Intestinal Metaplasia of the "Cardia": Accurate Differentiation of Gastric or Esophageal Origin With an Expanded Biopsy Protocol.

Whether intestinal metaplasia (IM) distal to the endoscopic gastroesophageal junction (GEJ), that is, the cardia, is gastric or esophageal or both is controversial. Biopsies from this region are believed to be unreliable in resolving this issue and are not recommended. Our objective was to develop an accurate method of histologic diagnosis for IM of the cardia. An expanded biopsy protocol was employed in 986 patients irrespective of indication for endoscopy. This sampled columnar lined esophagus (CLE) when present, the endoscopic GEJ defined by the proximal limit of rugal folds, the area 1 cm distal to the GEJ, and distal stomach. The prevalence and associations of IM in these 4 locations were evaluated. IM was found in 79/91 patients with CLE above the GEJ. This was significantly associated with IM at the GEJ in 40/79 patients (P<0.001). The biopsy taken distal to the endoscopic GEJ had IM in 21/79 patients. No patient with CLE had IM in the distal stomach. In patients without CLE, IM was present at or distal to the endoscopic GEJ in 221 patients. In 32 patients, this was significantly associated with IM in the distal stomach (P<0.001). The remaining 189/986 (19.2%) patients had IM limited to the GEJ region. These data, in association with recent evidence, indicate that IM limited to the area distal to the GEJ in patients without distal gastric IM represents microscopic Barrett esophagus in a dilated distal esophagus. This is presently mistaken for IM of the proximal stomach because of a flawed endoscopic definition of the GEJ.

Proposed approach to the challenging management of progressive gastroesophageal reflux disease.

The progression of gastroesophageal reflux disease (GERD) in patients who are taking proton pump inhibitors (PPIs) has been reported by several investigators, leading to concerns that PPI therapy does not address all aspects of the disease. Patients who are at risk of progression need to be identified early in the course of their disease in order to receive preventive treatment. A review of the literature on GERD progression to Barrett's esophagus and the associated physiological and pathological changes was performed and risk factors for progression were identified. In addition, a potential approach to the prevention of progression is discussed. Current evidence shows that GERD can progress; however, patients at risk of progression may not be identified early enough for it to be prevented. Biopsies of the squamocolumnar junction that show microscopic intestinalization of metaplastic cardiac mucosa in endoscopically normal patients are predictive of future visible Barrett's esophagus, and an indicator of GERD progression. Such changes can be identified only through biopsy, which is not currently recommended for endoscopically normal patients. GERD treatment should aim to prevent progression. We propose that endoscopically normal patients who partially respond or do not respond to PPI therapy undergo routine biopsies at the squamocolumnar junction to identify histological changes that may predict future progression. This will allow earlier intervention, aimed at preventing Barrett's esophagus.

How the pathologist can aid in the assessment of gastroesophageal reflux disease.

PURPOSE OF REVIEW: To provide new concepts regarding the early pathologic changes of gastroesophageal reflux disease (GERD) that are associated with damage to the lower esophageal sphincter (LES). RECENT FINDINGS: A body of evidence exists that cardiac mucosa is a metaplastic esophageal epithelium rather than a normal gastric epithelium. Recent studies in asymptomatic volunteers suggest a potential mechanism for cardiac metaplasia in the squamous epithelium of the esophagus. SUMMARY: The concept that cardiac mucosa is esophageal, not gastric, suggests that the widely accepted endoscopic definition of the gastroesophageal junction (GEJ) is incorrect. I propose that the true GEJ is the proximal extent of gastric oxyntic epithelium. If there is cardiac mucosa lining proximal rugal folds, that cardiac mucosa-lined region is the dilated distal esophagus, not the proximal stomach. The dilated distal esophagus is the pathologic expression of damage to the abdominal segment of the LES. This concept suggests a new test for measuring damage to the abdominal LES and a new understanding of the disease of GERD based on the measured amount of LES damage. This opens the door to new research and change in objectives in the management of reflux disease from control of symptoms to prevention of complications such as Barrett's esophagus and adenocarcinoma.

