Is there a set of histologic changes that are invariably reflux associated?

Many histologic changes have been described in the esophageal squamous mucosa in patients with gastroesophageal reflux disease (GERD), including dilated intercellular spaces, balloon cells, intrapapillary vessel dilation, elongated papillae, basal cell hyperplasia, acanthosis, intraepithelial eosinophils, Langerhans cells, and p53 protein overexpression. To define a set of histologic changes that are invariably reflux associated, we examined the histologic changes in esophageal specimens from normal controls, patients with GERD, patients without GERD but with a suspicion of other pathology, and patients with esophageal carcinoma. We also examined biopsy specimens from sites with differing endoscopic features, including cloudy white and reddened mucosa. A definitive set of reflux-associated histologic changes could not be defined from the small number of biopsy specimens examined in the present study. Histologic changes indicative of GERD are likely to be found somewhere in the esophagus in all patients with GERD, but these changes are nonspecific. A set of histologic changes that are invariably reflux associated may exist, but these changes are nonspecific. To develop a set of characteristic reflux-associated features, endoscopists may perform targeted biopsies from several sites with various endoscopic features and at different stages of disease.     

Differences in Clinical Characteristics between Patients with Non-Erosive Reflux Disease and Erosive Esophagitis in Korea

Gastroesophageal reflux disease (GERD) is caused by abnormal reflux of gastric contents into the esophagus. GERD can be divided into two groups, erosive esophagitis and non-erosive reflux disease (NERD). The aim of this study was to compare the clinical characteristics of patients with erosive esophagitis to those with NERD. All participating patients underwent an upper endoscopy during a voluntary health check-up. The NERD group consisted of 500 subjects with classic GERD symptoms in the absence of esophageal mucosal injury during upper endoscopy. The erosive esophagitis group consisted of 292 subjects with superficial esophageal erosions with or without typical symptoms of GERD. Among GERD patients, male gender, high body mass index, high obesity degree, high waist-to-hip ratio, high triglycerides, alcohol intake, smoking and the presence of a hiatal hernia were positively related to the development of erosive esophagitis compared to NERD. In multivariated analysis, male gender, waist-to-hip ratio and the presence of a hiatal hernia were the significant risk factors of erosive esophagitis. We suggest that erosive esophagitis was more closely related to abdominal obesity.     

Barrett's esophagus: a comprehensive review and update

Barrett's esophagus (BE) is a known precursor to esophageal adenocarcinoma. In the United States, a prevalence of up to 25% is reported in high risk populations and it is identified in about 5% of patients with gastroesophageal reflux disease (GERD). The diagnosis of BE requires endoscopically identifying columnar (“salmon colored”) mucosa, taking biopsies from targeted areas and then confirming histologically. The American College of Gastroenterologists updated its criteria in 2016, introducing a length requirement. This brief review addresses diagnosis of BE and its various associated challenges; identifying dysplasia, grading it, and management.     

Barrett-?sophagus

Barrett's esophagus (BE), a well-known complication of gastroesophageal reflux disease (GERD), constitutes a precancerous condition for adenocarcinoma of the distal esophagus. The so-called Barrett's carcinoma shows increasing incidences in countries of the western hemisphere; new data, however, indicate that the rise in incidence is not quite as dramatic as previously assumed. The definition of BE is currently changing: despite good reasons for a purely endoscopic definition of BE, goblet cells are still mandatory for this diagnosis in Germany and the USA. Dysplastic changes in the epithelium are the most important risk factor for the development of Barrett's adenocarcinoma and recently dysplasia was subclassified into a more frequent adenomatous (intestinal) and a non-adenomatous (gastric-foveolar) types. The gold standard for diagnosing dysplasia is still H&E staining. The histological diagnosis of dysplasia is still encumbered by a significant interobserver variability, especially regarding the differentiation between low grade dysplasia and inflammatory/reactive changes and the discrimination between high grade dysplasia and adenocarcinoma. Current data, however, show much higher interobserver agreement in endoscopic resection specimens than in biopsies. Nevertheless, the histological diagnosis of dysplasia should be corroborated by an external second opinion because of its clinical consequences. In endoscopic resections of early Barrett's adenocarcinoma, the pathological report has to include a risk stratification for the likelihood of lymphogenic metastases.     

