TP53 mutations in malignant and premalignant Barrett''s esophagus

In order to improve the efficacy of endoscopic surveillance of Barrett's esophagus, markers of neoplastic progression in addition to dysplasia are required. The aim of the present study was to assess TP53 mutational analysis as a method of identifying patients with Barrett's esophagus who are at greatest risk of adenocarcinoma, for whom endoscopic surveillance is most appropriate. TP53 mutational analysis was initially performed on premalignant and malignant tissue from 30 patients undergoing esophagectomy for adenocarcinoma, and on premalignant biopsies from 48 patients participating in a Barrett's surveillance program. Surveillance patients were followed up endoscopically and histologically for a median of 5 years following TP53 assessment. Mutational analysis was performed by single-strand conformation polymorphism analysis and direct DNA sequencing. TP53 mutations were detected in 10 of 30 esophageal adenocarcinomas, and were more common in well-differentiated carcinomas. An identical TP53 mutation was detected in carcinoma and adjacent dysplasia. Two patients with premalignant Barrett's esophagus had TP53 mutations and one of these patients developed adenocarcinoma on follow up whilst the other has not yet progressed beyond metaplasia. No patient without TP53 mutation developed high-grade dysplasia or adenocarcinoma. TP53 mutations are detected in 33% of esophageal adenocarcinomas and in 4% of premalignant Barrett's esophagus in patients undergoing endoscopic surveillance. TP53 mutation can be detected before the development of high-grade dysplasia or carcinoma, and may be useful in stratifying the risk of adenocarcinoma in patients with Barrett's esophagus.     

Predictors of progression in Barrett''s esophagus II: baseline 17p (p53) loss of heterozygosity identifies a patient subset at increased risk for neoplastic progression

OBJECTIVES: Most patients with Barrett's esophagus do not progress to cancer, but those who do seem to have markedly increased survival when cancers are detected at an early stage. Most surveillance programs are based on histological assessment of dysplasia, but dysplasia is subject to observer variation and transient diagnoses of dysplasia increase the cost of medical care. We have previously validated flow cytometric increased 4N fractions and aneuploidy as predictors of progression to cancer in Barrett's esophagus. However, multiple somatic genetic lesions develop during neoplastic progression in Barrett's esophagus, and it is likely that a panel of objective biomarkers will be required to manage the cancer risk optimally. METHODS: We prospectively evaluated endoscopic biopsies from 325 patients with Barrett's esophagus, 269 of whom had one or more follow-up endoscopies, by a robust platform for loss of heterozygosity (LOH) analysis, using baseline 17p (p53) LOH as a predictor and increased 4N, aneuploidy, high-grade dysplasia, and esophageal adenocarcinoma as outcomes. RESULTS: The prevalence of 17p (p53) LOH at baseline increased from 6% in negative for dysplasia to 57% in high-grade dysplasia (p < 0.001). Patients with 17p (p53) LOH had increased rates of progression to cancer (relative risk [RR] = 16, p < 0.001), high-grade dysplasia (RR = 3.6, p = 0.02), increased 4N (RR = 6.1, p < 0.001), and aneuploidy (RR = 7.5, p < 0.001). CONCLUSIONS: Patients with 17p (p53) LOH are at increased risk for progression to esophageal adenocarcinoma as well as high-grade dysplasia, increased 4N, and aneuploidy. 17p (p53) LOH is a predictor of progression in Barrett's esophagus that can be combined with a panel of other validated biomarkers for risk assessment as well as intermediate endpoints in prevention trials.     

Barrett's esophagus. Prevalence and incidence of adenocarcinoma

Between January 1973 and January 1989, 241 patients with Barrett's esophagus were treated at the Lahey Clinic Medical Center, Burlington, Mass. Of these patients, 65 presented with adenocarcinoma in Barrett's esophagus for a prevalence rate of 27%. Of 176 patients followed up for a total of 497 patient-years, adenocarcinoma developed in five patients for an incidence of one per 99 patient-years. The development of adenocarcinoma during endoscopic surveillance 1, 2, 2, 4, and 10 years after the initial diagnosis of Barrett's esophagus emphasizes the importance of long-term endoscopic and histologic surveillance. All five patients had severe dysplasia before adenocarcinoma developed. Yearly endoscopic follow-up examination is recommended for all patients with Barrett's esophagus unless mild dysplastic changes are found, in which case surveillance should be increased. Patients with severe dysplasia who are otherwise acceptable candidates for operation should be advised to have esophageal resection.     

