食管腺癌和Barrett食管

原发于食管的腺癌约占食管癌的5％～10％，食管腺癌患者中约86％起源于Barrett食管，少数来自异位胃粘膜或食管粘液腺体。Barrett食管是食管腺癌最重要的危险因素，而食管特殊型肠上皮化生是食管腺癌的癌前病变。对诊断为Barrett食管的患者应纳入内镜监测计划，定期追踪和监视观察，使肿瘤在早期阶段检出。     

P53蛋白在原发性食管腺癌和Barrett氏食管中的表达

本研究对10例食管癌高发区的原发性食管腺癌手术切除标本和32例门诊病人的Barrett氏食管内镜粘膜活检标本进行了病理组织学检查，同时进行了抗癌基因P53的检测。结果显示：30%的原发性食管腺癌和47％的Barrett氏食管出现P53蛋白的阳性表达，表明P53阳性表达可能是Barrett氏食管上皮到食管腺癌发生过程中一个极早期的改变。对这些病人将进行长期的随访研究。在国人中，原发性食管腺癌和Barrett氏食管的关系，尚需进一步的、多方面的深入研究来确定。     

Barrett食管与食管腺癌

Barrett食管为Barrett 1950年首先报道,系指食管下段粘膜的鳞状上皮为柱状上皮所取代的一种病理现象。自Morson等报道在Barrett食管上发生腺癌以来,其与食管腺癌的关系越来越受到重视。有人认为Barrett食管事实上是一种癌前病变。     

食管腺癌和Barrett食管

原发于食管的腺癌约占食管癌的5%～10%,食管腺癌患者中约86%起源于Bsrrett食管,少数来自异位胃粘膜或食管粘液腺体.Barrett食管是食管腺癌最重要的危险因素,而食管特殊型肠上皮化生是食管腺癌的癌前病变.对诊断为Barrett食管的患者应纳入内镜监测计划,定期追踪和监视观察,使肿瘤在早期阶段检出.     

周期蛋白B1和D1在重度反流性食管炎、Barrett食管和食管腺癌中的表达及相关性研究

 目的　探讨周期蛋白（Cyclin）B1及D1在Barrett食管、Barrett食管合并不典型增生（DY）和食管腺癌中表达的临床意义。方法　应用免疫组织化学SP法测定68例患者食管组织标本Cyclin B1和Cyclin D1,其中重度反流性食管炎（RE）25例,Barrett食管（BE）35例,其中8例DY,8例食管腺癌（EA）,另取10例正常食管黏膜组织作为对照。结果　Cyclin B1 和Cyclin D1在 BE、DY、EA组检测样本中均有高表达,而在正常对照组及RE组黏膜组织中仅有少量表达,差异有统计学意义（P＜0.01）,且Cyclin D1表达从肠化生-不典型增生-腺癌组织依次增高（分别为50.04、 67.94、74.31）,差异有统计学意义（P＜0.01）。结论　Cyclin B1和 cyclin D1可以作为肿瘤进展标志物来评估Barrett食管患者进展为腺癌的危险性,并可能是食管腺癌发生过程中的早期事件。     

食管腺癌与Barrett’s食管基因表达谱的研究

 目的 探讨从Barrett’s食管到食管腺癌的癌变过程中基因表达谱的变化。 方法 取同一食管腺癌患者大体手术标本经病理确诊的腺癌组织、Barrett’s 食管组织及正常组织,分别提取组织上皮的总RNA并纯化mRNA;将mRNA逆转录合成以Cy5和Cy3标记的cDNA链做探针,分别混合后在两张基因表达谱芯片上进行杂交。用扫描仪扫描芯片荧光信号,用软件对扫描图像进行分析。 结果 食管腺癌与正常食管上皮比较差异2倍以上共有214个基因;Barrett’s食管与正常食管上皮比较差异2倍以上共有90个基因。而Barrett’s食管组织和食管腺癌组织均下调的基因有24个,均上调的基因有21个。其中符合从Barrett’s食管到食管腺癌演变趋势的基因中,上调的有9个,下调的有18个。 结论 这些基因或其产物可作为Barrett’s食管具有癌变高危性的检测指标     

