago de Barrett’s não é consensual, o que é um problema relevante pois o número de doentes em vigilância será diferente consoante se considere ou não a metaplasia intestinal como um pré-requisito para o diagnóstico. A displasia é o único marcador de risco validado na prática clínica, mas a concordância intra e interobservador é fraca. Portugal continua a ser um país de baixa incidência de adenocarcinoma do esófago, desconhecendo-se se tal se relaciona com uma baixa prevalência ou um baixo risco de cancro do esófago de Barrett. O objectivo principal desta Tese é determinar a incidência de adenocarcinoma e de displasia de alto grau numa população de doentes portugueses com esófago de Barrett. Os objectivos secundários são identificar variáveis demográficas e clínicas associadas à progressão neoplásica no esófago de Barrett; avaliar o risco de progressão para adenocarcinoma e displasia de alto grau associado ao diagnóstico de displasia de baixo grau e indefinido para displasia; avaliar o significado dos segmentos de esófago revestidos por epitélio colunar sem evidência de metaplasia intestinal. Dos resultados há a salientar: 1. A incidência baixa de adenocarcinoma (0.9 casos por 1000 doentes/ano de vigilância) e de displasia de alto grau/adenocarcinoma (3.1 casos por 1000 doentes/ano de vigilância) na população portuguesa com esófago de Barrett. 2. A extensão do esófago de Barrett como única variável com impacto no risco de displasia de alto grau/adenocarcinoma. A incidência observada nos segmentos curtos (3cm) foi muito baixa (0,7 casos por 1000 doentes/ano de vigilância). 3. Concordância intra-observador e inter-observador semelhante (moderada) no diagnóstico de displasia de baixo grau. Se dois ou mais patologistas concordaram no diagnóstico prévio de displasia de baixo grau, a taxa de progressão para displasia de alto grau e adenocarcinoma observada foi muito elevada (62,5% no intervalo de 1 a 8 anos). 4. O esófago revestido por epitélio colunar sem metaplasia intestinal com 2 ou mais centímetros de extensão (n=15) partilha semelhanças clínicas e endoscópicas com o esófago de Barrett, excepto que os doentes são mais jovens. A metaplasia intestinal foi documentada após vigilância média de 7,1 anos. 5. As heterotopias de mucosa gástrica extensas do esófago distal são raras, mas muitas vezes diagnosticadas como esófago de Barrett. Descrevem-se critérios endoscópicos e histológicos que os permitem distinguir. Contudo alguns guidelines permitem classificá-las como esófago de Barrett. 6. A expressão quase universal de vilina, proteína que se localiza no prato estriado, foi observada no epitélio cárdico de uma população pediátrica com doença do refluxo. Estes resultados permitem concluir: 1. O baixo risco de adenocarcinoma e displasia de alto grau/adenocarcinoma com esófago de Barrett aconselha à reavaliação dos intervalos de vigilância actualmente propostos pelos guidelines, nomeadamente para os segmentos curtos onde intervalos de cinco anos parecem seguros. 2. A evidência recente da indicação para ablação endoscópica do esófago de Barrett com displasia de baixo grau confirmada por dois patologistas gastrointestinais experientes é aplicável no nosso pais . 3. A definição actual de esófago de Barrett ainda não é suficientemente precisa para incluir todos os doentes em risco de cancro do esófago e para excluir os que não têm risco. Palavras-chaves: esófago de Barrett, esófago revestido por epitélio colunar, metaplasia intestinal, adenocarcinoma do esófago, displasia, vigilância.
Barrett’s esophagus results from the metaplastic replacement of the normal squamous lining of the distal esophagus by a columnar epithelium, related to gastro-esophageal reflux. Barrett’s esophagus is recognized as a pre-neoplastic condition through the sequence metaplasia dysplasia adenocarcinoma, and endoscopic surveillance is advised by the guidelines. However Barrett’s esophagus definition lacks consensus. The question of the definition of Barrett’s esophagus is relevant because the number of patients in surveillance will be very different depending upon intestinal metaplasia being or not a prerequisite for diagnosis. Dysplasia is the sole validated clinical cancer risk factor, but intraobserver and interobserver agreement was observed to be weak. Portugal remains a country with low incidence of esophageal adenocarcinoma, and it is not known if this is related to a low prevalence or to a low cancer risk of Barrett’s esophagus. The principal objective of this Thesis is to calculate the incidence of adenocarcinoma and high-grade dysplasia in cohort of Portuguese Barrett’s patients. Secondary objectives are to identify clinical and demographics variables associated with cancer risk in Barrett’s esophagus; to evaluate the risk of high-grade dysplasia or adenocarcinoma associated with the diagnosis of low-grade dysplasia and indefinite for dysplasia; to evaluate the clinical meaning of columnar-lined esophagus without intestinal metaplasia. From the results obtained in these studies, we must note: 1. A low incidence of adenocarcinoma (0.9 cases per 1000 patient/year of follow-up) and high-grade-dysplasia/adenocarcinoma (3.1 cases per 1000 patient/year of follow-up) in the Portuguese population with Barrett’s esophagus. 2. Barrett’s esophagus length was the sole variable associated with high-grade dysplasia/adenocarcinoma risk. A very low incidence of high-grade dysplasia/adenocarcinoma (0.7 cases per 1000 patient/year of follow-up) was observed in short segments (≤ 3 cm). 3. Intraobserver and interobserver agreement in the diagnosis of low-grade dysplasia was similar (moderate). If two or more pathologists agreed with a previous diagnosis of low-grade dysplasia, the rate of progression to high-grade dysplasia and adenocarcinoma was very high (62.5%). 