3p21, 5q21, 9p21 and 17p13.1 allelic deletions are potential markers of individuals with a high risk of developing adenocarcinoma in Barrett's epithelium without dysplasia

BACKGROUND/AIMS: A common genetic abnormality detected in Barrett's adenocarcinoma is LOH (loss of heterozygosity) at the sites of known or putative tumor suppressor genes. Thus, some deletions have also been determined in peritumoral Barrett's epithelium. These findings suggest that a tissue field of somatic genetic alterations precede the histopathological phenotypic changes of carcinoma. We investigated 32 cases of Barrett's esophagus with no evidence of dysplasia for LOH at 5q21 (APC), 3p21, 9p21 (p16) and 17p13.1 (p53) chromosomal regions. METHODOLOGY: Two groups were randomly selected and compared: 16 cases of Barrett's epithelium adjacent to adenocarcinoma and 16 cases of Barrett's epithelium with no evidence of malignant transformation in a 5-10 years follow-up period. In three adenocarcinomas cases several previous endoscopic biopsies of Barrett's esophagus were available. RESULTS: We determined frequent allelic losses in adenocarcinomas at p53 (54%), p16 (50%), 3p21 (40%) and 5q21 (33%). Identical LOH was present in most cases in the Barrett's epithelium adjacent to adenocarcinoma. LOH at these loci was unusual in Barrett's epithelium with no evidence of malignant transformation. However, in cases where sequential endoscopic biopsies were performed in advance to the adenocarcinoma diagnosis LOH was already present in the Barrett's epithelium. CONCLUSIONS: We suggest that LOH at these loci may be present before the onset of the malignant growth and LOH studies may supplement the histopathological evaluation of Barrett's epithelium. LOH at 3p21, 5q21, 9p21 and 17p13 chromosomal regions in cells of Barrett's epithelium without dysplasia may have a role as a potential marker for individuals with a high risk of developing adenocarcinoma.     

Prospective multivariate analysis of clinical, endoscopic, and histological factors predictive of the development of Barrett's multifocal high-grade dysplasia or adenocarcinoma

OBJECTIVE: Our goal was a prospective follow-up of Barrett's esophagus to determine what clinical, endoscopic, and histological features at the time of initial diagnosis are predictive of the development of Barrett's adenocarcinoma or multifocal high-grade dysplasia (HGD). METHODS: Newly diagnosed Barrett's esophagus patients were prospectively followed with a standardized endoscopic and bioptic surveillance protocol. Features examined by chi2 and stepwise logistic regression analyses as potential predictors the development of multifocal HGD or adenocarcinoma included age, length of Barrett's segment, hiatal hernia size, severity of dysplasia at diagnosis, severity of dysplasia during surveillance, and type of long-term medical treatment. RESULTS: One hundred-eight Barrett's patients have had follow-up ranging from 12 months to 101 months (mean +/- SD, 39.9+/-20.8 months), for a total of 361.8 patient-years. Overall, five patients developed multifocal HGD and five developed adenocarcinoma. The incidence of adenocarcinoma as well as multifocal HGD was 1 per 71.9 patient-years. Chi2 analysis showed progression to Barrett's multifocal HGD/adenocarcinoma was associated with hiatal hernia (p = 0.02), the length of Barrett's (p = 0.001), the presence of dysplasia at diagnoses (p < 0.001) or anytime during surveillance (p < 0.001). Stepwise logistic regression analysis revealed progression to multifocal HGD or adenocarcinoma was significantly and independently associated with presence of dysplasia at diagnosis (p < 0.0001) or anytime during follow-up (p < 0.03), hiatal hernia size (p < 0.02, for hernia > or =3 cm), and length of Barrett's (p = 0.009, >2 cm). CONCLUSIONS: Endoscopic and histological features of Barrett's esophagus patients at initial diagnosis are predictive of risk of progression to cancer.     

Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma

BACKGROUND: The efficacy of endoscopic biopsy surveillance of Barrett's oesophagus in reducing mortality from oesophageal cancer has not been confirmed. AIMS: To investigate the impact of endoscopic biopsy surveillance on pathological stage and clinical outcome of Barrett's carcinoma. METHODS: A clinicopathological comparison was made between patients who initially presented with oesophageal adenocarcinoma (n = 54), and those in whom the cancer had been detected during surveillance of Barrett's oesophagus (n = 16). RESULTS: The surveyed patients were known to have Barrett's oesophagus for a median period of 42 months (range 6-144 months). Prior to the detection of adenocarcinoma or high grade dysplasia, 13 to 16 patients (81%) were previously found to have low grade dysplasia. Surgical pathology showed that surveyed patients had significantly earlier stages than non-surveyed patients (p = 0.0001). Only one surveyed patient (6%) versus 34 non-surveyed patients (63%) had nodal involvement (p = 0.0001). Two year survival was 85.9% for surveyed patients and 43.3% for non-surveyed patients (p = 0.0029). CONCLUSIONS: The temporal course of histological progression in our surveyed patients supports the theory that adenocarcinoma in Barrett's oesophagus develops through stages of increasing severity of dysplasia. Endoscopic biopsy surveillance of Barrett's oesophagus permits detection of malignancy at an early and curable stage, thereby potentially reducing mortality from oesophageal adenocarcinoma.     

DNA Content in Barrett''s Esophagus and Esophageal Malignancy

Barrett's esophagus is a premalignant condition; endoscopic surveillance is often performed to search for early adenocarcinoma of the esophagus. In an attempt to detect early changes of malignancy, we have added the use of flow cytometry to routine endoscopic surveillance procedures. DNA histograms were generated from biopsy samples by utilizing a specific DNA fluorochrome (4',6-diamidino-2-phenylindole) and flow cytometry. Sixty-three samples from patients with esophagitis, Barrett's esophagus, and esophageal malignancy were analyzed. An abnormal DNA histogram (aneuploidy) was detected in 79% of esophageal malignancies. In addition, aneuploidy was detected in seven patients with Barrett's esophagus, two of whom had dysplasia. DNA quantification with flow cytometry may be a useful adjunct in screening patients with Barrett's esophagus for early malignant change.     

Fluorescence in situ hybridization of cytologic specimens from Barrett's esophagus: a pilot feasibility study

BACKGROUND: Endoscopic brush cytology is a promising surveillance technique for Barrett's esophagus. However, there is a need for ancillary biomarkers to increase the sensitivity of cytology and to allow identification of patients at increased risk for disease progression. The aims of this study were to evaluate the feasibility of fluorescence in situ hybridization of endoscopic brush cytology specimens and to determine if there are specific chromosomal changes in cytologic specimens from patients with cancer that are not present in patients without dysplasia. METHODS: Archival cytology slides from 16 patients with Barrett's esophagus were studied: 8 negative for dysplasia and 8 positive for adenocarcinoma. Fluorescence in situ hybridization was used to detect two alterations: HER-2 gene (17q11.2-q12) and 20q13.2 region amplification. OBSERVATIONS: For 7 of 8 adenocarcinoma cases, there was amplification/aneusomy of at least one of the two analyzed regions by fluorescence in situ hybridization. None of the samples negative for dysplasia were abnormal for either of the two genomic regions studied. CONCLUSIONS: Fluorescence in situ hybridization is feasible by using routine Barrett's esophagus cytologic specimens. Differences in genomic makeup can be detected in cells from patients negative for dysplasia and in those with adenocarcinoma.     