Barrett食管患者食管腺癌的发病率低于估计值

背景流行病学资料显示Barrett食管患者发展为食管腺癌和异型增生的概率显著增加,该研究旨在通过大样本人群队列对照研究来确定Barrett食管患者发生食管腺癌的发病率。方法该研究在丹麦病理协会和丹麦肿瘤协会两大机构的协助下,统计了1992～2009年期间丹麦11028名Barrett食管患者。     

食管腺癌生物标记物的研究进展

 食管腺癌（esophageal adenocarcinoma，EAC）在西方国家发病率有逐年增加的趋势，往往伴随Barrett’S食管（Barrett’s esophagus，BE）的发生。Barrett’s化生已经被公认为是一种癌前病变，是发生食管腺癌的危险因素之一。预测腺癌发生最可靠的方法是从组织学上发现有高度的非典型性增生，对BE进行长期的内镜和组织学随访可预防食管腺癌的发生和获得早期发现。尽管EAC常伴随Barrett’s化生，但仍有大部分病人并不能从这种内镜检查中诊断出BE。 随着分子生物学的发展以及对BE 和EAC 流行病学研究的深入,人们逐渐探索生物标记物( biomarker) 在BE 和EAC 早期诊断和判断预后方面的重要意义。为了早期诊断EAC ,提高其生存率,最有希望的方法是对生物标记物的鉴定。从肿瘤发病的分子学角度看,对BE 和EAC 的生物标记物研究较多的主要有以下几类。     

原发性食管腺癌——附外科治疗27例报告

 本文报告原发性食管腺癌27例,占同期食管癌的1.1%(27/2456)。27例全部施行了手术切除,术后一、二、三、四年生存率分别为66.7%(18/27)、34.6%(9/26)、19.0(4/21)和7.7%(1/13),无五年生存者。疗效较食管鳞癌显著为未食管腺癌组织来源有三种:食管本身腺体、食管的异位胃粘膜、Barrett食管。组织学分四种类型:单纯性腺癌、腺鳞癌、表皮粘液样癌和囊性腺样癌,其中以单纯性腺癌和腺鳞病占绝大多数(26/27)。食管腺癌的诊断须有病理检查证实。早期手术是首选治疗方法。     

Barrett′s食管在国人中的发病率及P53、EGFr在其中的表达

本研究对1448例名河南省食管癌高发区农村自然人群中进行了Barrett’s食管的内镜普查和病理组织学检查。同时对1991～1995年门诊病人中Barrett’s食管的检出率进行总结。用免疫组织化学染色法检测了P53、EGFr在Barrett’s食管中的表达。结果显示：自然人群中Barrett’s食管的患病率为0．69％，返流性食管炎的检出率8．9％。门诊病人中Barrett’s食管检出率为1．6％。p53阳性表达率为29％、EGFr为56％。研究表明Barrett’s食管中p53、EGFr的阳性表达是一种很早的生物学改变，其实际意义需长期的随访研究来确定。     

p53 in esophageal adenocarcinoma: a critical reassessment of mutation frequency and identification of 72Arg as the dominant allele

p53 alterations have been implicated in the progression of Barrett's esophagus to esophageal adenocarcinoma. However, the wide range of reported p53 alteration frequencies in esophageal adenocarcinoma makes using p53 as a marker of malignant transformation of Barrett's esophagus problematic. To determine the utility of p53 in Barrett's esophagus monitoring, the frequency of p53 alteration was critically reassessed using esophagectomy specimens of 40 cases of esophageal adenocarcinoma, including 10 with Barrett's esophagus and high-grade dysplasia, 8 with low-grade dysplasia and 7 with no dysplasia. DNA was extracted from tumor cells isolated by laser capture microdissection to maximize the assay sensitivity and mutations in exons 4-8 of p53 were determined by PCR direct sequencing. Mutations in p53 were identified in 75% (30/40) of the esophageal adenocarcinoma. p53 protein overexpression, detected by immunohistochemistry, was found in 58% (23/40) of the esophageal adenocarcinoma, 60% (6/10) of Barrett's esophagus with high-grade dysplasia, 12% (1/8) of Barrett's esophagus with low-grade dysplasia, and 0% of Barrett's esophagus without dysplasia. In addition to the mutations, a predominance of the 72Arg allele (89% homozygous) was found over the 72Pro allele in this series. p53 mutation frequency in this study was higher than reported in most of the literature and DNA sequencing detected more p53 alterations than immunohistochemical staining. However, p53 appeared to be a late marker in the neoplastic transformation, and no p53 change was found in approximately 25% of the adenocarcinoma. We concluded that p53 is insufficient as a single marker for Barrett's esophagus monitoring but may be useful as part of a panel due to its high specificity.     

