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PubMed1993

Comparative studies of cardia carcinoma and infracardial gastric carcinoma.

In a part retrospective, part prospective study, 354 carcinomas of the cardia were compared with 1259 infracardial gastric carcinomas with regard to the age and sex of the patients, macroscopic classification, microscopic classifications, depth of invasion, and survival rates. Mortality rates are generally higher in cardia carcinoma than in stomach carcinoma. The difference is due to the significantly poorer survival of cardia carcinoma patients in stage I, while mortality rates in stages II, III, and IV of both types are approximately similar. Highly significant differences were also found with regard to sex ratio, incidence of macro- and microscopic subtypes, and invasive growth. The typical cardia carcinoma occurs preferentially in men, is mostly well-delineated, and is manifested as an ulcerated or polypoid, well-differentiated tumor of expansive growth, corresponding to Laurén's intestinal type. These results confirm the concepts of McPeak and Warren, MacDonald, and Siewert et al., that the carcinoma located in the cardia must be seen as a separate entity of gastric carcinoma.

Aged↗
PubMed1993

Adenocarcinomas of esophagus and cardia in comparison with gastric carcinoma.

Since the carcinomas of the cardia and the adenocarcinomas of the esophagus show many similarities in their histological and morphological descriptions, a detailed comparative study was attempted on the basis of 66 esophageal carcinomas in adenoid differentiation, 359 carcinomas of the cardia, 1288 gastric carcinomas in infracardial localisation, and 492 squamous carcinomas of the esophagus. The evaluation yielded no significant differences between the adenocarcinomas of the esophagus and the cardia neither in age and sex distribution nor with regard to the classifications of Borrmann, WHO, Ming, and Laurén, but a significant discrimination was possible between esophageal and cardial adenocarcinoma together, on the one hand, and infracardial gastric carcinoma on the other. Furthermore, esophageal adenocarcinomas were localized preferentially in the lower third, unlike squamous carcinomas of the same organ. These results suggest that esophageal adenocarcinoma and carcinoma of the cardia must be considered as one separate entity, probably originating from a common stem cell. They further suggest that the cardia belongs to the esophagus rather than to the stomach.

Adenocarcinoma↗
PubMed2004

Carcinoma of the cardia: classification as esophageal or gastric cancer?

INTRODUCTION: The cardia is the anatomical borderland between the esophagus and stomach. Carcinomas of the cardia are regarded to share features of both, esophageal and gastric cancers. Controversy exists concerning their appropriate classification and whether these tumors comprise--in respect to tumor biology, pathophysiology as well as clinical features--an entirely separate entity. CLASSIFICATION: In order to distinguish cardia carcinomas from other adenocarcinomas arising within the vicinity of the esophagogastric junction, a classification system has been introduced from a surgical viewpoint, and is now well established and increasingly used worldwide. According to the topography of the main tumor mass, cardia carcinomas (AEG II) are distinguished from adenocarcinomas of the distal esophagus (AEG I) and subcardiac gastric cancers (AEG III). The tumor-node-metastasis (TNM) staging system by the International Union Against Cancer (UICC) does not provide a separate classification for tumors of the esophagogastric junction. The use of the classification for esophageal or for gastric cancers is recommended, irrespective of the elementary differences in the classification of lymphatic spread implemented herein. DISCUSSION: New aspects concerning this controversial debate are discussed based on current insights into the pathogenesis and the cellular origin of these entities. The controversies concerning the classification of cardia carcinomas and the failure of the current esophageal and gastric cancer staging systems to reflect the peculiarities of this entity accurately, present a strong argument in favor of a new classification system.

Adenocarcinoma↗
PubMed2001

A squamous cell carcinoma of the gastric cardia showing submucosal progression.