Losses of heterozygosity on chromosomes 9p and 17p are frequent events in Barrett's metaplasia not associated with dysplasia or adenocarcinoma

OBJECTIVE: Losses of heterozygosity (LOH) on chromosomes 9p and 17p frequently accompany malignant transformation of Barrett's esophagus (BE). They have been reported in adenocarcinoma, dysplasia, and adjacent metaplasia of patients with long-segment BE (LSBE). This study aimed to evaluate and compare the frequency of LOH on 9p and 17p in patients with long- and short-segment BE (SSBE) without dysplasia or adenocarcinoma. METHODS: Matched metaplasia and blood DNA were evaluated for LOH on chromosomes 9p and 17p in patients with a previous diagnosis of BE and no dysplasia or cancer. RESULTS: We included 18 patients (12 long-segment BE and six short-segment BE). The overall prevalence of LOH was 61% (10 of 18), with no significant difference between LSBE (58%) and SSBE (50%). The frequencies of LOH on 9p and 17p were similar (35% and 39%, respectively), with 18% of the patients showing losses at both chromosomes. CONCLUSIONS: LOH on 9p and 17p are highly frequent events in BE, even in the absence of dysplasia and adenocarcinoma. The presence of these abnormalities in non-neoplastic epithelium suggests they might be useful markers for risk stratification within endoscopic surveillance programs.     

Barrett's esophagus. Correlation between flow cytometry and histology in detection of patients at risk for adenocarcinoma

The value of endoscopic surveillance biopsy for dysplasia and carcinoma in patients with Barrett's esophagus is controversial. One reason is that the available histologic criteria are not adequate to separate patients with lesser degrees of dysplasia or predysplastic changes who are at increased risk for carcinoma and therefore require more frequent surveillance from those patients who are not at increased risk. We used flow cytometry and histology to evaluate 317 biopsy specimens from 64 consecutive patients who were in a cancer surveillance program for Barrett's esophagus and 3 additional patients with adenocarcinoma in Barrett's esophagus. Specimens from 10 patients had aneuploid cells; 9 of these had dysplasia or carcinoma, or both, but 1 patient had only specialized metaplastic epithelium. Twenty specimens ahd G2/tetraploid fractions greater than 6%; all 20 came from patients who had cancer or dysplasia, or were indefinite for dysplasia. All patients with dysplasia or adenocarcinoma had evidence of genomic instability (aneuploidy) or abnormalities of mucosal proliferation by flow cytometry, even when the dysplasia was focal or difficult to recognize histologically. In a small subset of patients with specialized metaplastic epithelium whose specimens were histologically negative or indefinite for dysplasia, the mucosa had aneuploid cell populations or proliferative abnormalities that were otherwise found only in dysplasia or carcinoma. Additional study may prove that this subset of patients merits more frequent endoscopic biopsy surveillance because of an increased risk for developing carcinoma. Because the abnormalities we have detected by flow cytometry correlate well with the conventional histologic diagnoses of dysplasia and carcinoma, they may prove to be a valuable objective adjunct in the diagnosis of dysplasia and carcinoma in Barrett's esophagus.     