Gains and amplifications of c-myc, EGFR, and 20.q13 loci in the no dysplasia-dysplasia-adenocarcinoma sequence of Barrett's esophagus

The progression of Barrett's esophagus to esophageal adenocarcinoma is often characterized by the accumulation of genetic abnormalities. The goal was to evaluate the copy number alterations of several oncogene loci, including 7p12 [epidermal growth factor receptor (EGFR)], 8q24 (c-myc), and 20q13 in the sequence of no dysplasia-dysplasia-adenocarcinoma of Barrett's esophagus. Fluorescence in situ hybridization with DNA probes for the centromeric region of chromosome 7 and the locus-specific regions of 7p12 (EGFR), 8q24 (c-myc), and 20q13 was applied on 99 brush cytology specimens of patients with Barrett's esophagus with different stages of dysplasia or esophageal adenocarcinoma. Gains (3-4 copies) of chromosome 17, 8q24 (c-myc), and 20q.13 loci were found in the low frequencies in nondysplastic Barrett's esophagus. Their frequencies increased with the stage of dysplasia and reached a high incidence in esophageal adenocarcinoma. Amplification (>4 copies) of at least 1 of the loci was observed in 14% of high-grade dysplasia and increased to 50% in esophageal adenocarcinoma (P = 0.015). The most frequently amplified locus was c-myc (18%), followed by 20q13 (13%) and EGFR (11%) in the high-grade dysplasia/esophageal adenocarcinoma cases. High amplification levels (>10 copies) of the loci were more frequent in esophageal adenocarcinoma (72%) compared with high-grade dysplasia (20%; P = 0.049). Amplifications of the c-myc, EGFR, and 20q12 loci may serve as diagnostic markers to identify patients with Barrett's esophagus with high-grade dysplasia or esophageal adenocarcinoma. Gains of the loci might be of value as prognostic markers because they are already present in nondysplasia cases and may precede the later event of the amplification as observed in high-grade dysplasia and esophageal adenocarcinoma.     

Familiality in Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction.

BACKGROUND AND AIM: The familial aggregation of Barrett's esophagus, adenocarcinoma of the esophagus, and adenocarcinoma of the gastroesophageal junction, jointly termed familial Barrett's esophagus, may represent a complex genetic trait. The aim of this study was to determine the proportion of patients with these diseases who have familial Barrett's esophagus. METHODS: Information on gastroesophageal reflux symptoms, known risk factors for Barrett's esophagus, and family history of Barrett's esophagus and cancers, was collected at six hospitals using a structured questionnaire from probands with either long-segment Barrett's esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction. Family history of Barrett's esophagus or esophageal cancer in a first- or second-degree relative was determined by reviewing medical records of all relatives reported to be affected. RESULTS: Seventy one of 411 (17.3%) probands reported an affected first- and/or second-degree relative. Upon review of medical records of the reportedly affected relatives, familial Barrett's esophagus was definitively determined in the case of 30 (7.3%) probands comprising 17 of 276 (6.2%) with Barrett's esophagus, 11 of 116 (9.5%) with adenocarcinoma of the esophagus, and 2 of 21 (9.5%) with adenocarcinoma of the gastroesophageal junction. The diagnosis in the relative reported by the proband to be affected was found not to be Barrett's esophagus or adenocarcinoma in 15 (3.6%) cases. The diagnosis could not be determined in 26 (6.3%) cases in which the proband reported an affected relative. There were no significant differences in age of disease onset, gender, race, or gastroesophageal reflux symptoms between definitive familial Barrett's esophagus probands and nonfamilial probands. CONCLUSION: Familial Barrett's esophagus can be confirmed in 7.3% of persons presenting with Barrett's esophagus, adenocarcinoma of the esophagus, or adenocarcinoma of the gastroesophageal junction.     