We report a case of squamous cell carcinoma (SCC) of the gastric cardia showing submucosal progression with direct invasion of the liver. A 71-year-old man was admitted with dysphagia. Esophagogastroscopy showed a protruding tumor covered with normal gastric mucosa in the anterior wall of the gastric cardia, although no abnormal findings were detected in the esophagus, including the esophagogastric junction. Serum SCC-related antigen level was elevated (6.6 ng/ml; normal level, less than 2.5 ng/ml). Endoscopic biopsy specimens taken from this tumor did not show malignant cells. Based on these findings, the preoperative diagnosis was a submucosal tumor of the stomach. Laparotomy was done; however, the tumor was not resected because it had direct invasion to the left lateral segment of the liver and adjacent tissues. As the tumor showed continuous bleeding from the stomach after surgery, total gastrectomy, combined with transhiatal lower esophagectomy, left lateral segmentectomy of the liver, splenectomy, and distal pancreatectomy was performed. Because histologic findings showed poorly or moderately differentiated SCC with direct invasion of the liver, the final diagnosis was SCC of the gastric cardia showing submucosal progression with hepatic invasion. Such a case of SCC of the gastric cardia showing submucosal progression is rare, and accurate preoperative diagnosis was very difficult. However, it may be important to consider SCC of the gastric cardia in such a situation.

Aged↗
PubMed2001

Inflammation in the cardia.

The detection of chronic inflammation and intestinal metaplasia at the gastric side of a normal-appearing esophagogastric junction started active research on gastric cardia pathology. The main causes for this interest have been the increasing incidence of gastroesophageal reflux disease (GERD) and cardia adenocarcinoma. Many controversies still exist. It is even controversial whether noninflamed gastric cardia epithelium is a normal structure present at birth or an acquired lesion as a consequence of GERD. Similarly, the pathogenesis of chronic inflammation and intestinal metaplasia of gastric cardia are a matter of debate. Some researchers consider these lesions to be a consequence of Helicobacter pylori infection, whereas others think that chronic cardia inflammation and intestinal metaplasia are consequences of GERD. In this paper we review recent published studies in this field.

Adenocarcinoma↗
PubMed1999

Adenocarcinomas of the distal oesophagus and gastric cardia are one clinical entity. Rotterdam Oesophageal Tumour Study Group.

BACKGROUND: Adenocarcinomas of the distal third of the oesophagus and the gastric cardia have similar characteristics but different staging criteria are being used. In the present study the question is addressed whether these tumours should be regarded and staged as one clinical entity. METHODS: From January 1987 to January 1997, 252 patients with an adenocarcinoma of the oesophagus (n = 111) or gastric cardia (n = 141) underwent transhiatal resection. Pathology, pathological tumour node metastasis (pTNM) stage and survival were analysed retrospectively, and a comparison was made between tumours of the oesophagus and gastric cardia. RESULTS: Barrett's epithelium was diagnosed in 54 per cent of oesophageal adenocarcinomas compared with 13 per cent of adenocarcinomas of the gastric cardia (P < 0. 001). Oesophageal carcinomas had a more favourable pT stage, fewer positive locoregional lymph nodes (pN1-2 56 versus 62 per cent; P = 0.3), but more distant metastases accounted for by positive lymph nodes around the coeliac axis (pM1 19 versus 4 per cent; P < 0.001). Five-year overall survival (26 versus 27 per cent; P = 0.9) and survival according to tumour stage were no different between the groups. Multivariate analysis showed that the location of the primary tumour was not an independent prognostic factor. CONCLUSION: Adenocarcinomas of the distal oesophagus and gastric cardia should be regarded as one clinical entity. Uniform staging criteria for both malignancies are recommended.

Adenocarcinoma↗
PubMed2001

Inverse association between intake of cereal fiber and risk of gastric cardia cancer.

BACKGROUND & AIMS: Recent data show that salivary nitrites form carcinogenic nitrosamines, especially at the gastric cardia. Wheat fiber has been shown to neutralize such mutagen formation. Our aim was to evaluate the association between dietary fiber and cancers of the esophageal and gastric cardia. METHODS: We examined data from a large-scale population-based case-control study of risk factors for adenocarcinoma of the gastric cardia and esophagus and squamous cell carcinoma of the esophagus. RESULTS: We found a strong dose-dependent inverse association between total dietary fiber intake and risk of gastric cardia adenocarcinoma, which was driven mainly by intake of cereal fiber. The odds ratio among individuals in the highest quartile of cereal fiber intake compared with the lowest was 0.3 (95% confidence interval, 0.2-0.5; P trend < 0.0001). High intake of cereal fiber was also associated with a moderately decreased risk of esophageal adenocarcinoma, but no linear dose-risk trend was observed. There was no association between dietary fiber and esophageal squamous cell carcinoma. CONCLUSIONS: High intake of cereal fiber may significantly lower the risk of gastric cardia cancer.

