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Adenocarcinoma at the Esophago-Gastric (EG) Junction

René Lambert, MD

René Lambert, MD
Screening Group
International Agency for Research on Cancer (IARC)
Lyon, France

Morphology of the esophagogastric junction

Esophageal and gastric tumors are often classified in a single group because they are detected in the two steps of the same diagnostic procedure: upper GI endoscopy.

Adenocarcinoma at the EG junction, is located in the distal third of the esophagus (C15.5 in the ICD classification of tumors) or in the proximal part of the stomach or cardia (C16.0). In most countries, there are much more cases at the cardia, than in the distal esophagus. Siewert classified cancer at the EG junction in 3 groups with respect to the central point of the tumor: Group I with an esophageal origin; Group II with an origin in the gastric cardia; and Group III with a sub-cardial origin. The esophagus joins the stomach at the level of the diaphragmatic pinch, when  there is no hiatal hernia. As shown in Figure 1, the EG region includes the distal part of the esophagus up to 2 cm above the squamo-columnar junction of the epithelium, just above the pinch of the diaphragm and also the proximal part of the stomach, or cardia, down to 2 cm below this epithelial junction. Above the epithelial junction, or Zline, superficial and parallel epithelial capillaries offer an endoscopic landmark of the squamous epithelium. Below the Z-line, the upper pole of the longitudinal folds of the gastric mucosa is the endoscopic landmark of the proximal part of the stomach. The short segment of gastric cardiac mucosa is coated with cardiac epithelial cells organized in short pits and glands. This segment is in continuity with the fundic or oxyntic epithelium of the stomach where parietal cells are visible. The distinct  epithelial types at the EG junction are shown in Figure 2. In addition, small islets of cardiac mucosa are often present in the squamous epithelium above the Z-line and islets of intestinal metaplasia may develop above or below this Z-line. If there is a hiatal hernia, the respective positions of the endoscopic landmarks are modified: the esophago-gastric junction moves to a position proximal to the pinch of the diaphragm and a segment of the stomach is located in the thorax. In the columnar lined, or Barrett’s esophagus, the squamocolumnar epithelial junction will ascend in the distal esophagus which is then lined by a segment of columnar metaplasia showing cardiac columnar cells and intestinal metaplasia. The length of this metaplastic segment is variable and very short segments (<1 cm) of columnar metaplasia are often misdiagnosed.

 

Figure 1: Anatomical sectors at the esophagogastric junction: 1-distal esophagus, 2-esophago-gastric epithelial junction, 3-mucosa of the cardia, 4-mucosa of the fundus.

 

Figure 2: Epithelial types at the esophagogastric junction: 1-squamous cell epithelium, 2-squamo-columnar epithelial junction, 3-columnar cardiac epithelium, 4-fundic epithelium with parietal cells, 5-islets of intestinal metaplasia.

Esophageal cancer

Squamous cell cancer is the most frequent type of esophageal tumor, and in many countries adenocarcinoma is relatively rare. The relative  proportions of both types of esophageal tumor are shown in cancer registries with histological data. In the period 1993-97 the proportion of adenocarcinoma (both sexes) was only 4.2% in Japan (Osaka registry), 5.4% in Korea (Seoul registry), and 9.5% in France (Bas Rhin registry). Higher proportions of adenocarcinoma occur in the same period in Northern Europe with 27.0% in Sweden, (Country registry); 29.6% in Norway (Country registry), and 52.0% in the caucasian population of the USA (SEER registries). In Western countries the incidence of adenocarcinoma in the esophagus tends to increase. The annual variation during the period 1973-1993 in the SEER registries of the USA was +8.6% in males and +6.8% in females, in the white population.

Stomach cancer

Stomach cancer is a frequent tumor: in the database GLOBOCAN the respective numbers of incident cases in more and in less developed countries were in 2002 207,000 and 439,000 in men, and 120,000 and 233,000 in women. The risk of stomach cancer in men is about twice that of women in both high and low-risk countries. It is estimated that gastric adenocarcinoma is located distally to the cardia in 82% of cases. In the Lauren classification, gastric adenocarcinoma is classified in 2 categories: an “intestinal” type with recognizable glands and a “diffuse” type without cohesion between the cells. Areas of highest incidence are found in Eastern Asia, Western South America, and Eastern Europe. In Japan, in 1999 an analysis of 11 population-based registries showed that stomach cancer accounted for 23% of cancer cases in men in 1999 and 15% in women. In the database GLOBOCAN, the age standardized incidence rate /100,000 of stomach cancer in Japan in East Asia was estimated in 2002 at 62.1 in males and 26.1 in females; the respective figures were much lower: 7.2 and 3.3 in the USA. However since the period 1963-65 there is a continuous decreasing trend for the incidence of stomach cancer in Asia.

