LETTER TO THE EDITOR Should Adenocarcinoma of the Esophagogastric Junction Be Classified as Gastric or Esophageal Cancer, or Else as a Distinct Clinical Entity? To the Editor: read with great interest the article by Suh and colleagues,1 titled “Should Adenocarcinoma of the Esophagogastric Junction Be Classified as Esophageal Cancer? A Comparative Analysis According to the Seventh AJCC TNM Classification.” Adenocarcinoma of the esophagogastric junction (AEJ) continues to receive great attention from the scientific community for its constant rise in incidence and unclear cause(s) and for controversies regarding its classification, staging, and treatment. The recently introduced AJCC TNM classification radically changed the categorization of AEJ. According to the seventh edition of the AJCC TNM classification, all tumors located within 5 cm below the anatomic esophagogastric junction (EGJ) and infiltrating the junction have to be classified as esophageal cancers. Accordingly, Siewert type II and III tumors are considered and staged as esophageal cancers. Suh and colleagues, after analyzing 497 AEJ patients and 4027 patients with gastric cancer (GC), recommended the integration of Siewert type II and III tumors into gastric AEJ and proposed to consider type II and III AEJ as part of GC irrespective of the EGJ involvement. Looking at this study, some considerations should be made about the differences in clinicopathological characteristics, long-term results, and surgical approach observed among AEJ case series with respect to their geographic area of provenience.
I
CLINICOPATHOLOGICAL CHARACTERISTICS In the study by Suh and colleagues, AEJ represented 11% of cases. Such a frequency is comparable with data reported by Japanese and other Far Eastern series, yet lower than data from Continental Europe and even lower than data from the United Kingdom and the United States. Furthermore, further differences are evident: no type I AEJ was operated on during the study period, type
Disclosure: The author declares no conflicts of interest. C 2014 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/14/26104-e0107 DOI: 10.1097/SLA.0000000000000524
II tumors represented less than 30%, and type III tumors represented the vast majority. In Western series, Siewert type I and II tumors are much more represented, being largely predominant in studies from the United Kingdom and the United States. Type I AEJ has epidemiological and histological characteristics virtually identical to distal esophageal adenocarcinoma, with almost every case associated with Barrett’s esophagus. Conversely, type III AEJ resembles noncardia GC, with similar rate of intestinal and diffuse types and a strong association with Heliobacter pylori infection. Type II AEJ shows epidemiological and histological characteristics across esophageal and gastric adenocarcinoma. Both intestinal and diffuse types are observed, with intestinal tumors being both associated with Barrett’s esophagus and H. pylori–induced atrophic gastritis and intestinal metaplasia and diffuse tumors associated with H. pylori–induced Ecadherin mutation. These considerations may reflect the epidemiological and histological differences observed in type II tumors between Eastern and Western series. Whereas in Korea, Japan, and other Far Eastern countries, type II AEJ seems to relate to the same causative/causal factors of noncardia GC in countries where gastroesophageal reflux disease and obesity are widespread (ie, United Kingdom, United States, and Northern Europe), reflux-induced metaplasia-dysplasiacarcinoma sequence represents the main path to type II AEJ. Probably, in countries such as Italy, Germany, and France, where Barrett’s esophagus is less common and GC is still present, both H. pylori– and reflux-induced metaplasia represent important causes of type II AEJ. The lack of differences in main clinicopathological characteristics demonstrated by Suh and colleagues between AEJ and GC and between type II and III AEJ matches perfectly with this hypothesis. Similar is the reported percentage of diffuse-type tumors.