Anatomy of reflux: a growing health problem affecting structures of the head and neck

Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are sibling diseases that are a modern-day plague. Millions of Americans suffer from their sequelae, ranging from subtle annoyances to life-threatening illnesses such as asthma, sleep apnea, and cancer. Indeed, the recognized prevalence of GERD alone has increased threefold throughout the 1990s. Knowledge of the precise etiologies for GERD and LPR is becoming essential for proper treatment. This review focuses on the anatomical, physiological, neurobiological, and cellular aspects of these diseases. By definition, gastroesophageal reflux (GER) is the passage of gastric contents into the esophagus; when excessive and damaging to the esophageal mucosa, GERD results. Reflux that advances to the laryngopharynx and, subsequently, to other regions of the head and neck such as the larynx, oral cavity, nasopharynx, nasal cavity, paranasal sinuses, and even middle ear results in LPR. While GERD has long been identified as a source of esophageal disease, LPR has only recently been implicated in causing head and neck problems. Recent research has identified four anatomical/physiological "barriers" that serve as guardians to prevent the cranial incursion of reflux: the gastroesophageal junction, esophageal motor function and acid clearance, the upper esophageal sphincter, and pharyngeal and laryngeal mucosal resistance. Sequential failure of all four barriers is necessary to produce LPR. While it has become apparent that GER must precede both GERD and LPR, the head and neck distribution of the latter clearly separates these diseases as distinct entities warranting specialized focus and treatment.     

Barrett's esophagus and Barrett's-related dysplasia.

Barrett's esophagus is a complication of chronic gastroesophageal reflux disease and can be diagnosed when there is an endoscopic abnormality in which a biopsy shows evidence of specialized columnar epithelium, characterized by the presence of acid mucin-containing goblet cells. Much of the controversy in this body of literature relates to the complex anatomy of the esophagogastric junction and the difficulty in precisely identifying this landmark at endoscopy. By definition, in Barrett's esophagus, the squamocolumnar junction is proximal to the esophagogastric junction. Although fundic-type or cardiac-type (junctional) columnar epithelium may be present in Barrett's esophagus, it is only the presence of specialized columnar epithelium that is diagnostic of this condition. Patients with Barrett's esophagus are at risk of progressing to esophageal dysplasia and adenocarcinoma. There are several problems with using dysplasia as a marker for increased cancer risk in these patients, including problems with sampling error and intra- and interobserver variation in the recognition of dysplasia. It may be difficult to distinguish regenerative epithelial changes from dysplasia, low-grade from high-grade dysplasia, and high-grade dysplasia from intramucosal adenocarcinoma. Finally, there are relatively few prospective data evaluating the natural history of high-grade dysplasia. The management of patients with Barrett's-related dysplasia is controversial and varies from institution to institution. Future emphasis should be on cost-effective techniques for sampling as much of the esophageal mucosa as possible in patients who are at the highest risk of progressing to dysplasia and adenocarcinoma. Identification of biomarkers that identify such patients before the histologic recognition of dysplasia will be an area of intensive research.     

Progression to cancer in Barrett's esophagus is associated with genomic instability

Barrett's esophagus is a condition in which metaplastic columnar epithelium replaces squamous esophageal epithelium as a consequence of chronic gastroesophageal reflux. Patients with this condition are at increased risk for the development of adenocarcinoma. To better understand the progression to adenocarcinoma in this disease, we studied abnormalities in DNA content of epithelial cells in Barrett's esophagus. Using flow cytometry, we examined the spatial distribution of abnormal nuclear DNA contents (aneuploidy) in the esophagi of 14 patients with Barrett's adenocarcinoma. Multiple (2 to 14) populations of aneuploid cells were seen in 12 of the 14 cases. Some early carcinomas appeared to be associated with a single aneuploid population of cells. Surrounding dysplastic epithelium often contained multiple, different overlapping aneuploid populations. These data suggest that neoplastic progression in Barret's esophagus is associated with a process of genomic instability which leads to evolution of multiple aneuploid populations, with the ultimate development of a clone of cells capable of malignant invasion. Thus, detection of multiple aneuploid populations of cells in Barrett's esophagus may indicate a high risk of cancer. Barrett's esophagus provides a unique and readily accessible model for the study of neoplastic progression in human epithelial malignancy.     

