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.

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.

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.

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.

Genetic variations in angiogenesis pathway genes predict tumor recurrence in localized adenocarcinoma of the esophagus.

OBJECTIVE: The aim of this study was to determine whether the risk of systemic disease after esophagectomy could be predicted by angiogenesis-related gene polymorphisms. SUMMARY BACKGROUND DATA: Systemic tumor recurrence after curative resection continues to impose a significant problem in the management of patients with localized esophageal adenocarcinoma (EA). The identification of molecular markers of prognosis will help to better define tumor stage, indicate disease progression, identify novel therapeutic targets, and monitor response to therapy. Proteinase-activated-receptor 1 (PAR-1) and epidermal growth factor (EGF) have been shown to mediate the regulation of local and early-onset angiogenesis, and in turn may impact the process of tumor growth and disease progression. METHODS: We investigated tissue samples from 239 patients with localized EA treated with surgery alone. DNA was isolated from formalin-fixed paraffin-embedded normal esophageal tissue samples and polymorphisms were analyzed using polymerase chain reaction-restriction fragment length polymorphism and 5'-end [gamma-P] ATP-labeled polymerase chain reaction methods. RESULTS: PAR-1 -506 ins/del (adjusted P value=0.011) and EGF +61 A>G (adjusted P value=0.035) showed to be adverse prognostic markers, in both univariate and multivariable analyses. In combined analysis, grouping alleles into favorable versus nonfavorable alleles, high expression variants of PAR-1 -506 ins/del (any insertion allele) and EGF +61 A>G (A/A) were associated with a higher likelihood of developing tumor recurrence (adjusted P value<0.001). CONCLUSION: This study supports the role of functional PAR-1 and EGF polymorphisms as independent prognostic markers in localized EA and may therefore help to identify patient subgroups at high risk for tumor recurrence.

Esophageal intraepithelial eosinophils in dysphagic patients with gastroesophageal reflux disease.

BACKGROUND: Patients with gastroesophageal reflux disease (GERD) often complain of dysphagia and are frequently found to have intraepithelial eosinophils on esophageal biopsy. AIM: The aim of this study was to investigate the relationship between dysphagia and the number of intraepithelial eosinophils in patients with GERD. METHODS: Review of all patients studied in our esophageal function laboratory from 1999 to 2007 identified 1,533 patients with increased esophageal acid exposure. Patients who complained of dysphagia without mechanical or motor causes were identified and divided into three groups based on whether dysphagia was their primary, secondary or tertiary symptom. A control group consisted of randomly selected GERD patients with no dysphagia. The highest number of intraepithelial eosinophils per high-power field (HPF) in biopsies from the squamocolumnar junction (SCJ) and esophageal body was compared across groups. RESULTS: There were 71 patients with unexplained dysphagia. Dysphagia was the primary symptom in 13 (18%), secondary symptom in 34 (48%), and tertiary symptom in 24 (34%) patients. The number of eosinophils differed between the four groups, with the highest number in those with dysphagia as the primary symptom (P = 0.0007). This relationship persisted whether biopsies were from the SCJ (P = 0.0057) or esophageal body (P = 0.0096). CONCLUSION: An association exists between the number of intraepithelial eosinophils and dysphagia in GERD patients, with the highest number of eosinophils in those with the primary symptom of dysphagia.

Validation of a rodent model of Barrett's esophagus using quantitative gene expression profiling.

BACKGROUND: A rodent model of gastroduodenal-esophageal reflux can result in replacement of squamous esophageal mucosa with intestinal-type columnar mucosa and carcinoma. The validity of this model is debated, as it is unproven whether this mucosa is intestinal metaplasia due to reflux or represents migration of adjacent jejunal mucosa above the anastomosis. The aim of this study was to evaluate the esophageal intestinal-type mucosa in these animals by measuring expression of trefoil factor genes (TFF-1, -2, -3) and comparing it with adjacent jejunum in order to determine its etiology. METHODS: Twenty-five rats underwent esophagojejunostomy at the ligament of Treitz to induce reflux of gastric and duodenal contents. The animals were sacrificed at 16 weeks (n = 14) and 30 weeks (n = 11). After sacrifice, the distal esophagus, jejunum, and colon were obtained. RNA was isolated, reverse transcribed, and messenger RNA (mRNA) expression of TFF-1, -2, and -3 was measured with real-time polymerase chain reaction (PCR). Linear discriminant analysis classified samples based on gene expression. RESULTS: Esophageal intestinal-type mucosa was present at sacrifice in 18 animals. Compared to jejunum, the expression of TFF-1 and TFF-2 mRNA in the intestinal mucosa of the distal esophagus was increased (p = 0.0007 and p < 0.0001, respectively). Expression of TFF-3 was also increased in esophageal intestinal mucosa compared with jejunum (p = 0.0002), but there was significant overlap in expression between these tissues for this gene. Linear discriminant analysis misclassified esophageal intestinal-type mucosa as jejunum in only one case. In no cases was jejunum misclassified as esophageal intestinal-type mucosa. CONCLUSION: The gene expression profile of esophageal intestinal-type mucosa following surgically induced reflux in a rodent model indicates that this represents intestinal metaplasia, not proximal migration of jejunum. This validates this model for studying the pathogenesis of Barrett's esophagus. Use of this model has potential for assessment of the impact of various therapies on the natural history of reflux disease.