Adenocarcinoma at EG junction, in the cardia

In a report from Parkin the respective numbers of adenocarcinomas classified at cardia or in distal esophagus in the SEER registries of the USA (1973-95) were 6,300 and 2,694 for the white population and 311 and 43 for the black population; the respective numbers were 2,203 and 358 in the registries of 4 regions in France (in 1978-92) and 2,151 and 15 in the Osaka registry of Japan (in 1980-93). Adenocarcinoma at the cardia differs from adenocarcinoma in the distal esophagus in the profile of molecular markers: the ratio cytokeratins - CK7 high /CK20 low - is more frequent for tumors located at the cardia, and so is the TP 53 mutation, as shown at the Paris Workshop.

Adenocarcinoma at EG junction, in the esophagus

The tumor arises from an area with columnar metaplasia, which is a pre-neoplastic condition. The risk of malignancy in columnar metaplasia of the esophagus is estimated at 1 case for 200 patients followed during one year. The risk is higher in the male sex, with Caucasian ethnicity and a long history of reflux symptoms. The risk is lower in females and in people with Asian or African ethnicity. The risk of malignancy increases with the length of columnar metaplasia in the esophagus, but short segments at the EG junction deserve attention because they are more frequent. The mechanisms by which columnar metaplasia develops in the mucosa of the distal esophagus, exposed to irritation from acid and the injurious effect of bile acids and salts, are still debated. Western experts propose that, after destruction of the squamous epithelium by  bile and acid stress, multipotent esophageal stem cells expressing cytokeratin, proliferate and differentiate into a columnar type. Eastern experts consider that there is a direct proliferation of the islands of esophageal cardiac mucosa, exposed to the same factors. In the sequence leading from inflammation to metaplasia and then cancer, the intraluminal generation of nitric oxide from dietary nitrate occurs at the EG junction with formation of carcinogenic N nitroso-compounds. Western experts consider that adenocarcinoma develops selectively from areas with intestinal metaplasia. Most experts in Asia think that adenocarcinoma can also develop in the absence of intestinal metaplasia, from areas with metaplasia showing only columnar cardiac cells.

Causal factors for adenocarcinoma at EG junction

In the upper digestive tract, neoplastic lesions develop in a background of chronic inflammation of the mucosa and submucosa. Endogenous factors, in particular bile and acid from duodeno-gastric and gastro-esophageal reflux, have an irritative action, combined with multiple exogenous toxic and infectious agents like alcohol, tobacco, nitrites, food contaminants, H. pylori in the stomach and HPV in the esophagus.

In the cardia: chronic inflammation of the mucosa in the distal verge of the squamo-columnar epithelial junction, is frequent. Carditis is characterized by elongated pits, hyperplasia and islets of intestinal metaplasia. The prevalence of carditis in the adult population is high and  intestinal metaplasia has been demonstrated at endoscopy in up to 25% of persons with, or without, reflux symptoms. Gastric carcinogenesis follows the pathway described by Correia - atrophic chronic gastritis - intestinal metaplasia - intraepithelial neoplasia. Atrophic gastritis increases the intraluminal pH with transformation of nitrites (NO2) in NO under the influence of the inducible nitric oxide synthetase (i-NOS). This chain reaction towards nitrosation results in the endoluminal formation of carcinogens and is inhibited by anti-oxidants (ascorbic acid). The etiology of carditis is multifactorial: contact with unbuffered acid, mechanical trauma and H. pylori infection. The causal factors linked to lifestyle in stomach cancer are linked to diet and tobacco: a high intake of mucosal irritants such as salt and nitrates causes chronic  inflammation and superficial gastritis. In Japan, during the follow-up of a cohort of subjects with atrophic gastritis, the risk of stomach cancer increased 1.8-fold by the consumption of salty and spicy food. A high intake of fruit and vegetables is associated with a reduced risk of stomach cancer and anti-oxidants, such as beta-carotene, alpha-tocopherol (vitamin E), ascorbic acid (vitamin C), prevent the formation of carcinogens in the gastric lumen. The risk of stomach cancer also increases in both sexes with the duration of smoking and number of cigarettes smoked. These factors play a role altogether in distal stomach cancer and in proximal cancer at the cardia. H. pylori, an infectious agent, is another major causal factor in distal gastric cancer, but it plays a marginal role in proximal gastric cancer at the level of the cardia. The Helicobacter and Cancer Collaborative Group confirmed in prospective studies the association between H. pylori infection and the subsequent development of distal cancer (O.R. = 2.97), while there was no increased risk for the cardia site (O.R. = 0.99). The prevalence of H. pylori infection in humans is estimated at 74% in developing countries and 58% in developed countries. However, the incidence of stomach cancer is not high in African countries, in contrast to the very high prevalence of H. pylori infection. According to Parkin it can be estimated that in 2002 around 590,000 cases of gastric cancer were attributable to H. pylori infection. The cycle of infection is through oral contamination in childhood, increased contamination with age, possible sero-conversion after eradication and possible reinfestation.