A New Pathologic Assessment of Gastroesophageal Reflux Disease: The Squamo-Oxyntic Gap.

Diagnosis of gastroesophageal reflux disease (GORD) is delayed by the lack of uniform histopathologic criteria for diagnosis. The only practical value of pathology is the assessment of columnar lined esophagus (CLO). As a result, GORD is treated with acid suppressive drug therapy until there is a failure to control symptoms and/or advanced adenocarcinoma develops. The reasons why there is a failure of pathologic diagnosis are two false dogmas that result in two widely believed fundamental errors. These are the belief that cardiac epithelium normally lines the proximal stomach (1) and that the gastroesophageal junction (GOJ) is defined by the proximal limit of rugal folds (2). When these false dogmas are eradicated by existing powerful evidence, the pathology of GERD falls into the following stages, all defined by histology: (a) The normal state where the esophageal squamous epithelium transitions at the GOJ to gastric oxyntic epithelium with no intervening cardiac epithelium; (b) cardiac metaplasia of the squamous epithelium due to exposure to gastric juice results in cephalad movement of the squamo-columnar junction (SCJ). This creates the squamo-oxyntic gap and the dilated distal esophagus, which is distal to the endoscopic GOJ. The length of the squamo-oxyntic gap in the dilated distal esophagus is concordant with the shortening of the abdominal segment of the lower esophageal sphincter (LOS); (c) in the early stages, the gap is <5 mm and the LOS retains its competence. Reflux is uncommon and patients are asymptomatic; (d) the squamo-oxyntic gap increases in length, concordant with the amount of shortening of the LOS, which becomes increasingly incompetent. At a gap length of 5-15 mm, reflux is sufficient to cause symptoms, but in most patients, symptoms are controllable and the patients are normal at endoscopy. The gap is entirely within the dilated distal esophagus, which is mistaken by present criteria for proximal stomach. (e) The last stage of GORD is when the squamo-oxyntic gap is >15 mm. In these patients, reflux is severe with increasingly uncontrollable symptoms and columnar lined esophagus, both irreversible states.Understanding this pathophysiology of GORD by these new histologic criteria will allow diagnosis at the earliest and eminently reversible stages of the disease. This can open the door to new methods of treatment that will have the potential to prevent progression to the irreversible phase of GORD, including columnar lined esophagus. If successful, this will effectively prevent progression to adenocarcinoma.

Intestinal Metaplasia is Present in Most if Not All Patients Who Have Undergone Endoscopic Mucosal Resection for Esophageal Adenocarcinoma.

Barrett esophagus is presently defined in the United States by the presence of intestinal metaplasia in columnar-lined esophagus based on the premise that the risk for adenocarcinoma depends on the presence of intestinal metaplasia. Recently, arguments have been made that nonintestinalized cardiac epithelium is also at risk and should be included in the definition of Barrett esophagus, as it is in England and Japan. One of these arguments is that residual intestinal metaplasia is frequently absent around early adenocarcinomas removed by endoscopic mucosal resection (EMR). We reviewed 27 EMRs performed in 21 patients. Residual intestinal metaplasia was absent in 10/27 (37%) EMR specimens. An in-depth study of these 10 cases showed that 3 had intestinal metaplasia in a concurrent second EMR specimen, 4 had intestinal metaplasia in prior biopsy material available in our unit, and 2 had intestinal metaplasia in an esophagectomy that followed the EMR. The single patient in whom no intestinal metaplasia was found, neither in biopsies nor in EMR, and who did not undergo an esophagectomy had been under surveillance for Barrett esophagus for over 20 years. We conclude that the frequent absence of residual intestinal metaplasia around an adenocarcinoma in an EMR specimen is the result of sampling error. When evaluated in depth by looking at history, biopsies preceding the EMR, and esophagectomy following the EMR, all of these patients with adenocarcinoma had intestinal metaplasia in their columnar-lined esophagus. This indicates that intestinal metaplasia is a necessary precursor to adenocarcinoma of the esophagus.