Adenocarcinoma↗
PubMed2000

The epidemiology of oesophageal adenocarcinoma: has the cancer of gastric cardia an influence on the rising incidence of oesophageal adenocarcinoma?

BACKGROUND: Owing to overgrowth and definitional problems in classification, the cancer of gastric cardia may affect significantly the epidemiological analysis of oesophageal adenocarcinoma. The purpose of the present study was to evaluate the changes in the incidence of all the adenocarcinomas near the gastrooesophageal junction. METHODS: Trends in the incidence rates of adenocarcinoma of the oesophagus and the gastric cardia were described through the Finnish Cancer Registry. The annual age-standardized incidence rates during 1976-95 were analysed by a linear regression technique. RESULTS: The total incidence of oesophageal carcinoma remained around 3.5/100,000 in men, and decreased from 2.8 to 1.3/100,000 in women. The incidence of oesophageal adenocarcinoma increased from 0.28 to 0.77/100,000 (nearly 300%) in males, and from 0.08 to 0.11 per 100,000 in females. There were no significant changes with time in the incidence rate of gastric cardia cancer in either sex. Combined gastric cardia and oesophageal adenocarcinoma incidence rates remained stable in women, and increased slightly, but significantly, from 2.4 to 2.9/100,000 in men. CONCLUSION: Oesophageal adenocarcinoma has increased significantly in men in Finland, but the combined incidence of cancers of the gastro-oesophageal junction has increased only slightly. To overcome the difficulties in classification of oesophageal adenocarcinoma and the cancer of gastric cardia in the epidemiological studies, the focus should be on all adenocarcinomas at or near the oesophagogastric junction.

Adenocarcinoma↗
PubMed1997

Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia.

BACKGROUND: Incidence rates for adenocarcinomas of the esophagus and gastric cardia have risen steeply over the last few decades. To determine risk factors for these tumors, we conducted a multicenter, population-based, case-control study. METHODS: The study included 554 subjects newly diagnosed with esophageal or gastric cardia adenocarcinomas, 589 subjects newly diagnosed with esophageal squamous cell carcinoma or other gastric adenocarcinomas, and 695 control subjects. Estimates of risk (odds ratios [ORs] and corresponding 95% confidence intervals [CIs]) were calculated for the four tumor types separately and for esophageal and gastric cardia adenocarcinomas combined. RESULTS: Risk of esophageal and gastric cardia adenocarcinomas combined was increased among current cigarette smokers (OR = 2.4; 95% = 1.7-3.4), with little reduction observed until 30 years after smoking cessation; this risk rose with increasing intensity and duration of smoking. Risk of these tumors was not related to beer (OR = 0.8; 95% CI = 0.6-1.1) or liquor (OR = 1.1; 95% CI = 0.8-1.4) consumption, but it was reduced for drinking wine (OR = 0.6; 95% CI = 0.5-0.8). Similar ORs were obtained for the development of noncardia gastric adenocarcinomas in relation to tobacco and alcohol use, but higher ORs were obtained for the development of esophageal squamous cell carcinomas. For all four tumor types, risks were higher among those with low income or education. CONCLUSIONS: Smoking is a major risk factor for esophageal and gastric cardia adenocarcinomas, accounting for approximately 40% of cases. IMPLICATIONS: Because of the long lag time before risk of these tumors is reduced among ex-smokers, smoking may affect early stage carcinogenesis. The increase in smoking prevalence during the first two thirds of this century may be reflected in the rising incidence of these tumors in the past few decades among older individuals. The recent decrease in smoking may not yet have had an impact.

Adenocarcinoma↗
PubMed1986

Cancer of the distal esophagus and cardia. Incidence, tumorous infiltration, and metastatic spread.