Esophageal pH exposure and epithelial cell differentiation.

It is proposed that epithelial changes induced by gastroesophageal reflux disease are related to the pH environment of the esophageal lumen. We hypothesized that the various types of esophageal epithelium are associated with specific pH environments that induce their formation. The aim of this study was to compare the luminal pH environment to the histology of the distal esophageal epithelium in patients with gastroesophageal reflux disease. A total of 197 symptomatic patients with increased esophageal acid exposure on 24-hour pH monitoring were grouped according to the histology based on biopsies from the distal esophagus: 17 with squamous epithelium, 126 with cardiac epithelium (CE), and 54 with Barrett's epithelium (BE). All were free of Helicobacter pylori infection and monitored off acid suppression therapy. Acid exposure was expressed as the percent of time the luminal pH was at intervals of 0-1, 1-2, 2-3, 3-4, 4-5, 5-6, and 6-7 over a 24-hour period. Patients with BE spent significantly more time at pH intervals 2-3, 3-4, and 4-5 than those with CE. This pattern switched at pH interval 5-6, where patients with cardiac mucosa spent more time than those with BE. Patients with squamous and CE had similar pH exposure at all intervals. Patients with BE have significantly longer exposure time at the pH interval of 2 to 5 compared to those with cardiac and squamous epithelium. This suggests that the exposure of stem cells to a luminal pH between 2 and 5 may trigger the differentiation of CE into intestinalized CE.

Histopathology of the endoscopic esophagogastric junction in patients with gastroesophageal reflux disease.

BACKGROUND: Discrepancy exists between the endoscopic (rugal folds) and the histopathologic (oxyntic mucosa) definition of proximal stomach. We compared endoscopy and histopathology of the esophagogastric junction in patients with gastroesophageal reflux disease. METHODS: A total of 102 consecutive patients (60 women) with gastroesophageal reflux disease prospectively underwent endoscopy including multilevel biopsy sampling at the level of the rise of rugal folds (level 0), and also 0.5 cm and 1.0 cm distal and 0.5 cm and > or = 1 cm proximal to this point. Columnar lined esophagus (CLE) was cataloged according to the histopathologic Paull-Chandrasoma classification and esophagitis according to the endoscopic Los Angeles classification. Hiatal hernia was diagnosed if the endoscopic rugal folds commenced > or = 2 cm above the diaphragm; competency of the esophagogastric valve was graded according to the Hill classification. RESULTS: All patients had histopathologic CLE with maximal presence at level 0 (97%) and a decrease towards proximal and distal biopsy levels (level -0.5 cm, 81%; level -1.0, 28%; level + 0.5 cm, 40%; level + 1.0 cm, 18%). Histopathologic CLE (distance between CLE-positive biopsy levels) was longer than endoscopic CLE (P < 0.001). All 19 patients with intestinal metaplasia (18.6%) were identified from 4-quadrant biopsies obtained at the squamocolumnar junction and at 0.5 cm distal from it. Persons with intestinal metaplasia were significantly older, had increased frequency of endoscopic hiatal hernia, higher Hill grade and presence of endoscopic CLE (P < 0.05); no significant difference was observed regarding sex, endoscopic esophagitis or length of endoscopic and histopathologic CLE (P > 0.05). None of the patients had dysplasia or carcinoma. CONCLUSIONS: In patients with gastroesophageal reflux disease the esophagogastric junction cannot be identified by endoscopy but requires histopathology of multilevel biopsies. The squamocolumnar junction harbors the highest yield of intestinal metaplasia.

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.

Adenocarcinomas of the distal esophagus and "gastric cardia" are predominantly esophageal carcinomas.