Inter-Observer Variability in the Interpretation of Endoscopic Mucosal Resection Specimens of Esophageal Adenocarcinoma: Interpretation of ER specimens.

INTRODUCTION: Endoscopic resection (ER) has revolutionized the staging and therapy of superficial esophageal adenocarcinoma. Pathologic evaluation allows an assessment of the risk of lymph node metastases based on tumor characteristics. The aim of this study was to assess the inter-observer variability in pathologic assessment of ER specimens of esophageal adenocarcinoma. METHODS: We performed a retrospective study on ER specimens of superficial esophageal adenocarcinoma from four US institutions. Original endoscopic resection slides were re-reviewed by two blinded, experienced (study) gastrointestinal pathologists for the depth of tumor invasion, tumor grade, and the presence of lymphovascular invasion (LVI). Discordance was considered present only when both study pathologists disagreed with the original report. RESULTS: There were 25 ER specimens reviewed for this study, and discordance occurred in 12 of the 25 specimens (48%) for the depth of tumor invasion. In most cases (83%), the discordance was related to overstaging a true T1a lesion. We found that only 38% of true T1a lesions were correctly staged for depth of invasion. Less commonly discordance was secondary to understaging a true T1b lesion. There was concordance between the two study pathologists in 22/25 cases (88%) on the depth of invasion. Discordance was present for tumor grade in 8/18 cases (44%) and for LVI in 4/16 cases (25%). Concordance between the study pathologists was 80% for tumor grade and 88% for LVI. CONCLUSIONS: There was an alarmingly high rate of discordance (48%) between the study pathologists and the original pathology assessment for the depth of tumor invasion in ER specimens. This was particularly common for lesions called T1b on the original pathology report. Since critical decisions are made regarding esophageal preservation or esophagectomy on the basis of the pathologic interpretations of ER specimens, it behooves surgeons to understand the inter-observer variability. Review of ER specimens by an experienced GI pathologist is recommended to ensure that patients receive the appropriate treatment for superficial esophageal adenocarcinoma.

Emerging Concepts for the Endoscopic Management of Superficial Esophageal Adenocarcinoma.

INTRODUCTION: Endoscopic therapy has revolutionized the treatment of Barrett's esophagus with high-grade dysplasia (HGD) or intramucosal adenocarcinoma by allowing preservation of the esophagus in many patients who would previously have had an esophagectomy. This paradigm shift initially occurred at high-volume centers in North America and Europe but now is becoming mainstream therapy. There is a lack of uniform guidelines and algorithms for the management of these patients. Our aim was to review important concepts and pitfalls in the endoscopic management of superficial esophageal adenocarcinoma. METHODS: A small group colloquium consisting of gastroenterologists, surgeons, and pathologists reviewed published data and discussed personal and institutional experiences with endotherapy for HGD and superficial esophageal adenocarcinoma. RESULTS: The group reviewed data and provided recommendations and management algorithms for seven areas pertaining to endoscopic therapy for Barrett's HGD and superficial adenocarcinoma: (1) patient selection and evaluation; (2) imaging and biopsy techniques; (3) devices; (4) indications for resection versus ablation; (5) ER specimen handling, processing, and pathologic evaluation; (6) patient care and follow-up after endoscopic therapy; and (7) complications of endoscopic therapy and treatment options. CONCLUSIONS: Endoscopic therapy is preferred over esophagectomy for most patients with HGD or intramucosal adenocarcinoma, and may be applicable to select patients with submucosal tumors. Clear guidelines and management algorithms will aid physicians and centers embarking on endoscopic therapy and enable a standardized approach to the management of these patients that is applicable internationally.

Can the Risk of Lymph Node Metastases Be Gauged in Endoscopically Resected Submucosal Esophageal Adenocarcinomas? A Multi-Center Study.