The report concerns the findings of autopsies performed at the Institute of Pathology, The University of Düsseldorf, where 68 patients with cancer of the distal esophagus and 117 patients with cancer of the cardia were observed between 1950 and 1982. The total number of autopsies during this 33-year observation period was 46,593. The male:female ratio was 5.8:1 in cancer of the distal esophagus, and 4.3:1 in cancer of the cardia. During the observation period, cancer of the distal esophagus accounted, on average, for about 40% of all esophageal cancers, whereas the percentage of cancers of the cardia among all gastric cancers was 15.4% on average. While the incidence of gastric cancer has decreased overall, a relative increase in cancers of the cardia has been found, especially in the last 8 years. In histological terms, most of the malignomas of the distal esophagus were squamous cell carcinomas (84%), and most of the cancers of the cardia were adenocarcinomas (96%). Tumor spread and lymphogenous and hematogenous metastasizing are discussed, and the findings are compared with the literature.

Adenocarcinoma↗
PubMed1994

Mortality from gastric cardia and lower esophagus cancer and occupation.

The incidence of adenocarcinoma of the gastric cardia and esophagus is increasing steadily in the United States. Little is known about the etiology of these cancers. We used occupation and industry information on the death certificates from 24 states (1984 to 1989) to conduct a case-control analysis of gastric cardia and gastric cardia/lower esophagus cancer. Risks were also calculated for other gastric cancers combined. Controls were deaths from other causes except cancer and gastrointestinal disorders. Increased risks of gastric cardia and cardia/lower esophagus among white women were found for administrative jobs (cardia odds ratio (OR) = 3.9; 95% confidence interval (CI), 1.5-9.8) and health professionals (cardia OR = 1.8; 95% CI, 0.6-5.3). Occupations associated with a lower socioeconomic status showed no significant excess risks. A similar pattern in risks was seen for men.

Adult↗
PubMed2007

Is intestinal metaplasia a necessary precursor lesion for adenocarcinomas of the distal esophagus, gastroesophageal junction and gastric cardia?

Adenocarcinoma of the distal esophagus and gastroesophageal junction are believed to arise in Barrett's esophagus with intestinal metaplasia. Whether adenocarcinoma can arise in columnar lined esophagus without intestinal metaplasia is in doubt. Whether adenocarcinoma of the gastric cardia arises in intestinal metaplasia of the gastric cardia is also in doubt. We aim to evaluate the relationship of size and stage of adenocarcinoma of the distal esophagus, gastroesophageal junction and gastric cardia to intestinal metaplasia and other types of columnar epithelium. Seventy-four patients who had esophagogastrectomy for adenocarcinomas in this region were examined histologically to assess the frequency of residual intestinal metaplasia in the surrounding epithelium. Tumors without residual intestinal metaplasia were evaluated for the presence of other columnar epithelia and correlated with tumor size and stage. Cardiac mucosa was present around all tumors. Residual intestinal metaplasia was present in 48 (65%) tumors, including 33/38 (87%) distal esophageal, 10/25 (45%) junctional and 5/11 (45%) gastric cardia tumors. The prevalence of intestinal metaplasia was 100% in all tumors that were less than 1 cm in maximum diameter and all intramucosal tumors. The prevalence of residual intestinal metaplasia decreased with increasing tumor size and stage. These data strongly support the contention that adenocarcinomas of this region, including those in the gastric cardia, arise in intestinal metaplastic epithelium. The absence of residual intestinal metaplasia in larger tumors is the result of tumor overgrowing the intestinal metaplasia from which it arose.

Adenocarcinoma↗
PubMed1999

Characteristics of intestinal metaplasia in the gastric cardia.

OBJECTIVE: Intestinal metaplasia of the gastroesophageal junction is frequently grouped together with Barrett's esophagus. The area of the gastroesophageal junction is comprised of the distal esophagus and the gastric cardia. The aim of the present study was to assess whether intestinal metaplasia in the distal esophagus and gastric cardia represent two different entities with a different set of risk factors. METHODS: Patients presenting for elective upper endoscopy were enrolled into a prospective study. The presence of gastritis and intestinal metaplasia was evaluated in gastric biopsies taken from the antrum, corpus, and cardia. Barrett's esophagus was defined by the presence of any length of columnar mucosa above the gastroesophageal junction. RESULTS: Of 302 patients, 50 patients had intestinal metaplasia of the gastric cardia, 73 Barrett's esophagus, and 116 erosive esophagitis. Men were more prone than women to develop Barrett's esophagus or erosive esophagitis. Both conditions were also more common among whites than nonwhites. Smoking was particularly common among patients with Barrett's esophagus. Patients with cardiac intestinal metaplasia did not share these demographic characteristics. The prevalence of daily reflux symptoms, erosive esophagitis, and Barrett's esophagus was similar among patients both with and without cardiac intestinal metaplasia. However, atrophy and intestinal metaplasia of the gastric antrum and corpus were found more frequently among patients with than without cardiac intestinal metaplasia. CONCLUSIONS: Intestinal metaplasia of the gastric cardia is different from Barrett's esophagus. Although cardiac intestinal metaplasia is closely associated with signs of gastritis in other parts of the stomach, gastroesophageal reflux disease does not seem to be a risk factor. A diagnosis of Barrett's esophagus should not be made based on the presence of intestinal metaplasia within the cardiac portion of the gastroesophageal junction.