LONG-TERM SURVIVAL RESULTS In keeping with previous Japanese and Korean studies, comparable survival rates for AEJ and GC were reported by Suh and colleagues. Interestingly, the survival rates for type II and III AEJ are more than 3-fold higher than those usually reported in Western series on AEJ and more than 2-fold higher than those reported on GC. The authors justified this difference in relation to a more advanced stage of the disease, an insufficient abdominal lymph node clearing, and a higher propensity to transthoracic approach of Western series. Regarding the stage of the disease, the percentage of early cancers is definitively high (38%), as is the number of node-negative tumors (59%). However, looking at the stage-
Annals of Surgery r Volume 261, Number 4, April 2015
by-stage comparison, significant differences remain evident.2 In our experience, as in other experiences from Continental Europe and the United Kingdom, despite an adequate mediastinal and abdominal lymphadenectomy, the chance of cure for node-positive patients is limited to cases with a small number of perigastric metastatic lymph nodes.3 If we assume that in Korea, AEJ shares with GC long-term results, clinicopathological characteristics, and causative/causal factors, the differences in long-term results observed in Western series may be related to the already described geographic variability in incidence, histological features, and prognosis of GC.4 Positive H. pylori status has been demonstrated to be extremely high in patients with GC in Far Eastern countries (>90%). We recently confirmed the results reported by Meimarakis and colleagues5 that negative H. pylori status correlates with a poor prognosis and is more frequently observed in type II and III AEJ.6 These features together with the possible different cause(s) of “certain” type II tumors may partly explain the huge difference in survival observed for AEJ between Eastern and Western series.
SURGICAL APPROACH It is almost accepted that type I AEJ is treated as a distal esophageal carcinoma and type III AEJ as a gastric carcinoma, whereas the treatment of type II AEJ is still greatly debated. No differences in long-term results have been demonstrated for type II AEJ in 2 randomized, multicenter, controlled studies; the first comparing extended transthoracic versus transhiatal esophagegtomy in a Dutch trial,7 the second comparing total gastrectomy plus distal esophagectomy performed through a left thoracoabdominal approach versus an abdominal transhiatal approach in a Japanese trial.8 The possibility of achieving a potentially curative resection with adequate clear proximal margins in type III and type II AEJ with no evidence of Barrett’s esophagus has been demonstrated to be quite high through an abdominal transhiatal approach.9 Unfortunately, the study by Suh and colleagues did not analyze the extent of gastric and esophageal resection or the extent of esophageal involvement that required a transthoracic approach to be clearly resected. Seemingly, the extent of mediastinal lymph node dissection was not specified. Probably, the surgical approach in type II AEJ should be based on the stage of the disease, the length of invasion of the esophagus and stomach, and the probable origin of the tumor (ie, esophageal vs gastric).
CONCLUSIONS Tumors arising in proximity of the EGJ show peculiar cause(s), clinicopathological www.annalsofsurgery.com | e107
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 4, April 2015
Letter to the Editor
characteristics, and long-term results, with type II AEJ representing the most complex and composite type. These figures seem to vary greatly between Eastern and Western series. The aforementioned hypothesis on 2 possible origins of type II AEJ may help explain this difference. The adoption of a specific classification and staging system for tumors involving the EGJ should be encouraged with the aim of reaching a clear and final definition. Corrado Pedrazzani, MD Divisione di Chirurgia Generale Ospedale S. Maria del Carmine APSS Trento, Italy [email protected] [email protected]
e108 | www.annalsofsurgery.com
REFERENCES 1. Suh YS, Han DS, Kong SH, et al. Should adenocarcinoma of the esophagogastric junction be classified as esophageal cancer? A comparative analysis according to the seventh AJCC TNM classification. Ann Surg. 2012;255: 908–915. 2. Gertler R, Stein HJ, Langer R, et al. Long-term outcome of 2920 patients with cancers of the esophagus and esophagogastric junction. Evaluation of the new Union Internationale Contre le Cancer/American Joint Cancer Committee staging system. Ann Surg. 2011;253:689–698. 3. Pedrazzani C, de Manzoni G, Marrelli D, et al. Lymph node involvement in advanced gastroesophageal junction adenocarcinoma. J Thorac Cardiovasc Surg. 2007;134:378–385. 4. Marrelli D, Pedrazzani C, Corso G, et al. Different pathological features and prognosis in gastric cancer patients from high-risk and low-risk areas of Italy. Ann Surg. 2009;250:43–50.