Endoscopic resection (ER) allows for local therapy of superficial esophageal cancers. Factors reported to be associated with an increased risk of lymph node metastases in patients with adenocarcinoma are poor differentiation, lymphovascular invasion (LVI), and submucosal invasion >500 µ. The aim of this study was to determine whether depth of invasion and tumor characteristics in an ER specimen can be used to gauge the risk of lymph node metastases in patients with superficial esophageal adenocarcinoma. Patients from seven US centers that had ER of an adenocarcinoma followed by an esophagectomy were identified. The ER pathology slides were rereviewed by three experienced GI pathologists for depth of invasion, presence of LVI, and tumor differentiation. The findings from the ER specimen were correlated with the presence and number of lymph node metastases in the final esophagectomy specimen. There were 19 T1a and 23 T1b tumors. A median of 24 nodes were resected per patient. None of the T1a tumors had involved lymph nodes despite the presence of LVI in 5% and poor differentiation in 21% of patients. In contrast, 26% of T1b tumors had involved nodes. None of the four patients with submucosal invasion ≤500 µ, no LVI, and no poor differentiation had involved nodes. However, with an increasing number of risk factors, the likelihood of involved lymph nodes increased, reaching 50% when all three factors were present. Endoscopic therapy appears appropriate for intramucosal tumors and may be an option for low-risk T1b tumors. Esophagectomy is preferred for patients with submucosal invasion and one or more risk factors.

Inverted lymphoglandular polyp in descending colon.

A 47-year-old male with a history of left colon cancer, status post left colon resection for 12 years, presented with rectal bleeding. Colonoscopic examination revealed an 8 mm sessile polyp in the proximal descending colon. Microscopic examination showed that the surface of this polyp was covered with a layer of normal colonic mucosa with focal surface erosion. In the submucosal layer, an intimate admixture of multiple cystically dilated glands and prominent lymphoid aggregates with germinal centers was seen. The glands were lined by columnar epithelium. Immunohistochemical staining showed the glands were positive for CK20 and CDX2 and negative for CK7, with a low proliferative index, mostly consistent with reactive colonic glands. The patient remained asymptomatic after one-year follow-up. A review of the literature shows very rare descriptions of similar lesions, but none fits exactly this pattern. We would designate this inverted lymphoglandular polyp and present this case to raise the awareness of recognizing this unusual histological entity.

Small bowel dissemination of coccidioidomycosis.

Gastrointestinal coccidioidomycosis is extremely rare, with less than 10 cases reported in the literature. We report a case of small bowel dissemination of coccidioidomycosis in a 21-year-old African American male with a history of living in San Joaquin Valley. The patient presented with one week of abdominal pain, nausea, shortness of breath, intermittent fever, and sweat, and one month of abdominal distention. A chest radiograph revealed complete effusion of left lung. A computed tomography scan of the abdomen showed diffuse small bowel thickening and enhancement, as well as omental and peritoneal nodules, and ascites. The coccidioidal complement fixation titer was 1 : 256. The duodenal biopsy revealed many spherules filled with round fungal endospores. Later, blood fungal culture showed positivity for Coccidioides immitis. The final diagnosis is disseminated coccidioidomycosis involving lungs, blood, and duodenum. Despite aggressive antifungal therapy, the patient's clinical situation deteriorated and he succumbed to multisystem organ failure one and half months later. A high index of suspicion for gastrointestinal coccidioidomycosis should be maintained in patients from an endemic area presenting as abdominal distention and pain.

Strongyloidiasis hyperinfection in a patient with a history of systemic lupus erythematosus.

Strongyloidiasis is a parasitic disease caused by Strongyloides stercoralis, a nematode predominately endemic to tropical and subtropical regions, such as Southeast Asia. Autoinfection enables the organism to infect the host for extended periods. Symptoms, when present, are non-specific and may initially lead to misdiagnosis, particularly if the patient has additional co-morbid conditions. Immunosuppressive states place patients at risk for the Strongyloides hyperinfection syndrome (SHS), whereby the organism rapidly proliferates and disseminates within the host. Left untreated, SHS is commonly fatal. Unfortunately, the non-specific presentation of strongyloidiasis and the hyperinfection syndrome may lead to delays in diagnosis and treatment. We describe an unusual case of SHS in a 30-year-old man with a long-standing history of systemic lupus erythematosus who underwent a partial colectomy. The diagnosis was rendered on identification of numerous organisms during histologic examination of the colectomy specimen.