Endoscopic surveillance in Barrett's esophagus

Barrett's esophagus (BE), a complication of chronic gastroesophageal reflux disease (GORD), is a condition that is premalignant for adenocarcinoma of the esophagus and esophagogastric junction. Esophageal adenocarcinoma, once an uncommon entity, has been growing rapidly in incidence over the last two decades in several parts of the world. Barrett's esophagus is a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy (American College of Gastroenterology guidelines). Because of its premalignant nature, it is recommended that patients with BE undergo regular endoscopic surveillance. The recommendation for endoscopic surveillance is based on unproved and controversial assumptions including: 1) the assumption that Barrett's esophagus adversely influences survival; 2) the assumption that endoscopic surveillance can reliably detect early, curable neoplasia in the columnar lined esophagus. Moreover, the low incidence of adenocarcinoma (reported cancer incidence rates in prospective studies on BE range between 0.5% and 1.9%) is used to support an approach of not surveying patients with Barrett's esophagus. Despite these not convincing data, endoscopic surveillance is considered 'reasonable' and 'desirable' by the gastroenterological associations and consensus meetings. Endoscopic surveillance for cancer in Barrett's esophagus (BE) is performed primarily to seek dysplasia, to prevent the progression to invasive malignancy; however, one of the limitations of using dysplasia is a lack of understanding of its natural history. The efficacy of endoscopic surveillance for Barrett's esophagus is likely to remain unclear for a long time. The American College of Gastroenterology has recommended the following practice guidelines: a) for patients with no dysplasia, surveillance endoscopy is recommended at an interval of every 2 to 3 years; b) for patients with low grade dysplasia, surveillance endoscopy every 6 months for the first year is recommended, followed by yearly endoscopy if the dysplasia has not progressed in severity; c) for patients with high grade dysplasia, two alternatives are proposed after the diagnosis has been confirmed by an expert gastrointestinal pathologist. One alternative is intensive endoscopic surveillance until intramucosal cancer is detected at an interval of every 3-6 months. The other alternative is esophageal resection. In the situation of indeterminate dysplasia, whereas the pathologist can not come to definite diagnosis, control biopsies are proposed after 2 months of adequate acid suppression by means of proton pump inhibition. In all cases, the technique of random, four quadrant biopsies taken every 2 cm in the columnar-lined esophagus for standard histologic evaluation is recommended. Any grossly abnormal areas may be biopsied too. One can expect however that during the next future these protocol will change considering new data on dysplasia detection (biochemical markers, flow cytometry), new techniques to identify dysplasia (chromoendoscopy, endosonography, coherence optical tomography, fluorescence techniques) and development of better ablative techniques. At present a marker other than dysplasia identifying a high risk group for cancer on which to focus endoscopic surveillance has not yet been established.     

The incidence of adenocarcinoma and dysplasia in Barrett''s esophagus

OBJECTIVE: The reported incidence of adenocarcinoma in Barrett's esophagus is variable. The aim of this study was to determine the incidence of dysplasia and adenocarcinoma in a population of patients with Barrett's esophagus followed prospectively and to compare these findings with other series. METHODS: All patients enrolled in the Cleveland Clinic Foundation's Barrett's esophagus registry from 1979 to 1995 were followed. Barrett's esophagus was defined as intestinal metaplasia anywhere in the tubular esophagus. The incidence of dysplasia and adenocarcinoma in these patients was recorded systematically. RESULTS: A total of 136 patients (91 male, 45 female) were followed in an endoscopic surveillance program for a mean of 4.2 yr and a total of 570 patient-years of follow-up. Thirty patients (22%) had short segment Barrett's esophagus. Two adenocarcinomas developed during follow-up, yielding an incidence of one per 285 patient-years of follow-up. Low grade dysplasia developed in 24 patients, whereas high grade dysplasia developed in four patients. CONCLUSIONS: Our study suggests that the incidence of adenocarcinoma in Barrett's esophagus is lower than initially thought. However, large multicenter studies are required to clarify the epidemiological and clinical factors related to the development of dysplasia and adenocarcinoma in Barrett's esophagus.     