Barrett Esophagus↗
PubMed2003

Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus.

BACKGROUND: Adenocarcinomas of the gastric cardia and distal oesophagus are at present often considered as one clinical entity because of their comparable increasing incidence, prognosis, and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype. AIMS: The aim of this study was to analyse expression of cyclooxygenase 2 (COX-2) in cardia carcinomas, and correlate this expression with clinicopathological parameters and survival. The results were compared with the prognostic value of COX-2 found for Barrett carcinomas. METHODS: Tumour sections of 134 consecutive patients undergoing potentially curative surgery for an adenocarcinoma of the gastric cardia and substantially invading the distal oesophagus were immunohistochemically stained using a COX-2 monoclonal antibody. Specimens were blindly scored based on intensity and extent of COX-2 immunopositivity. RESULTS: COX-2 expression was negative to weak in 59% ("COX-2 low") and moderate to strong in 41% ("COX-2 high") of tumours. This was significantly lower than in Barrett carcinomas (p<0.0001). COX-2 expression was not correlated with any clinicopathological parameter. A correlation between elevated COX-2 expression and reduced survival, as described for Barrett carcinomas, was not identified for cardiac carcinomas. CONCLUSIONS: There is a difference in COX-2 expression with respect to intensity and prognostic significance between adenocarcinomas of the gastric cardia and distal oesophagus. This suggests a different pathogenesis and different genetic constitution of these two cancers. Based on these findings, the role of selective COX-2 inhibitors in the treatment of adenocarcinomas of the gastric cardia is less promising than in Barrett carcinomas.

Adenocarcinoma↗
PubMed2004

Loss of heterozygosity and immunohistochemistry of adenocarcinomas of the esophagus and gastric cardia.

PURPOSE: Adenocarcinomas of the distal esophagus and gastric cardia are two tumors that have many features in common. They have similar prognoses, treatment modalities, and patterns of dissemination. The etiology is different, with gastroesophageal reflux disease playing a major role for esophageal adenocarcinoma, in contrast to adenocarcinoma of the gastric cardia. In the present study, we investigated several genetic and immunohistochemical features of adenocarcinomas of the distal esophagus and gastric cardia. EXPERIMENTAL DESIGN: Sixty-two resection specimens of either adenocarcinoma of the esophagus or adenocarcinoma of the gastric cardia were carefully selected. The genetic analysis included loss of heterozygosity of several tumor suppressor genes known to be involved in esophagogastric carcinogenesis. Immunohistochemical studies included the analysis of p53, c-Met, c-erbB-2, beta-catenin, and cyclooxygenase-2. In addition, a mutation analysis of the Tcf1 gene was done by direct sequencing. RESULTS: Patients with cardiac carcinoma had a significantly worse tumor stage and poorer differentiation on histology. Loss of heterozygosity analysis did not reveal significant differences between esophageal adenocarcinoma and cardiac adenocarcinoma. Immunohistochemical analysis revealed significantly more nuclear accumulation of beta-catenin and overexpression of cyclooxygenase-2 in patients with esophageal adenocarcinoma, compared with patients with cardiac carcinoma. No mutation was found in the Tcf1 gene in either tumor type. CONCLUSIONS: Although adenocarcinomas of the distal esophagus and gastric cardia have many features in common, we have found some evidence that they might form two different entities.

Adenocarcinoma↗
PubMed2004

Intestinal metaplasia of gastric cardia and carditis in Japanese patients with Helicobacter pylori infection.