Histologic definition of gastro-esophageal reflux disease.

PURPOSE OF REVIEW: To review recent data supporting the development of new histology-based definitions of gastro-esophageal reflux disease (GERD). RECENT FINDINGS: Three precisely definable columnar epithelial types--cardiac, oxyntocardiac and intestinal--may be interposed between esophageal squamous epithelium and gastric oxyntic (acid secreting) mucosa. This enables definition of a new histologic concept: the squamo-oxyntic gap. The squamo-oxyntic gap is zero or very small in autopsies performed on patients without evidence of GERD. The gap progressively increases in length with the severity of GERD, indicating that the squamo-oxyntic gap is a marker for chronic GERD. The distal part of the gap lines gastric-type rugal folds and, therefore, is distal to the present endoscopic definition of the gastro-esophageal junction. I contend that this distal gap segment (which has esophageal submucosal glands) is actually the dilated distal esophagus; this is the pathologic correlate of destruction of the abdominal segment of the lower esophageal sphincter. The dilated distal esophagus is mistaken for 'gastric cardia' by present endoscopic definitions. SUMMARY: I believe that these data support the adoption of novel histologic definitions of GERD as follows: the presence of any squamo-oxyntic gap defines GERD; the length of the gap is a measure of severity of chronic GERD; and the presence of intestinal metaplasia in the gap defines Barrett esophagus and cancer risk.

Effect of Barrett's esophagus surveillance on esophageal preservation, tumor stage, and survival with esophageal adenocarcinoma.

OBJECTIVES: Surveillance endoscopy has been recommended for patients with Barrett's esophagus; however, recent studies have questioned the importance owing to the new, lower, estimates of the rate of progression of Barrett's esophagus to cancer. The aim of the present study was to compare the tumor stage, survival, and frequency of esophageal preservation in patients who presented with progression of Barrett's esophagus within a surveillance program versus those who presented with prevalent disease. METHODS: A retrospective chart review was performed of all patients treated for high-grade dysplasia or esophageal adenocarcinoma from 2005 to 2010. The surveillance group included patients who had had at least 1 endoscopy and biopsy confirming intestinal metaplasia (with or without low-grade dysplasia) 6 months or more before the endoscopy showing progression. RESULTS: A total of 224 patients were included in the present study, 36 in the surveillance group and 188 in the prevalence group. The surveillance patients had significantly earlier stage tumors (P < .0001) and were more likely to undergo endoscopic therapy and to keep their esophagus (44% vs 11%, P < .0001) than were patients with prevalent disease. Furthermore, the patients in the surveillance group were less likely to have lymph node metastases and had better overall and disease-free survival. No patient with high-grade dysplasia or an intramucosal tumor died of cancer. CONCLUSIONS: Patients within a surveillance program for Barrett's esophagus had better survival and were less likely to have an esophagectomy than those who presented with prevalent disease. Treatment of intramucosal cancer was curative, and improved survival with surveillance was not secondary to lead time bias. Surveillance endoscopy remains important in patients with Barrett's esophagus.

The GCTM-5 epitope associated with the mucin-like glycoprotein FCGBP marks progenitor cells in tissues of endodermal origin.

Monoclonal antibodies against cell surface markers are powerful tools in the study of tissue regeneration, repair, and neoplasia, but there is a paucity of specific reagents to identify stem and progenitor cells in tissues of endodermal origin. The epitope defined by the GCTM-5 monoclonal antibody is a putative marker of hepatic progenitors. We sought to analyze further the distribution of the GCTM-5 antigen in normal tissues and disease states and to characterize the antigen biochemically. The GCTM-5 epitope was specifically expressed on tissues derived from the definitive endoderm, in particular the fetal gut, liver, and pancreas. Antibody reactivity was detected in subpopulations of normal adult biliary and pancreatic duct cells, and GCTM-5-positive cells isolated from the nonparenchymal fraction of adult liver expressed markers of progenitor cells. The GCTM-5-positive cell populations in liver and pancreas expanded greatly in numbers in disease states such as biliary atresia, cirrhosis, and pancreatitis. Neoplasms arising in these tissues also expressed the GCTM-5 antigen, with pancreatic adenocarcinoma in particular showing strong and consistent reactivity. The GCTM-5 epitope was also strongly displayed on cells undergoing intestinal metaplasia in Barrett's esophagus, a precursor to esophageal carcinoma. Biochemical, mass spectrometry, and immunochemical studies revealed that the GCTM-5 epitope is associated with the mucin-like glycoprotein FCGBP. The GCTM-5 epitope on the mucin-like glycoprotein FCGBP is a cell surface marker for the study of normal differentiation lineages, regeneration, and disease progression in tissues of endodermal origin.