Histopathologic changes in gastroesophageal reflux disease. A study of 126 bioptic and autoptic cases

The histologic diagnosis of reflux esophagitis is still complicated by the lack of a consensus opinion on what is the normal mucosa in the area of the gastroesophageal junction (GEJ). Most authors consider GEJ as the junction between the squamous and the cardiac epithelium. The cardiac mucosa is composed of mucinous or mixed mucinous-oxyntic glands. These glands are in fact indistinguishable from metaplastic mucosa that arises in the distal esophagus in consequence of gastroesophageal reflux (GER). The cardiac mucosa shows invariably chronic inflammatory changes referred to as "carditis". The cause of "carditis" is GER and/or Helicobacter pylori (HP) infection. In our series of 120 endoscopic biopsies of the GEJ and distal esophagus the cardia type mucosa (CM) was always present. In 15 cases, it was accompanied by oxyntocardiac mucosa. Both mucosa types showed chronic inflammation that is after exclusion of HP infection regarded as a strong diagnostic sign of the gastroesophageal reflux disease (GERD). In two cases with clinical symptoms of GERD, a few HP were found on the CM. Therefore we diagnosed them as GERD with secondary HP infection. In 17 cases, CM displayed intestinal metaplasia (IM) predominantly of incomplete type and no dysplasia. This IM expressed MUC6 in the glandular zone of the mucosa like it did in the neighboring glands, whereas in the surface and foveolar epithelium the MUC6 was negative or only slightly and focally positive. On the other hand, IM in the surface and foveolar epithelium was reactive for MUC5AC. The positivity and distribution of CK7 and CK20 was very similar in the Barrett's mucosa, cardiac mucosa and antral mucosa. In one specimen of esophagus resected for adenocarcinoma, CM with incomplete IM was found in the vicinity of the tumor. Squamous metaplastic epithelium was often seen near the orifices of submucosal esophageal glands in these areas, indicating the metaplastic nature of the glandular mucosa in the distal esophagus. In the GEJ of 5 autopsy cases of children with spastic quadriplegia (age range 7-10 years) CM in a short segment (0.5-3 mm in length), probably of metaplastic origin was identified, showing chronic inactive inflammation.     

Mucin expression and proliferating cell index of esophageal Barrett's adenocarcinoma

Barrett's esophagus is a premalignant condition associated with gastroesophageal reflux disease, and consists of mucosa with a metaplastic columnar epithelium (specialized columnar epithelium). In this study, we examined the expression of mucin and the Ki-67 labeling index (LI) in 15 cases of esophageal Barrett's adenocarcinoma, and clarified the significance of incomplete intestinal metaplasia of Barrett's mucosa as a premalignant lesion. Gastric mucin (MUC5AC, HGM, and/or MUC6) was detected in 93.3% of the adenocarcinomas, while MUC2 and CD10 (markers of intestinal phenotypes) were detected in 73.3% and 46.2%, respectively. The Ki-67 LI was 34.1% in Barrett's adenocarcinoma. In all cases, gastric mucin was found in the non-neoplastic Barrett's mucosa around the adenocarcinoma. MUC2 was detected in 86.7% of proximal non-neoplastic mucosa and 100% of distal non-neoplastic mucosa, while CD10 was found in 20.0% of proximal non-neoplastic mucosa and 40.0% of distal non-neoplastic mucosa of Barrett's adenocarcinoma. In conclusion, Barrett's esophageal mucosa with intestinal metaplasia and a high Ki-67 LI is suggested to be more important as a premalignant lesion, and predominantly found in the proximal rather than distal region of Barrett's esophagus.     

非糜烂性反流病患者胃食管交界顺应性增加

目的揭示非糜烂性反流病(NERD)的生物力学机制。方法纳入自2014年10月4日至2015年9月30日就诊于中日友好医院消化内科门诊符合NERD诊断的17例患者及健康志愿者17名。使用内镜联合Endo Flip技术对胃食管交界的横截面面积(CSA)、球囊内压力和顺应性(Δv/Δp)进行测定。结果随球囊容积增加,胃食管交界处的顺应性NERD组显著高于对照组(P0.01),而横截面积和球囊内压力变化不明显。结论非糜烂性反流病患者的胃食管交界的顺应性增加可能是其重要的发病机制之一。     

Haplotypes of the IL-1 gene cluster are associated with gastroesophageal reflux disease and Barrett’s esophagus

Objectives

Gastroesophageal reflux (GERD) is a one of the major public health problem that can lead to reflux esophagitis (RE), Barrett’s esophagus (BE), and esophageal adenocarcinoma (EAC). The aim of our study was to determine the impact of IL-1 gene polymorphisms on the development of GERD, RE and BE.

Methods

Three hundred and thirty-three Czech patients with gastroesophageal reflux and 165 healthy controls were included in this case-control study. Four polymorphisms in the genes of the IL-1 cluster [IL-1A(-889C/T), IL-1B(−511C/T), IL-1B(+3953C/T), and IL-1RN(VNTR)] were analyzed.