AIM: The purpose of this study was to determine the prevalence of intestinal metaplasia of the gastric cardia in Japanese patients with Helicobacter pylori infection. METHODS: One hundred and fifty-seven patients with H. pylori infection participated in this study. Four biopsy specimens were taken from antrum, lesser and greater curvatures of stomach, and cardia for histological examination. The patients were divided into three groups: those < or = 39 years of age (group A), those 40-59 years old (group B), and those > or = 60 years of age (group C). RESULTS: The proportions of the patients with intestinal metaplasia of the gastric cardia in the three groups were 12, 39, and 65%, respectively. Their intestinal metaplasia of gastric cardia scores were 0.2, 0.54, and 0.81, respectively (significant difference among groups A, B, and C: p < 0.05), according to the updated Sydney classification. CONCLUSION: The prevalence of intestinal metaplasia of the gastric cardia and carditis in Japanese patients with H. pylori infection was similar to that of metaplasia of antrum and lesser curvature of the stomach.

Adolescent↗
PubMedDate not supplied

[Analysis of clinicopathological, tumor cell proliferation and apoptosis parameters in adenocarcinoma of the gastric cardia].

BACKGROUND/AIMS: In view of the increased incidence of carcinoma of the cardia over recent years, this work had the aim of studying the clinicopathological aspects, cell proliferative and tumor apoptotic indices of this neoplasm, their interrelations and possible influences on the prognosis. MATERIAL AND METHODS: Forty cases of adenocarcinoma of the cardia were studied between 1988 and 2001, with a minimum clinical follow-up of 3 years. Patients were excluded if they had previous chemotherapy or radiotherapy treatment, presented early neoplasia, or died during the operations or for other reasons unrelated to cancer. Gender; age, Laurén and Ming histological type, staging, and the presence or absence of intestinal metaplasia, epithelial dysplasia and Helicobacter pylori in the adjacent mucosa were analyzed. The apoptotic index was evaluated via hematoxylin-eosin in the primary tumor. To analyze the cell proliferation tumor, PCNA was utilized. The immunohistochemical technique utilized was streptavidin-biotin-peroxidase. For the survival analysis, cases with distant metastasis upon diagnosis were excluded. For the statistical analysis, the Student t and Mann-Whitney tests, Kaplan-Meier curves and Cox regression model were utilized. RESULTS: The mean age was 61 years (median: 63). There was predominance of the male gender (72.5%), diffuse histological type (55%) and infiltrative histological type (72.5%), and the more advanced stages (III and IV: 67.5%). There was no association with intestinal metaplasia and/or H. pylori. No epithelial dysplasia was detected in adjacent mucosa in any of the cases. The mean apoptotic index was 7.05 in 10 high power fields and 11.40 in 500 cells (2.28%). The mean positivity to PCNA was 275.05 cells in ten high power fields and 409.33 in 500 cells (81.9%). There was a positive correlation between the cell proliferative and apoptotic indices. There was a positive correlation for intestinal histological type with PCNA and apoptotic indices, in 10 high power fields. The mean survival was 28.41 months. Age over 63 and apoptotic index over 7.05 showed a negative correlation with survival, in multivariate analysis. CONCLUSIONS: Adenocarcinoma of the cardia predominated in male adults of mean age 61 years, and the predominant type was diffuse in more advanced stages. There was a correlation between apoptosis and tumoral cell proliferation. Survival in cases of adenocarcinoma of the cardia is still low. Both age and apoptosis were independent prognostic factors in cancer of the cardia.

Adenocarcinoma↗
PubMed1980

The gastric cardia in double-contrast study: its dynamic image.

Difficulties in evaluating the gastric cardia are well known and may often be resolved with the double-contrast technique. Special views to show the cardia en face were obtained in 200 double-contrast examinations. Four basic patterns were recognized. Similar appearances could be reproduced by protruding or retracting the lower end of the esophagus during the radiography of intact stomachs obtained at autopsy. Influenced by muscle relaxants, swallowing, or deep breathing, cardia patterns were found to be interchangeable in the same patient and same examination. The disappearance of the protrusion pattern at the cardia in the course of swallowing is an important means of distinguishing normality from a tumor in this area. Any significant deviation from the normal geometry of the cardia as displayed by double contrast indicates an abnormality. Examples of abnormalities are illustrated.

Carcinoma↗