BACKGROUND: Adenocarcinoma of the distal esophagus and gastric cardia are defined by the relationship of its epicenter to the gastro-esophageal junction, which is presently defined as the end of the tubular esophagus. We have recently suggested that the true gastro-esophageal junction is best defined by the proximal limit of gastric oxyntic mucosa. AIM: To reclassify adenocarcinomas of this region by the relationship of the tumor to the proximal limit of gastric oxyntic mucosa. METHODS: Seventy-four patients who had esophago-gastrectomy for adenocarcinomas in this region were classified as adenocarcinoma of distal esophagus (38 patients) and gastric cardia (36 patients) by present criteria. The epithelial type at the epicenter and distal edge of these tumors was assessed. RESULTS: The epicenter of the tumor in 64 patients with noncircumferential tumors had squamous (5 cases), cardiac (21 cases), oxynto-cardiac (4 cases), and intestinal (Barrett-type) (34 cases) epithelia. None had gastric oxyntic mucosa. Of the 10 patients with circumferential tumors, 7 had cardiac or oxynto-cardiac epithelium at the distal tumor edge. CONCLUSIONS: If the gastro-esophageal junction is defined histologically as the proximal limit of oxyntic mucosa, 71/74 patients would be classified as adenocarcinoma of the distal esophagus. The other 3 patients were questionable as to gastric or esophageal origin. We suggest that this reclassification based on the proposed new definition of the gastro-esophageal junction provides an explanation for the epidemiologic relationship that exists between adenocarcinoma of the "gastric cardia" and gastro-esophageal reflux disease.

Reduction of interleukin 8 gene expression in reflux esophagitis and Barrett's esophagus with antireflux surgery.

HYPOTHESIS: Chronic inflammation of esophageal mucosa secondary to refluxed gastric juice increases gene expression of interleukin 8 (IL-8). Antireflux surgery can reduce this overexpression. DESIGN: Prospective analysis of archival paraffin-embedded tissue. SETTING: Academic tertiary medical center. PATIENTS AND METHODS: One hundred eight patients with reflux symptoms were classified according to pH monitoring and endoscopic and histologic findings. Twenty patients did not have reflux or mucosal injury; 47 had reflux disease (16 esophagitis and 31 Barrett's esophagus), 20 had dysplasia, and 21 had adenocarcinoma. Microdissection was performed to exclude inflammatory cells and stromal tissue. After RNA isolation and reverse transcription, IL-8 messenger RNA expression was measured using quantitative real-time polymerase chain reaction. All patients with reflux disease had Nissen fundoplication with biopsies at matched levels within the esophagus preoperation and postoperation. RESULTS: Expression of IL-8 was increased in patients with reflux compared with those without reflux. Patients with the highest IL-8 expression were those with Barrett's dysplasia and adenocarcinoma (P<.001). In patients with reflux, Nissen fundoplication led to significantly decreased IL-8 expression compared with preoperative levels in esophagitis (P = .01) and Barrett's esophagus (P = .03). CONCLUSIONS: Interleukin 8 messenger RNA expression increases during the progression of reflux disease from normal squamous mucosa to esophageal adenocarcinoma. Elimination of reflux with Nissen fundoplication significantly reduces IL-8 expression in both squamous and Barrett's mucosa. These results demonstrate that effective antireflux surgery can modulate the gene expression of esophageal mucosa and may impact the natural history of reflux disease.

Towards the molecular characterization of disease: comparison of molecular and histological analysis of esophageal epithelia.

Reliable quantification of gene expression offers the possibility of more accurate and prognostically relevant characterization of tissues than potentially subjective interpretations of histopathologists. We measured the expression of 18 selected genes and compared them to histological features in a spectrum of esophageal disease to evaluate the feasibility of molecular characterization of normal and pathologic esophageal epithelia. Esophageal tissue biopsies from 82 patients with foregut symptoms were laser capture microdissected, and the expression levels of 18 selected genes were measured by quantitative real-time polymerase chain reaction. Linear discriminant analysis, which uses combinations of genes to distinguish between histological groups, was performed to compare gene expression and the following five histological groups: (1) normal squamous epithelium (n = 35), (2) reflux esophagitis (n = 13), (3) non-dysplastic Barrett's (n = 33), (4) dysplastic Barrett's (n = 16), (5) adenocarcinoma (n = 31). A panel of seven genes had 90-94% predictive power to distinguish non-dysplastic and dysplastic Barrett's esophagus. Clustering analysis revealed structure in gene expression values even in the absence of histology. Expression levels in 17 genes differed significantly across histological groups. Classification based on gene expression agreed with histopathological assessment in the following percentage of cases: normal squamous epithelium = 53%, reflux esophagitis = 31%, non-dysplastic Barrett's = 76%, dysplastic Barrett's = 40%, and adenocarcinoma = 59%. Interestingly, predictive power improved markedly when inflammatory and dysplastic tissues were removed (77-94%). Gene expression classification agrees well with histopathological examination. When differences occur, it is unclear whether this effect is due to intraobserver variability in pathological diagnosis or to a genuine difference between gene expression and histopathology.

A proposal for a new validated histological definition of the gastroesophageal junction.

