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Cancer of the Esophagogastric Junction: classification and etiology.

Romeo Giuli MD,resident.
School of General and Emergency Surgery.
University of Siena.   Italy.

June 2001.     Review Article.

During recent decades there has been an alarming rise in the incidence and prevalence of the adenocarcinoma of the esophagogastric junction in the Western world, in contrast to the decreasing prevalence of gastric cancer. Primarily it is the consequence of an increase in the rate of adenocarcinoma of the distal esophagus.
In addition the locations of gastric tumors is shifting from the distal portion of the stomach to the proximal stomach and the gastric cardia.

The optimal surgical approach needs a clear definition and classification of these tumors.
Some authors classify tumors arising at or close to the esophagogastric junction as esophageal carcinomas, others define them as gastric carcinomas and yet others consider them as an entity separate from esophageal and gastric cancer.
Stein, Feith and Siewert define adenocarcinoma of the esophagogastric junction as tumours which have their center within 5 cm proximal or distal to the anatomical cardia and have differentiated three distinct tumour entities within this area:

AEG type I: adenocarcinoma of the distal esophagus usually arises from an area with specialized intestinal metaplasia of the esophagus, ie, Barrett's esophagus, and may infiltrate the esophagogastric junction from above.

AEG type II: true carcinoma of the cardia arises from the cardiac epithelium or short segments with intestinal metaplasia at the esophagogastric junction.

AEG type III: subcardial gastric carcinoma infiltrates the esophagogastric junction and distal esophagus from below.

This classification is purely morphological, and it is based on the anatomical location of the tumour center or in patients with advanced tumours the location of the tumour mass.
The diagnostic itinerary includes a combination of contrast radiogram, endoscopy with orthograde and retroflexed view of the esophagogastric junction, computer tomography and intraoperative observations.
At the consensus conference during the second international gastric cancer congress held in Munich in April 1997 this classification was approved ( 1 ).

A series of observations in the recent literature provides justification for such a differentiation:

there is a more marked preponderance of male sex in patients with type I tumours than in those with type II or III tumours.

Patients with type I tumour are more likely to have hiatal hernia and a long history of gastro esophageal reflux disease, compared with patients with type II or III tumours.

The so called Barrett's esophagus with subsequent development of progressively severe dysplastic changes is the main precursor lesion for adenocarcinoma in the distal esophagus ( found in more than 80% of patients).
Type II and III tumours may also arise from short segments of intestinal metaplasia at or below the cardia, but it happens in less than 40 per cent of patients with carcinoma of the cardia and in less than 10 per cent of those with subcardial carcinoma. There is a strong association between Helicobacter Pylori and intestinal metaplasia at or below the gastric cardia on the contrary the specialized intestinal metaplasia in the distal esophagus is refluxed related.
Furthermore dysplasia seems to be an infrequent phenomenon in areas of intestinal metaplasia at or below the cardia.

The prevalence of undifferentiated tumors and tumors with a non-intestinal growth pattern is rather low in AEG type I tumors and increases significantly from AEG type II to III tumors.

The expression of cytokeratins and cell adhesion molecules and the prevalence and pattern of genetic abnormalities show marked differences between the three AEG tumor types.

The various tumor entities have a different pattern of lymphatic spread: the main lymphatic pathways originating in the lower esophagus advance both cephalad into the mediastinum and caudad along the celiac axis, and those from the gastric cardia and subcardial region make their way to the celiac axis, the splenic hilum and the paraortic lymph nodes ( 2 ).

Further the prevalence of lymph node micrometastases in early tumor stages differ between type I and type II and III tumours ( 3 ). The rate of MM is more than three times greater in the patients with AEG II and AEG III tumors compared with patients with AEG I tumors (24% vs 7%). More importantly the finding of MM in the tumors of the patients with adenocarcinoma of the cardia or the subcardia has a negative prognostic impact that is similar to the finding of tumor cells by routine methods, whereas TCM alone has no such impact on patients prognosis. In contrast no negative prognostic impact for either TCM or MM has been seen in patients with AEG I tumors ( 7 ). Moreover the mucosal and submucosal cardia tumors have a 25% incidence of nodal metastases in comparison to a zero incidence for their esophageal counterparts ( 8 ).

Finally the activity of tumor metabolism on positron emission tomography markedly differ between type I and type II and III tumors ( 3 ). In fact FDG-PET scanning improves the clinical staging of lymph node involvement based on the increased detection of distant metastases and on the superior specificity compared with conventional imaging modalities. The mainstay of clinical staging is CT combined with EUS. However the accuracy of CT and EUS is far from optimal because it can both overstage and understage lymph nodes ( 9 ).

All these observations mean a possible heterogeneity in the pathogenesis and biological behaviour of adenocarcinomas arising in the proximity of the esophagogastric junction.
This classification provides a system for studying these mechanisms in more detail for defining treatments of such tumors ( 2 ).

Kodera et al show that a striking difference in the frequency of adenocarcinoma of the gastroesophageal junction exists between Japan and the West. Type I is unlikely to be included in the data concerning carcinoma of the gastroesophageal junction in Japan, but it may constitute up to one-third of the patients with this disease in the west.
At the same time the shift form the distal to proximal lesions, well documented in the West, has not been observed in Japan ( 4 ).
Moreover the incidence of early cardia carcinoma is very low in Japan, and obesity, smooking, drinking, Barrett esophagus, or GERD are not related to its occurrence, in contrast to reports in the West (10 ).


1) HJ Stein, M Feith, JR Siewert. Cancer of the esophagogastric junction. Surgical Oncology 9 (2000) 35-41.

2) JR Siewert, HJ Stein. Classification of the adenocarcinoma of the oesophagogastric junction. British Journal Surgery 1998, 85, 1457-1459.

3) JR Siewert, M Feith, M Werner and HJ Stein. Adenocarcinoma of the esophagogastric junction. Annals of Surgery, vol 232, n3 , 353-361; 2000.

4) Y Kodera, Y Yamamura, Y Shimuzu, A Torii, T Hirai, K Yasui, T Morimoto, T Kato. Adenocarcinoma of the gastroesophageal junction in Japan : relevance of Siewert's classification applied to 177 cases resected at a single institution. J Am Coll Surg 1999; 189:594-601.

5) BPL Wijnhoven, PD Siersema, WCJ Hop, H van Dekken and HW Tilanus on behalf of the Rotterdam Oesophageal Tumour Study Group. Adenocarcinoma of the distal oesophagus and gastric cardia are one clinical entity. British Journal Surgery 1999, 86, 529-535.

6) HJ Stein, A Sendler, U Fink and JR Siewert. Multidisciplinary approach to esophageal and gastric cancer. Surgical Clinics of North America. Vol 80 number 2 April 2000, 659-681.

7) J Mueller, H Stein, T Oyang, S Natsugoe, M Feith, M Werner, JR Siewert. Frequency and clinical impact of lymph node micrometastasis and tumor cell microinvolvement in patients with adenocarcinoma of the esophagogastric junction. Cancer 2000; 89: 1874-82.

8) SM Dresner, PJ Lamb, MK Bennett, N Hayes,SM Griffin. The pattern of metastatic lymph node dissemination from adenocarcioma of the esophagogastric junction. Surgery 2001; 129: 103-9.

9) T Lerut et al. Histopathologic validation of limph node staging with FDG-PET scan in cancer of the esophagus and gastroesophageal junction. Annals of Surgery 2000; 232,(6), 743-752.

10) T Okabayashi et al. Early carcinoma of the gastric cardia in Japan. Cancer 2000; 89: 2555-9.

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