Endoscopic follow-up of Barrett's esophagus: protocol and implications

The purpose of endoscopic surveillance in Barrett's esophagus is to detect dysplasia and to diagnose carcinoma in an early, treatable stage. Prospective trials that study the efficacy of a surveillance program in reducing mortality from esophageal adenocarcinoma are lacking. Retrospective studies have shown a significantly better outcome in patients with esophageal cancer that is detected during a surveillance program. Obviously, surveillance is only indicated for those patients fit enough to undergo esophagectomy if high-grade dysplasia (HGD) or malignancy is detected. There is no consensus upon what to do with HGD: some recommend esophagectomy when HGD is diagnosed, because an important proportion of these patients host an adenocarcinoma; others feel that histological proof of malignancy should be established before esophagectomy is proposed. Dysplasia is not a uniform process, causing sampling problems. Using a strict biopsy protocol is helpful to differentiate HGD from carcinoma, but contradictory results about this type of rigorous biopsy protocol have been published. Most groups propose four biopsy specimens, in a circular fashion, from every 2 cm of the Barrett-epithelium, with additional biopsies from any mucosal abnormality. Patients with long-segment Barrett's esophagus need endoscopic surveillance, even if they underwent antireflux surgery. At this moment there are not enough data to support a systematic surveillance of patients with short-segment's Barrett's esophagus. The following endoscopic strategy can be proposed. No dysplasia: surveillance every 2 years. Low-grade dysplasia: surveillance every year; in these cases it is recommended to repeat four-quadrant biopsies at 1 cm interval if numerous biopsies reveal dysplasia to detect foci of HGD/cancer. High-grade dysplasia: repeat immediately four-quadrant biopsies at 1 cm interval; if HGD is confirmed esophagectomy is advised to a patient with acceptable operative risk. Ablation therapy remains experimental.     

Prognostic factors in Barrett's esophagus: an immunohistochemical and morphometric study of 120 cases.

Barrett's esophagus is a condition in which the squamous mucosa that normally lines the distal esophagus is replaced by a columnar type of epithelium. Although it carries a clear risk of adenocarcinoma, the estimation of this risk and therefore the value of endoscopic screening remain highly controversial. AIM: To investigate more sensitive techniques to identify those patients who are at high risk of developing cancer and who need intensive endoscopic surveillance for early detection. METHODS: A morphologic, histochemical and morphometric study was performed on paraffin-embedded material from 120 patients with Barrett's esophagus and 18 with adenocarcinoma. In addition, each sample was analyzed immunohistochemically with proliferating cell nuclear antigen (PCNA), p53, c-erbB-2, CEA and EMA antibodies. RESULTS: In all zones of the glandular mucosa we found a higher percentage of PCNA-positive nuclei when the specialized epithelium was present. We saw PCNA expression in 75% of the patients with adenocarcinoma, and p53 expression in 15% of the patients without dysplasia, 37% of the patients with dysplasia and 44% of the patients with adenocarcinoma. Positivity for c-erbB-2 was found in 38% of the patients without dysplasia, 53% of those with dysplasia and 37% of those with adenocarcinoma. Aneuploidy was found in 70% of the patients with metaplasia or dysplasia and in all patients with adenocarcinoma. CONCLUSIONS: We conclude that p53, PCNA overexpression and aneuploidy are markers of risk for malignancy in Barrett's esophagus.     

Practice patterns for surveillance of Barrett's esophagus in the united states

BACKGROUND: Endoscopic surveillance of Barrett's esophagus is recommended to detect dysplasia or cancer at an early and potentially treatable stage. However, little is known about the clinical practice patterns for endoscopic surveillance in the United States. METHODS: A questionnaire regarding surveillance intervals, techniques and management approaches for patients with Barrett's esophagus was mailed to 1000 randomly selected members of the Clinical Practice Section of the American Gastroenterological Association. RESULTS: The response rate was 455 of 1000 (45%). Not all respondents answered all questions. Seventy-nine percent of respondents were in community practices, and 21% were in academic practices. Nearly all (96%) performed endoscopic surveillance, but it was practiced more commonly in the community (334 of 341 [98%]) than in the academic setting (83 of 93 [89%], p < 0.001). For patients without dysplasia, endoscopic surveillance was most commonly performed every 2 years (264 of 415 [64%]). Patients with low-grade dysplasia usually had surveillance endoscopy at 6-month intervals (215 of 413 [52%]), whereas those with high-grade dysplasia most commonly had endoscopy every 3 months (201 of 404 [50%]). These surveillance patterns did not differ between the academic and community groups. Random biopsies were performed by 93 of 403 (23%), 4-quadrant biopsies by 310 (77%). Most physicians (83%) used standard capacity forceps. Brush cytology was done uncommonly (69 of 414 [17%]). The most common indications for esophagectomy were high-grade dysplasia by 82% and cancer by 83%. Ablation therapy was performed for Barrett's esophagus without dysplasia by 3.5%, Barrett's with dysplasia by 20%, and cancer by 8%. CONCLUSIONS: Surveillance for Barrett's esophagus is widely practiced in the United States but there is considerable variation in interval and technique. A clearer consensus on endoscopic surveillance is warranted to optimize care of patients with Barrett's esophagus.     