Columnar-lined esophagus without intestinal metaplasia has no proven risk of adenocarcinoma.

Intestinal metaplasia in the columnar-lined esophagus (CLE) has long been recognized as the most significant histologic risk indicator for esophageal adenocarcinoma. Recent concern has been expressed, however, that nonintestinalized metaplastic columnar epithelia (cardiac epithelium in the esophagus) may also indicate risk. Of 2586 consecutive patients undergoing endoscopy and biopsy in the Foregut Surgery Department, we selected (a) 214 patients with a visible CLE who had systemic 4-quadrant biopsies at 1 to 2 cm intervals, with the most proximal biopsy straddling the squamocolumnar junction, and (b) 109 patients without systematic biopsy who had dysplasia or adenocarcinoma. In the first group, 187 (87.4%) patients had intestinal metaplasia, and 27 (12.6%) had cardiac epithelium. Dysplasia or adenocarcinoma was present in 55 patients, all with intestinal metaplasia; its presence was significantly higher than in the cardiac epithelium group, none of whom had dysplasia or adenocarcinoma (P=0.01). In the second group with limited sampling, 49 had only tumor tissue in the biopsy. Of 60 patients with nontumor epithelium, only 34 (56.7%) had residual intestinal metaplasia. We conclude that systematic biopsies of CLE as described in this study separate patients into those with and without intestinal metaplasia in such a manner as to remove the possibility of false-negative diagnosis of intestinal metaplasia. When intestinal metaplasia is absent using this biopsy protocol, the patient is at no or extremely low risk for dysplasia and cancer. When biopsies have a lower level of sampling of the segment of CLE, the absence of intestinal metaplasia cannot be interpreted as a true negative for intestinal metaplasia. Inadequate sampling is a powerful reason why the near absolute association between intestinal metaplasia and adenocarcinoma is not seen in some studies.

Intraluminal pH and goblet cell density in Barrett's esophagus.

INTRODUCTION: Goblet cells in Barrett's esophagus (BE) vary in their density within the Barrett's segment. Exposure of Barrett's epithelium to bile acids is a major stimulant for goblet cell formation. The dissociation of bile acids into forms that penetrate Barrett's epithelium is known to be pH dependent. We hypothesized that variations in the esophageal luminal pH environment explains the variability in goblet cell density. The aim of this study was to correlate esophageal luminal pH with goblet cell density in patients with BE. METHODS: A customized six-sensor pH catheter was positioned with the most distal sensor in the stomach and the remaining sensors located 1 cm below and 1, 3, 5, and 8 cm above the upper border of the lower esophageal sphincter in five normal subjects and six patients with long-segment BE. The luminal pH was measured by each sensor for 24-h and expressed as median pH. Patients with BE had four quadrant biopsies at levels corresponding to the location of the pH sensors. Goblet cell density was graded from 0 to 3 based on the number per high-power field. RESULTS: In normal subjects, the median pH values recorded in the sensors within the lower esophageal sphincter (LES) and esophageal body were all above 5. In patients with BE, the median pH recorded by the sensor within the LES was 2.8 and increased progressively to 4.7 in the sensor at 8 cm above the LES. Goblet cell density was significantly lower in the distal Barrett's segment exposed to a median pH of 2.2 and increased in the proximal Barrett's segment exposed to a median pH of 4.4 (p = 0.003). CONCLUSION: Patients with BE have a goblet cell gradient that correlates directly with an esophageal luminal pH gradient. This suggests that goblet cell differentiation is pH dependent and likely due to the effect of pH on bile acid dissociation.