In the esophagus: Gastroesophageal reflux disease (GERD) is the cause of columnar metaplasia in the esophagus. The exact prevalence of Barrett’s esophagus in the population is difficult to estimate because more than 80% of those patients are asymptomatic. A recent survey of persons with, or without, reflux symptoms who had an indication of colonoscopy and have accepted a simultaneous upper GI endoscopy detected Barrett’s esophagus in 6.8%; this is a disease of the white (Caucasian) and aged male persons. Alcohol consumption, smoking, and a diet poor in fruit and vegetable, are risk factors for development of cancer. The proportion of smokers in adenocarcinoma is higher (72%) at the esophageal site than in the cardia site (42%). In the distal esophagus several inflammation-related factors are overexpressed during the progression from metaplasia to neoplasia. Cyclo-oxygenase 2 catalyzes the production of prostaglandin E2, which activates the beta-Catenin growth-signaling pathway.

Endoscopic Diagnosis

The detection of adenocarcinoma at the EG junction occurs in 3 circumstances: in asymptomatic persons, in persons complaining from symptoms of gastro-esophageal reflux, and in persons with dysphagia. Diagnosis is based on upper GI endoscopy performed with a recent model of high-resolution video-endoscope, with optical magnification and image processing, like Narrow Band Imaging. The first step in the endoscopic exploration of the EG junction is assessment of the position of the epithelial squamo-columnar junction based on the top of gastric folds: a proximal migration of the epithelial junction suggests the presence of a segment with columnar metaplasia and the length of this segment should be estimated. A retroflexion in the stomach is performed to explore the EG junction from below, and attention is given to any irregularity in the mucosal surface and to changes in the clear pink color which can be more red or white. The exploration is completed by chromoscopy: the Lugol Iodine dye stains only the squamous cell epithelium and may ensure a better delineation of metaplasia in the distal esophagus, the solution of acetic acid enforces the contrast at the junction of columnar and squamous epithelium, and the indigocarmine dye (0.1%) is sprayed onto the areas with suspicion of neoplasia. Magnification aims to analyze the variations in the pit pattern or in the epithelial crests at the surface of the mucosa and detect in the distal esophagus areas of intestinal metaplasia where large and long parallel grooves separate the epithelial crests. Below the epithelial junction and at the level of the cardia, the mucosa shows regular epithelial crests separated by narrow grooves.

Magnification offers the best approach to detect and characterize neoplastic lesions in their early stage. The strategy of endoscopic diagnosis is in 2 steps: detection at first, then characterization, allowing prediction and classification of neoplastic lesions as premalignant (low grade or  high grade) or as confirmed cancer with evaluation of its depth as intra-mucosal, submucosal or deeper. The endoscopic prediction is then confirmed by biopsies. Endoscopic diagnosis is followed, when the diagnosis of neoplasia is confirmed at pathology, by other procedures including endosonography and CT scan. As a matter of fact, many premalignant lesions at the EG junction, can remain stable without progression to cancer for years; however their endoscopic resection is recommended as a rule.

Endoscopic treatment

After characterization of lesions located at the EG junction, and prediction of histology, treatment decision is between endoscopic resection or surgical treatment. Endoscopic resection, either in the distal esophagus or in the cardia, is proposed for low grade and high grade precancerous lesions, for intramucosal cancer and for cancer with a superficial invasion of the submucosa. En bloc resection, in a single specimen, is always preferred to piece-meal resection in multiple fragments; therefore the conventional EMR (endoscopic mucosal resection) should be restricted to neoplastic areas up to 2 cm in diameter. Larger lesions should either be treated by endoscopic resection en bloc with the ESD (endoscopic submucosal dissection) method or transferred to surgical treatment. The en bloc endoscopic resection is particularly adapted for the treatment of early adenocarcinoma in the cardia; after a direct hemi-circumferential incision (and submucosal dissection) of the upper part visible in the distal esophagus; the distal part of the lesion is resected from the stomach, with the endoscope in retroflexion. Of course all tumors resected at endoscopy should be carefully stretched in a cardboard before fixation for study by the pathologist.

Surgical treatment

The indications for surgery in the treatment of adenocarcinoma at the EG junction were described by Siewert with respect to 3 categories of tumors: type I for adenocarcinoma in the distal esophagus, type II for adenocarcinoma in the cardia, and type III for gastric subcardia adenocarcinoma infiltrating the EG junction. The treatment proposed varies with the type: transthoracic esophagectomy for type I, extended total gastrectomy for type II, and trans-hiatal extended gastrectomy for type III. Surgical treatment is proposed for a nonsuperficial, but localized, adenocarcinoma and for a large superficial carcinoma when the ESD technique of resection en bloc is not available.

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