Adenocarcinoma arising in Barrett's esophagus

The main goal of this study was to evaluate the development of adenocarcinoma in patients with Barrett's esophagus. During the period from January 1975 to December 1985, a total of 134 patients had endoscopically severe esophagitis and/or Barrett's esophagus. In these patients, 32 (24%) met the macroscopic and histologic criteria for the diagnosis of Barrett's esophagus. A check-up study of these patients was performed in 1987. Adenocarcinoma developed in three patients during the follow-up period of 166.1 patient-years. Dysplasia in the columnar epithelium was found in two of these patients six and 15 months before the diagnosis of adenocarcinoma. The third patient with adenocarcinoma was detected in endoscopic follow-up in 1987. In addition, the endoscopic examination showed unchanged Barrett's epithelium in all but three patients despite the operative and/or medical treatment 3–12 years (mean 6.7 years) earlier. We conclude that Barrett's esophagus is a potential premalignant condition and careful endoscopic surveillance for dysplasia in the columnar epithelium of the distal esophagus is mandatory in patients with Barrett's esophagus.     

Prediction of malignant potential in reflux disease: are cytokine polymorphisms important?

OBJECTIVES: Esophageal reflux is common in the Western world and can lead to a number of diseases, such as esophagitis, Barrett's esophagus, and adenocarcinoma. Barrett's predisposes to adenocarcinoma and endoscopic surveillance may lead to earlier detection of adenocarcinoma. However, clinical methods only identify one patient in 15 with Barrett's esophagus. The aim of this study was to find factors that may help identify patients with Barrett's earlier. METHODS: Blood samples and detailed histories were taken from 456 patients with gastroesophageal reflux who were recruited into three study groups: esophagitis, Barrett's esophagus without dysplasia, and Barrett's with dysplasia or adenocarcinoma. PCR was used to determine the frequency of five functional cytokine polymorphisms: interleukin-1 receptor antagonist position +2018 (IL-1 Ra +2018), interleukin-1 beta position -511 (IL-1 beta-511), tumor necrosis factor-alpha position -238 (TNF-alpha-238), interleukin-10 position +1082 (IL-10 +1082), and interleukin-4 receptor position -1902 (IL-4R -1902). RESULTS: IL-1 Ra +2018 genotype 2/2 was associated with Barrett's more commonly than esophagitis (OR-3.7, p= 0.0345). The IL-10 +1082 genotype 2/2 was more strongly associated with Barrett's and adenocarcinoma than esophagitis (OR-1.76, p= 0.056 and OR 1.96, p= 0.025, respectively). There were no differences for the IL-1 beta-511, IL-4R -1902, and TNF-alpha-238 polymorphisms. CONCLUSIONS: Cytokine polymorphisms are more commonly found in patients with Barrett's or adenocarcinoma than those with esophagitis. Together with demographic data, this may help identify those patients with Barrett's who would benefit from surveillance.     

Barrett's esophagus: Macroscopic markers and the prediction of dysplasia and adenocarcinoma