The dilated distal esophagus: a new entity that is the pathologic basis of early gastroesophageal reflux disease.

Present management algorithms for patients with gastroesophageal reflux disease (GERD) limit endoscopy to patients with advanced disease. When endoscopy is performed, biopsy is limited to patients who have a visible columnar-lined esophagus. Biopsy is not recommended for patients whose endoscopy is normal. This algorithm results in the failure to evaluate patients with early stages of GERD at a pathologic level. We report 714 patients with normal endoscopic findings irrespective of symptoms who had adequate biopsies taken from the squamocolumnar junction and the area 1-cm distal to this from mucosa that had rugal folds. Concurrent biopsies were also taken from the gastric body and/or antrum. All patients had a gap between their esophageal squamous epithelium and gastric oxyntic mucosa in the junctional region composed of oxyntocardiac ± cardiac ± intestinal epithelia. A total of 643 (90.1%) patients had no significant pathology in the gastric antrum and/or body, indicating that the squamooxyntic gap was an isolated abnormality in this region in all but 71 (9.9%) patients. The gap contained only oxyntocardiac epithelium in 71 (9.9%) patients, cardiac mucosa without intestinal metaplasia in 482 (67.5%) patients, and intestinal metaplasia in 161 (22.6%) patients. The pathologic interpretation of biopsies taken from the gastroesophageal junction is confusing and has significant interobserver variation. This results from lack of agreement as to whether these biopsies originate in the proximal stomach ("gastric cardia") or in the esophagus. We provide evidence that the presence of oxyntocardiac ± cardiac ± intestinal epithelia in biopsies from patients who are endoscopically normal is diagnostic of a dilated GERD-damaged distal esophagus. The dilated distal esophagus is the pathologic manifestation of destruction of the abdominal segment of the lower esophageal sphincter. Its presence is the pathologic basis of early GERD, which is missed if patients who are endoscopically normal are not biopsied, as is the present recommendation. Its recognition allows for accurate and evidence-based interpretation of biopsies from this region and removes the present confusion and permits the development of a reproducible pathologic diagnostic method.

Association of adenocarcinomas of the distal esophagus, "gastroesophageal junction," and "gastric cardia" with gastric pathology.

Controversy exists as to whether adenocarcinomas occurring in the gastroesophageal junctional region and gastric cardia originate in the esophagus or the stomach. Esophageal adenocarcinoma is known to be strongly associated with gastroesophageal reflux disease; gastric adenocarcinoma with Helicobacter pylori gastritis, and gastric intestinal metaplasia. This study evaluates the association of these tumors with pathologic findings in the biopsies of the gastric body and the antrum. It is hypothesized that if these malignancies are esophageal, they should have little or no significant association with gastric pathology; if they are gastric, these patients should have a high prevalence of gastric pathology. Between 2004 and 2008, 234 patients were diagnosed with high-grade dysplasia (HGD) and/or adenocarcinoma; 107 were distal esophageal, 79 straddled the distal end of the tubular esophagus, and 48 were in the "gastric cardia." Simultaneous biopsies of the distal body and antrum were present in 185 patients; 49 had biopsy of either antrum or body. Gastric biopsies were assessed for inflammation, H. pylori infection, and intestinal metaplasia. During this period, 2146 patients had nonmalignant columnar epithelia in the esophagus with similar assessment of the stomach; these acted as a control group. The gastric biopsy was normal in 201/234 (85.9%) patients and showed significant inflammation, H. pylori infection, and/or gastric intestinal metaplasia in 33/234 (14.1%) patients. There was no gastritis, H. pylori infection, or intestinal metaplasia in 88/107 (82.2%) of the patients with distal esophageal HGD and/or adenocarcinoma, 70/79 (88.6%) with junctional HGD and/or adenocarcinoma, and 43/48 (85.9%) with "gastric cardiac" HGD and/or adenocarcinoma. The incidence of gastritis was significantly higher in the patients with HGD and/or adenocarcinoma (33/234 or 14.1%) than in the control population (146/2146 or 9.0%; P=0.01). This difference was largely the result of a higher incidence of gastritis in patients with HGD and/or adenocarcinoma in the distal third of the esophagus (19/107 or 17.8%) versus the control population (146/2146 or 9.0%; P=0.01). The incidence of H. pylori positivity was also significantly higher in the patients with HGD and/or adenocarcinoma in the distal third of the esophagus (13/107 or 12.2%) than in the control population (117/2146 or 5.5%; P=0.01). There was no significant difference between the control group and the patients with junctional and gastric cardiac HGD and/or adenocarcinoma for gastritis, H. pylori infection, or the gastric intestinal metaplasia. The absence of gastritis, H. pylori, and the gastric intestinal metaplasia in 85.9% of the patients with HGD and/or adenocarcinoma of the gastroesophageal junctional region strongly suggest that most of these originate in the esophagus. In the small minority of patients whose HGD and/or adenocarcinoma were associated with gastric pathology, the incidence of gastritis and H. pylori infection was significantly higher in patients with HGD and/or adenocarcinoma in the distal third of the esophagus and not in the junctional and "gastric cardiac" tumors. This suggests that the reflux of the gastric juice whose composition has been altered by gastritis and H. pylori infection may be associated with an increased tendency to HGD and/or adenocarcinoma in the distal third of the esophagus.