Present definitions of the gastroesophageal junction (GEJ) are the point of flaring of the tubular esophagus and the proximal limit of the gastric rugal folds. Neither of these has been validated as the true GEJ. This study aims to validate the location of the true GEJ using the criterion of esophageal submucosal glands. Ten esophagogastrectomy specimens, in which there was a well-defined point of flaring of the tubular esophagus that coincided with the proximal limit of gastric rugal folds, were examined by complete histological mapping to evaluate the distribution of esophageal submucosal glands and surface epithelial types. Oxyntocardiac and cardiac mucosa with or without intestinal metaplasia were present under rugal folds distal to the end of tubular esophagus in all patients to a length of 0.31 to 2.05 cm. Submucosal glands were present in the tubular esophagus and in the proximal pouch distal to the tubular esophagus in a distribution that closely coincided with squamous epithelium, oxyntocardiac, cardiac, and intestinal epithelia. Submucosal glands were never found under oxyntic mucosa. We conclude that a variable part of the saccular region distal to the tubular esophagus contains esophageal submucosal glands, therefore representing reflux-damaged distal esophagus. This results in an error, where up to 2.05 cm of distal reflux-damaged dilated esophagus can be mistaken as proximal stomach when presently accepted definitions for the GEJ are used. The true GEJ is the proximal limit of gastric oxyntic mucosa defined by histology.

Molecular determinants in targeted therapy for esophageal adenocarcinoma.

HYPOTHESIS: Cyclooxygenase 2 (COX-2), vascular endothelial growth factor (VEGF), and epidermal growth factor receptor (EGFR) are useful biological determinants in targeted therapy for esophageal adenocarcinoma. DESIGN: Prospective analysis. SETTING: University tertiary referral center. PATIENTS: Sixteen patients with squamous mucosa and normal results of a pH study without mucosal injury (control group), 15 with Barrett esophagus (metaplasia group), and 44 with adenocarcinoma (carcinoma group). INTERVENTIONS: Biopsy specimens were obtained 3 cm above the gastroesophageal junction. Dysplastic tissue was additionally isolated from 9 of the patients in the carcinoma group. After laser-capture microdissection, quantitative real-time polymerase chain reaction was used to measure gene expression across the spectrum of the metaplasia-dysplasia-carcinoma sequence. MAIN OUTCOME MEASURES: Expression of COX-2, VEGF, and EGFR in each patient group. RESULTS: Expression of both COX-2 and VEGF was significantly up-regulated in patients with metaplasia, dysplasia, and cancer compared with controls (P<.01). Expression levels of both were significantly higher in cancer than in the metaplasia group (P<.05) and increased sequentially from metaplasia to dysplasia to cancer. Expression of VEGF was significantly higher in the dysplastic tissue than in nondysplastic Barrett epithelium (P<.05). No change in expression levels of EGFR was seen in the histologic progression to esophageal adenocarcinoma. CONCLUSION: Gene expression data suggest that pharmacologic inhibition of COX-2 and VEGF may be useful adjuncts in targeted therapy for esophageal adenocarcinoma.

Clinical biology and surgical therapy of intramucosal adenocarcinoma of the esophagus.

BACKGROUND: Mucosal ablation and endoscopic mucosal resection have been proposed as alternatives to surgical resection as therapy for intramucosal adenocarcinoma (IMC) of the esophagus. Acceptance of these alternative therapies requires an understanding of the clinical biology of IMC and the results of surgical resection modified for treatment of early disease. STUDY DESIGN: Retrospective review of 78 patients (65 men, 13 women; median age 66 years) with IMC who were treated with progressively less-extensive surgical resections (ie, en bloc, transhiatal, and vagal-sparing esophagectomy) from 1987 to 2005. RESULTS: The tumor was located in a visible segment of Barrett's esophagus in 65 (83%) and in cardia intestinal metaplasia in 13 (17%). A visible lesion was present in 53 (68%) and in all but 4 the lesion was cancer. In those patients with visible Barrett's, the tumor was within 3 cm of the gastroesophageal junction in 66% and within 1 cm in 37%. Esophagectomy was en bloc in 23, transhiatal in 31, vagal-sparing in 20, and transthoracic in 4. Operative mortality was 2.6%. Vagal-sparing esophagectomy had less morbidity, a shorter hospital stay, and no mortality. Of the patients who had en bloc resection, a median of 41 nodes were removed. One patient had one lymph node metastasis on hematoxylin and eosin staining and two others, normal on hematoxylin and eosin staining, had micrometastases on immunohistochemistry. Actuarial survival at 5 years was 88% and was similar for all types of resections. Two patients died from systemic metastases and seven from noncancer causes. CONCLUSIONS: IMC occurred in cardia intestinal metaplasia and in Barrett's esophagus. Two-thirds of patients with IMC had a visible lesion. Most tumors occurred near the gastroesophageal junction. Node metastases were uncommon, questioning the need for lymphadenectomy. A vagal-sparing technique had less morbidity than other forms of resection and no mortality. Survival after all types of resection was similar. Outcomes of endoscopic techniques should be compared with this benchmark.

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.