4. Columnar-lined esophagus without intestinal metaplasia with 2 or more centimeters in length (n=15) had clinical and endoscopic similarities with our cohort of Barrett’s esophagus, except for a younger age. Intestinal metaplasia was documented in 60% of the patients after a mean follow-up of 7.1 years. 5. Large lower esophageal gastric heterotopias are rare, but frequently misdiagnosed as Barrett’s esophagus. There are endoscopic and histological features allowing correct diagnosis. However, some guidelines allow classifying these patients as having Barrett’s esophagus. 6. An almost universal expression of the brush border protein villin was observed in cardiac epithelium from a pediatric population with reflux disease. The results from these studies allow for the following conclusions: 1. The low risk of adenocarcinoma and high-grade dysplasia in Barrett’s esophagus in Portugal justifies reassessment of surveillance intervals actually proposed by the guidelines, namely for short segments for which 5-year intervals seems safe. 2. The recent evidence favoring Barrett’s ablation in patients with low-grade dysplasia diagnosis agreed by two experienced gastrointestinal pathologists can be introduced in clinical practice in our country. 3. Present Barrett’s esophagus definitions are not yet sufficiently precise to include all the patients with esophageal cancer risk and to exclude those with no risk. Key words: Barrett’s esophagus; columnar-lined esophagus; intestinal metaplasia; esophageal adenocarcinoma; dysplasia; surveillance.
Barrett’s esophagus results from the metaplastic replacement of the normal squamous lining of the distal esophagus by a columnar epithelium, related to gastro-esophageal reflux. Barrett’s esophagus is recognized as a pre-neoplastic condition through the sequence metaplasia dysplasia adenocarcinoma, and endoscopic surveillance is advised by the guidelines. However Barrett’s esophagus definition lacks consensus. The question of the definition of Barrett’s esophagus is relevant because the number of patients in surveillance will be very different depending upon intestinal metaplasia being or not a prerequisite for diagnosis. Dysplasia is the sole validated clinical cancer risk factor, but intraobserver and interobserver agreement was observed to be weak. Portugal remains a country with low incidence of esophageal adenocarcinoma, and it is not known if this is related to a low prevalence or to a low cancer risk of Barrett’s esophagus. The principal objective of this Thesis is to calculate the incidence of adenocarcinoma and high-grade dysplasia in cohort of Portuguese Barrett’s patients. Secondary objectives are to identify clinical and demographics variables associated with cancer risk in Barrett’s esophagus; to evaluate the risk of high-grade dysplasia or adenocarcinoma associated with the diagnosis of low-grade dysplasia and indefinite for dysplasia; to evaluate the clinical meaning of columnar-lined esophagus without intestinal metaplasia. From the results obtained in these studies, we must note: 1. A low incidence of adenocarcinoma (0.9 cases per 1000 patient/year of follow-up) and high-grade-dysplasia/adenocarcinoma (3.1 cases per 1000 patient/year of follow-up) in the Portuguese population with Barrett’s esophagus. 2. Barrett’s esophagus length was the sole variable associated with high-grade dysplasia/adenocarcinoma risk. A very low incidence of high-grade dysplasia/adenocarcinoma (0.7 cases per 1000 patient/year of follow-up) was observed in short segments (≤ 3 cm). 3. Intraobserver and interobserver agreement in the diagnosis of low-grade dysplasia was similar (moderate). If two or more pathologists agreed with a previous diagnosis of low-grade dysplasia, the rate of progression to high-grade dysplasia and adenocarcinoma was very high (62.5%). 4. Columnar-lined esophagus without intestinal metaplasia with 2 or more centimeters in length (n=15) had clinical and endoscopic similarities with our cohort of Barrett’s esophagus, except for a younger age. Intestinal metaplasia was documented in 60% of the patients after a mean follow-up of 7.1 years. 5. Large lower esophageal gastric heterotopias are rare, but frequently misdiagnosed as Barrett’s esophagus. There are endoscopic and histological features allowing correct diagnosis. However, some guidelines allow classifying these patients as having Barrett’s esophagus. 6. An almost universal expression of the brush border protein villin was observed in cardiac epithelium from a pediatric population with reflux disease. The results from these studies allow for the following conclusions: 1. The low risk of adenocarcinoma and high-grade dysplasia in Barrett’s esophagus in Portugal justifies reassessment of surveillance intervals actually proposed by the guidelines, namely for short segments for which 5-year intervals seems safe. 2. The recent evidence favoring Barrett’s ablation in patients with low-grade dysplasia diagnosis agreed by two experienced gastrointestinal pathologists can be introduced in clinical practice in our country. 3. Present Barrett’s esophagus definitions are not yet sufficiently precise to include all the patients with esophageal cancer risk and to exclude those with no risk. Key words: Barrett’s esophagus; columnar-lined esophagus; intestinal metaplasia; esophageal adenocarcinoma; dysplasia; surveillance.
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Palavras-chave
Esófago de Barrett -Vigilância Esófago - Epitélio colunar Esófago - Metaplasia intestinal Esófago - Displasia Esófago - Adenocarcinoma