Results

Significant differences were found in IL-1RN 1/2 genotype between patients with GERD/RE and controls and in IL-1B+3953 T allele between patients with BE and healthy subjects. In addition, complex analysis revealed differences in IL-1 haplotype frequencies between the groups. Specifically, the haplotype TCCL was significantly more frequent (p = 0.016) in GERD patients than in controls and the haplotype CCCL more frequent (p = 0.008) in RE patients than in controls. However, in patients with BE, frequency of haplotype TCTL was lower (p = 0.05) and haplotypes CTCL and TCCL were higher (p = 0.03 and p = 0.02) in comparison with the controls.

Conclusions

Our results suggest that IL-1 haplotypes may be associated with susceptibility to GERD, RE and BE.     

Ski/SnoN expression in the sequence metaplasia-dysplasia-adenocarcinoma of Barrett's esophagus

Barrett's esophagus (BE) is a precancerous condition. However, the mechanisms underlying the transformation from metaplastic to dysplastic to adenocarcinomatous epithelium are still poorly understood. As loss of transforming growth factor-beta growth inhibition is considered a hallmark of several human neoplasms, we evaluated the expression of Ski and SnoN (proteins that antagonize transforming growth factor-beta signaling through physical interaction with Smad complex and by recruiting histone deacetylases), as markers of the transforming growth factor-beta signaling pathway, in BE with and without dysplasia. Biopsy samples from 37 patients (26 men, aged 60 +/- 8 years) with histologically proven BE were evaluated; 10 patients had concomitant low-grade dysplasia, 7 high-grade dysplasia (HGD), and 6 HGD associated with adenocarcinoma. Ski and SnoN expression was assessed immunohistochemically. Neither Ski nor SnoN was expressed in normal esophageal epithelium, but both were strongly expressed in BE tissue, with intense cytoplasmic positivity. Expression of these proteins decreased markedly in dysplastic areas in patients with low-grade dysplasia and was absent in those with HGD or HGD/adenocarcinoma. Ski and SnoN proteins are overexpressed in BE and may be involved in abnormal signaling elicited by transforming growth factor-beta in this epithelium, enhancing the tumorigenesis process. These observations might help to elucidate the molecular mechanisms involved in the BE tumorigenesis process.     

Esophageal preservation in five male patients after endoscopic inner-layer circumferential resection in the setting of superficial cancer: a regenerative medicine approach with a biologic scaffold

As a result of injury caused by chronic gastroesophageal reflux, Barrett's esophagus with high-grade dysplasia and esophageal adenocarcinoma are rapidly increasing problems in the United States. The current standard of care involves esophagectomy, a procedure associated with a high morbidity, a negative impact on long term quality of life, and a mortality rate of 1-6 percent. An entirely endoscopic technique for circumferential, long segment en bloc removal of the mucosa and submucosa with subsequent placement of a biologic scaffold material that promotes a constructive remodeling response and minimizes stricture is described herein. The results of this approach are reported for five patients with 4-24-month follow-up. Restoration of normal mature, K4+/K14+, squamous epithelium, and return to a normal diet without significant dysphagia is reported for all patients. Two of five patients show a small focus of recurrent Barrett's esophagus at the gastroesophageal junction, but the entire length and circumference of the reconstituted esophageal mucosa remains free of disease. This experience provides evidence that a regenerative medicine approach may, for the first time, enable aggressive endoscopic resection of early stage neoplasia without the need for esophagectomy and its associated complications.     

Proliferative characteristics of intestinalized mucosa in the distal esophagus and gastroesophageal junction (short-segment Barrett's esophagus): a case control study

Intestinalized epithelium in traditional long-segment Barrett's esophagus (BE) shows increased proliferative activity, which is postulated to be an early step in the metaplasia-dysplasia-carcinoma sequence. The aim of this study was to evaluate the proliferative activity of intestinalized epithelium of the distal esophagus and gastroesophageal junction (IMEGEJ). Tissue sections from 78 consecutive patients (20 with IMEGEJ, 58 without IMEGEJ) who had elective upper gastrointestinal endoscopy over a 6-month period were immunohistochemically stained with MIB-1, the Ki-67 proliferation-antigen-associated marker, for evaluation of the crypt MIB-1 proliferation index (PI), size of the proliferative zone (PZ), and the presence of surface epithelial staining. Data from the IMEGEJ and non-IMEGEJ groups, and from 15 age-matched patients with traditional long-segment BE (>3.0 cm), were compared statistically. IMEGEJ patients showed a statistically significant increase in the mean crypt PI compared with non-IMEGEJ controls (21.9+/-19.5 v 14.3+/-9.3; P=.01). In addition, IMEGEJ cases showed an increase in the mean crypt PZ (52.3+/-16.4 v 45.2+/-17.2; P=.05), and a trend toward an increase in the percentage of cases with MIB-1-positive surface epithelial cells (50% v 33%, P=.18). Patients with IMEGEJ did not differ from patients without IMEGEJ with respect to any other clinical or histological feature, including signs or symptoms of gastroesophageal reflux disease and presence or absence of esophagitis or carditis. The MIB-1 results of the patients with long-segment BE (MIB-1 PI = 22.6+/-20.5, MIB-1 PZ = 51.8+/-19.6, proportion of cases with MIB-1-positive surface cells = 66%) were similar to those with IMEGEJ. Intestinalized epithelium in the distal esophagus or gastroesophageal junction shows increased proliferative activity in comparison with patients without intestinalized epithelium. This finding supports an increased risk of carcinogenesis in patients with IMEGEJ.     