Nonsteroidal anti-inflammatory drugs and the esophageal inflammation-metaplasia-adenocarcinoma sequence

Observational studies suggest that nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of esophageal adenocarcinoma, but it is not known at what stage they may act in the esophageal inflammation-metaplasia-adenocarcinoma sequence. In an all-Ireland case-control study, we investigated the relationship between the use of NSAIDs and risk of reflux esophagitis, Barrett's esophagus, and esophageal adenocarcinoma. Patients with esophageal adenocarcinoma, long-segment Barrett's esophagus and population controls were recruited from throughout Ireland. Esophagitis patients were recruited from Northern Ireland only. Data were collected on known and potential risk factors for esophageal adenocarcinoma and on the use of NSAIDs, including aspirin, at least 1 year before interview. Associations between use of NSAIDs and the stages of the esophageal inflammation-metaplasia-adenocarcinoma sequence were estimated by multiple logistic regression. In total, 230 reflux esophagitis, 224 Barrett's esophagus, and 227 esophageal adenocarcinoma and 260 population controls were recruited. Use of aspirin and NSAIDs was associated with a reduced risk of Barrett's esophagus [odds ratio [OR; 95% confidence interval (95% CI)], 0.53 (0.31-0.90) and 0.40 (0.19-0.81), respectively] and esophageal adenocarcinoma [OR (95% CI), 0.57 (0.36-0.93) and 0.58 (0.31-1.08), respectively]. Barrett's esophagus and esophageal adenocarcinoma patients were less likely than controls to have used NSAIDs. Selection or recall bias may explain these results and the results of previous observational studies indicating a protective effect of NSAIDs against esophageal adenocarcinoma. If NSAIDs have a true protective effect on the esophageal inflammation-metaplasia-adenocarcinoma sequence, they may act early in the sequence.     

Hypermethylation of the AKAP12 promoter is a biomarker of Barrett's-associated esophageal neoplastic progression

The A-kinase anchoring protein 12 (AKAP12) is a kinase scaffold protein with known tumor suppressor activity. Recently, AKAP12 promoter hypermethylation was reported in gastric and colorectal cancers. We examined AKAP12 promoter hypermethylation using real-time methylation-specific PCR in 259 human esophageal tissues. AKAP12 hypermethylation showed highly discriminative receiver-operator characteristic (ROC) curve profiles, clearly distinguishing esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma and normal esophagus (P < 0.0001). AKAP12-normalized methylation values were significantly higher in Barrett's metaplasia (BE), dysplastic Barrett's, and EAC than in normal esophagus (P < 0.0000001). AKAP12 hypermethylation frequency was zero in normal esophagus but increased early during neoplastic progression, to 38.9% in BE from patients with Barrett's alone, 52.5% in dysplastic Barrett's metaplasia, and 52.2% in EAC. AKAP12 hypermethylation levels were significantly higher in normal esophageal epithelia from patients with EAC (mean = 0.00082) than in normal esophagi from patients without Barrett's or esophageal cancer (mean = 0.00007; P = 0.006). There was a significant correlation between AKAP12 hypermethylation and BE segment length, a known clinical neoplastic progression risk factor. In contrast, only 2 (7.7%) of 26 esophageal squamous cell carcinomas exhibited AKAP12 hypermethylation. Treatment of BIC and OE33 EAC cells with 5-aza-2'-deoxycytidine reduced AKAP12 methylation and increased AKAP12 mRNA expression. AKAP12 mRNA levels in EACs with unmethylated AKAP12 (mean = 0.1663) were higher than in EACs with methylated AKAP12 (mean = 0.0668). We conclude that promoter hypermethylation of AKAP12 is a common, tissue-specific event in human EAC, occurs early during Barrett's-associated esophageal neoplastic progression, and is a potential biomarker for the early detection of EAC.     

No association between hOGG1, XRCC1, and XPD polymorphisms and risk of reflux esophagitis, Barrett's esophagus, or esophageal adenocarcinoma: results from the factors influencing the Barrett's adenocarcinoma relationship case-control study.