The histologic squamo-oxyntic gap: an accurate and reproducible diagnostic marker of gastroesophageal reflux disease.

The present definition of gastroesophageal reflux disease (GERD) is based on clinical criteria that are difficult to reproduce accurately. This study provides a method to develop a histologic definition of GERD based on biopsies obtained from the affected esophagus. Pathology reports from 1655 patients who had upper gastrointestinal endoscopy and biopsy according to a systematic protocol were reviewed. Biopsies were obtained from the esophagus, around the gastroesophageal junction and the stomach: proximal, body, and antrum. Patients who had oxyntocardiac±cardiac±intestinal epithelia between the squamous epithelium proximally and the proximal limit of gastric oxyntic mucosa distally were defined as having a squamo-oxyntic gap. The length of the squamo-oxyntic gap varied from less than 1 cm in 1399 (84.5%) patients to greater than 5 cm in 80 (4.8%) of the patients. Only oxyntocardiac epithelium was seen in 190 (11.5%) of the patients, oxyntocardiac and cardiac epithelia in 898 (54.3%), and intestinal metaplasia in addition to the other 2 epithelial types in 567 (34.2%). The prevalence of intestinal metaplasia was directly proportional to length of the squamo-oxyntic gap, being 24.3% (340/1399) when the length was <1 cm, and 83.5% (147/176) with length 1 to 5 cm. All patients with a length more than 5 cm had intestinal metaplasia. The distribution of the 3 epithelia was constant irrespective of the length of the squamocolumnar gap; intestinal metaplasia, when present, was seen maximally in the proximal region of the gap, cardiac epithelium intermediate and oxyntocardiac epithelium in the most distal segment of the gap. The squamo-oxyntic gap started in a dilated region distal to the end of the tubular esophagus and distal to the proximal limit of the rugal folds and extended into the tubular esophagus. Distal gastric biopsies showed no evidence of significant inflammation, intestinal metaplasia or Helicobacter pylori infection in 1543 (93.2%) of the patients, indicating that the squamo-oxyntic gap was largely independent of gastric pathology. We provide evidence that the squamo-oxyntic gap is equivalent to the columnar-lined esophagus. Its presence is a specific and sensitive indicator of reflux and can be used as a cellular criterion to define GERD. The length of the squamo-oxyntic gap provides an accurate assessment of the severity of chronic GERD. The distal limit of the squamo-oxyntic gap, which is the junction between oxyntocardiac and gastric oxyntic epithelium is the true gastroesophageal junction. The presence of intestinal metaplasia within the squamo-oxyntic gap is the most accurate risk indicator for esophageal adenocarcinoma and defines Barrett esophagus.