BACKGROUND AND AIMS: Surveillance endoscopy has been advocated for patients with Barrett's esophagus but the cost-effectiveness of this has been questioned. The aim of this study is to identify an optimum surveillance protocol by examining if macroscopic markers at diagnosis predict the development of dysplasia. METHODS: The sample was 353 patients with Barrett's esophagus undergoing surveillance by a community-based group of gastroenterologists between 1981 and 2001. At diagnosis the presence of macroscopic and microscopic markers was noted. The presence and pattern of dysplasia and development of adenocarcinoma was documented during subsequent surveillance. RESULTS: Three hundred and fifty-three patients (71% male) underwent regular surveillance over 19 056 patient-months (median 42 months), having a median number of three surveillance endoscopies (range 1-40). Nine patients (seven male) developed adenocarcinoma (1/176 patient years) and four male patients developed high-grade dysplasia (1/397 patient years). Twelve of these 13 patients entered with one or more macroscopic markers: severe esophagitis, nodularity, Barrett's ulcer or stricture. Dysplasia risk was associated with macroscopic markers. Patients who entered with one marker were 6.7 times more likely to develop high-grade dysplasia/adenocarcinoma (HR = 6.7, 95% CI = 1.3, 35). Patients who entered with two or more markers were 14 times more likely to develop high-grade dysplasia/adenocarcinoma (HR = 14.1, 95% CI = 2.02, 102). CONCLUSIONS: The presence of severe esophagitis, Barrett's ulcer, nodularity or stricture at entry indicates a high-risk group for Barrett's esophagus. Cost-effectiveness of surveillance for these patients and those with dysplasia at entry would thus improve.     

Rigorous surveillance protocol increases detection of curable cancers associated with Barrett's esophagus

Esophageal adenocarcinoma is increasing in incidence and has a high mortality unless detected early. Barrett's esophagus is the only known risk factor for this cancer; however, whether endoscopic surveillance reduces morbidity and mortality is controversial. Endoscopic cancer surveillance programes for Barrett's esophagus are not routinely practiced in the UK, and this is the first study to examine whether a rigorous surveillance protocol increases the detection rate of early oesophageal cancer. All patients with a diagnosis of Barrett's esophagus or associated adenocarcinoma attending Havering Hospitals NHS Trust between 1992 and 1998 were included. A retrospective analysis was made of patients undergoing informal surveillance (96 patients, 1992–1997) and a prospective analysis was conducted following the implementation of a rigorous protocol (108 patients, 1997–1998). Over the same time periods Barrett's associated cancers diagnosed in patients not undergoing surveillance were analyzed (262 patients 1992–1997, 98 patients 1997–1998). From 1992 to 1997, one case of high-grade dysplasia was detected (N = 96, 1%). From 1997 to 1998, two cancers and three high-grade dysplasias were detected during rigorous surveillance (N = 108, 4.6%). Three of these patients have had curative esophagectomies (one high-grade dysplasia and two T1,N0,M0 tumors). In 1992–1997, 10 patients were found to have cancer in previously undiagnosed Barrett's esophagus (N = 262, 3.8%). Of 3/10 cancers treated surgically, one patient had a curative procedure (T1,N0,M0). In 1997–1998, nine patients were found to have de novo Barrett's esophagus cancer (N = 88, 10.2%) and three had curative resections (T1,N0,M0). Two of the patients with T1 lesions had no endoscopic evidence of cancer but were detected as a result of the multiple biopsy protocol. In conclusion, a rigorous biopsy protocol increases the detection of early cancer in Barrett's esophagus.     

The prevalence of Barrett's esophagus in patients with chronic peptic esophageal strictures

Both Barrett's esophagus and peptic stricture of the esophagus are consequences of chronic reflux esophagitis. Barrett's esophagus appears to be a premalignant condition, and continued histologic surveillance for dysplasia and carcinoma has been recommended for affected patients. While patients with peptic esophageal strictures and persistent reflux are at risk for the development of Barrett's epithelium, such patients often do not receive continued histologic surveillance if Barrett's epithelium is not identified on the initial endoscopic evaluation. Using endoscopic and peroral aspiration biopsy techniques, we studied the prevalence of Barrett's esophagus in 25 patients with chronic peptic esophageal strictures in whom Barrett's epithelium had not been identified previously. We found Barrett's esophagus in 11 (44%) of our 25 patients. One patient who did not have Barrett's esophagus was found to have an undifferentiated esophageal carcinoma. We conclude that patients with chronic peptic esophageal strictures frequently have Barrett's esophagus. A program of continued histologic surveillance seems advisable for such patients.