Reflux of gastric contents can lead to development of reflux esophagitis and Barrett's esophagus. Barrett's esophagus is a risk factor for esophageal adenocarcinoma. Damage to DNA may lead to carcinogenesis but is repaired through activation of pathways involving polymorphic enzymes, including human 8-oxoguanine glycosylase 1 (hOGG1), X-ray repair cross-complementing 1 (XRCC1), and xeroderma pigmentosum group D (XPD). Of the single nucleotide polymorphisms identified in these genes, hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln are particularly common in Caucasians and have been associated with lower DNA repair capacity. Small studies have reported associations with XPD Lys 751 Gln and esophageal adenocarcinoma. XRCC1 Arg 399 Gln has been linked to Barrett's esophagus and reflux esophagitis. In a population-based case-control study, we examined associations of the hOGG1 Ser 326 Cys, XRCC1 Arg 399 Gln, and XPD Lys 751 Gln polymorphisms with risk of esophageal adenocarcinoma, Barrett's esophagus, and reflux esophagitis. Genomic DNA was extracted from blood samples collected from cases of esophageal adenocarcinoma (n = 210), Barrett's esophagus (n = 212), reflux esophagitis (n = 230), and normal population controls frequency matched for age and sex (n = 248). Polymorphisms were genotyped using TaqMan allelic discrimination assays. Odds ratios and 95% confidence intervals were obtained from logistic regression models adjusted for potential confounding factors. There were no statistically significant associations between these polymorphisms and risk of esophageal adenocarcinoma, Barrett's esophagus, or reflux esophagitis.     

Primary esophageal adenocarcinoma--report of 19 cases

Primary esophageal adenocarcinoma is rare. Nineteen such cases treated in our hospital during 1972-1985 are reported. Of these patients, 15 were treated by surgery. Only one of them survived for more than 3 years. The prognosis was worse than that of the squamous cell carcinoma of the esophagus. Esophageal adenocarcinoma is of three origins: ectopic gastric mucosa, esophageal intrinsic gland, and Barrett's esophagus. In our series, only one case was proved to be due to malignancy of the Barrett's esophagus.     

Barretts carcinoma in a 25-year-old man with point mutation of the p53 tumor suppressor gene

Barrett's esophagus is a recognized risk factor for adenocarcinoma of the esophagus. Dysplasia in Barrett's epithelium is considered a precursor to malignancy. Several tumor suppressor genes, including p53, have recently been implicated in the pathogenesis of esophageal adenocarcinoma. However, the interval between the development of Barrett's esophagus, dysplasia, and frank malignancy is usually very long. A case of adenocarcinoma of the esophagus arising from Barrett's esophagus in a 25-year-old man is discussed. Point mutation in exon 8 of p53 was discovered in this patient's tumor and surrounding dysplastic Barrett's mucosa. To our knowledge, this is the youngest reported case of Barrett's-associated esophageal adenocarcinoma in the medical literature. It suggests that acquired somatic mutations in tumor suppressor genes may occur early in life and that these mutations may contribute to the development of dysplasia and cancer in Barrett's esophagus.     

Risk factors, DNA damage, and disease progression in Barrett's esophagus.

Esophageal adenocarcinoma develops on a background of Barrett's esophagus. A number of risk factors have been linked to both conditions, including gastroesophageal reflux and smoking. However, the molecular mechanisms by which these factors influence disease progression remain unclear. One possibility is that risk factors generate promutagenic DNA damage in the esophagus. The comet assay was used to measure DNA damage in esophageal (Barrett's and squamous) and gastric mucosa of Barrett's patients with (n = 24) or without (n = 50) associated adenocarcinoma or high-grade dysplasia in comparison with control patients (squamous mucosa) without Barrett's esophagus (n = 64). Patients completed a questionnaire detailing exposure to some of the known risk factors for Barrett's esophagus and adenocarcinoma. In Barrett's esophagus patients, DNA damage was higher in Barrett's mucosa compared with normal esophageal and gastric mucosa (P < 0.001). In addition, the highest quartile of DNA damage in Barrett's mucosa was associated with an increased risk (odds ratio, 9.4; 95% confidence interval, 1.1-83.4; P = 0.044) of developing adenocarcinoma or high-grade dysplasia compared with DNA damage levels in the lowest quartile. Smoking was associated with higher DNA damage in squamous epithelium in all patient groups (P < 0.01) and in Barrett's mucosa (P < 0.05) in Barrett's esophagus patients only. In controls only, current reflux was associated with higher DNA damage, whereas anti-inflammatory drug use resulted in lower levels. Collectively, these data imply a genotoxic insult to the premalignant Barrett's mucosa that may explain the genetic instability in this tissue and the progression to adenocarcinoma. There is an indication for a role for smoking in inducing DNA damage in esophageal mucosa but an understanding of the role of reflux requires further investigation.