Gastroesophageal reflux disease in preschool children with asthma]

BACKGROUND: In pediatric intractable asthma, there is occasionally an association with GERD (gastroesophageal reflux disease). It is not clear in which cases GERD should be suspected or how effective the GERD therapy is in treating the asthma. METHODS: Twenty-seven preschool children (<6 years of age) suffering from recurrent asthma attack in spite of asthma therapy underwent 24-hour esophageal pH monitoring. We examined retrospectively the incidence of GERD and the effectiveness of famotidine in GERD positive patients. RESULTS: 18 of the 27 patients (66.7%) had positive results (GERD positive group). In 12 of the 15 patients (80%) who underwent GERD therapy (famotidine), respiratory symptoms were decreased. In the GERD positive group, the incidence of acid reflux during waking hours was more frequent than during sleeping hours. In 8 of 12 patients (66.7%) in whom famotidine was effective, cough and wheeze often occurred during the daytime and corresponded with the time when acid reflux must commonly occurred. CONCLUSION: We conclude that children suffering from recurrent asthma attack in spite of asthma therapy must be examined for the presence of GERD.     

Large intra- and inter-individual variability of genes expression levels limits potential predictive value of molecular diagnosis of dysplasia in Barrett’s esophagus

Barrett's esophagus represents a well-defined precursor lesion of esophageal adenocarcinoma, although only a subset of patients with these lesions advances to invasive cancer. Currently, reliable markers predicting neoplastic progression in Barrett's esophagus are lacking. The only clinically useful risk factor is the presence of dysplasia in Barrett's epithelium, but its use as a prognostic marker of disease progression has several significant limitations. Thus, identification of biomarkers of potential prognostic value in dysplasia development in Barrett's esophagus is highly important. The aim of the study was to determine if expression levels of selected genes support histologic diagnosis of dysplastic changes in Barrett's esophagus. Upon rigorous sampling and independent histopathologic examination of endoscopic specimens by two experienced gastrointestinal pathologists, 56 patients with Barrett's esophagus (16 negative for dysplasia, 15 with indefinite, 21 with low-grade, and 4 with high-grade dysplasia) were selected for molecular analysis. The relative mRNA levels of ten selected genes were estimated by quantitative real-time polymerase chain reaction (PCR) analysis. Although expression of nine genes showed trends toward down- or upregulation during progression from Barrett's esophagus without dysplasia to Barrett's esophagus with high-grade dysplasia, only a decrease in S100A2 mRNA levels was statistically significant (P<0.05). However, there was considerable variation among individuals and significant overlapping of ranges. Furthermore, detailed, comparative analysis of serial samples from Barrett's mucosa and normal squamous epithelium shows large intra-individual variability of gene expression levels. In conclusion, expression of this set of ten genes cannot be used as a molecular marker aiding histological examination of dysplasia in Barrett's esophagus. Significant inter- and intra-patient variations of gene expression levels makes use of the selected genes impractical.     

Pathologic anatomy of Barrett's esophagus

It is most substantiated to define Barrett's esophagus as intestinal metaplasia of esophageal cardiac mucosa irrespective of its association with the endoscopically detected esophageogastric junction, which develops as a result of gastroesophageal reflux. There is a need for further investigations of the specific features of the cardiac-type mucosa. During endoscopic study, it is important to be alert when identifying short and ultrashort Barrett's esophagus and to sample sufficient biopsy material. A pathologist must differentiate three major types of the cylindrical epithelium of the esophagus: cardiac, acid-producing cardiac, and intestinal metaplasia, by diagnosing Barrett's esophagus in the latter case. Patients with the esophageal cardiac mucosa should be referred to as a risk group for its development.