5. Meimarakis G, Winter H, Assmann I, et al. Helicobacter pylori as a prognostic indicator after curative resection of gastric carcinoma: a prospective study. Lancet Oncol. 2006;7:211–222. 6. Marrelli D, Pedrazzani C, Berardi A, et al. Negative Helicobacter pylori status is associated with poor prognosis in patients with gastric cancer. Cancer. 2009;115:2071–2080. 7. Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1162–1169. 8. Sasako M, Sano T, Yamamoto S, et al. Left thoracoabdominal approach versus abdominaltranshiatal approach for gastric cancer of the cardia or subcardia: a randomized controlled trial. Lancet Oncol. 2006;7:644–651. 9. Barbour AP, Rizk NP, Gonen M, et al. Adenocarcinoma of the gastroesophageal junction. Influence of esophageal resection margin and operative approach on outcome. Ann Surg. 2009;246:1–8.
C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
I
CLINICOPATHOLOGICAL CHARACTERISTICS In the study by Suh and colleagues, AEJ represented 11% of cases. Such a frequency is comparable with data reported by Japanese and other Far Eastern series, yet lower than data from Continental Europe and even lower than data from the United Kingdom and the United States. Furthermore, further differences are evident: no type I AEJ was operated on during the study period, type
Disclosure: The author declares no conflicts of interest. C 2014 Wolters Kluwer Health, Inc. All Copyright rights reserved. ISSN: 0003-4932/14/26104-e0107 DOI: 10.1097/SLA.0000000000000524
II tumors represented less than 30%, and type III tumors represented the vast majority. In Western series, Siewert type I and II tumors are much more represented, being largely predominant in studies from the United Kingdom and the United States. Type I AEJ has epidemiological and histological characteristics virtually identical to distal esophageal adenocarcinoma, with almost every case associated with Barrett’s esophagus. Conversely, type III AEJ resembles noncardia GC, with similar rate of intestinal and diffuse types and a strong association with Heliobacter pylori infection. Type II AEJ shows epidemiological and histological characteristics across esophageal and gastric adenocarcinoma. Both intestinal and diffuse types are observed, with intestinal tumors being both associated with Barrett’s esophagus and H. pylori–induced atrophic gastritis and intestinal metaplasia and diffuse tumors associated with H. pylori–induced Ecadherin mutation. These considerations may reflect the epidemiological and histological differences observed in type II tumors between Eastern and Western series. Whereas in Korea, Japan, and other Far Eastern countries, type II AEJ seems to relate to the same causative/causal factors of noncardia GC in countries where gastroesophageal reflux disease and obesity are widespread (ie, United Kingdom, United States, and Northern Europe), reflux-induced metaplasia-dysplasiacarcinoma sequence represents the main path to type II AEJ. Probably, in countries such as Italy, Germany, and France, where Barrett’s esophagus is less common and GC is still present, both H. pylori– and reflux-induced metaplasia represent important causes of type II AEJ. The lack of differences in main clinicopathological characteristics demonstrated by Suh and colleagues between AEJ and GC and between type II and III AEJ matches perfectly with this hypothesis. Similar is the reported percentage of diffuse-type tumors.
LONG-TERM SURVIVAL RESULTS In keeping with previous Japanese and Korean studies, comparable survival rates for AEJ and GC were reported by Suh and colleagues. Interestingly, the survival rates for type II and III AEJ are more than 3-fold higher than those usually reported in Western series on AEJ and more than 2-fold higher than those reported on GC. The authors justified this difference in relation to a more advanced stage of the disease, an insufficient abdominal lymph node clearing, and a higher propensity to transthoracic approach of Western series. Regarding the stage of the disease, the percentage of early cancers is definitively high (38%), as is the number of node-negative tumors (59%). However, looking at the stage-
Annals of Surgery r Volume 261, Number 4, April 2015
by-stage comparison, significant differences remain evident.2 In our experience, as in other experiences from Continental Europe and the United Kingdom, despite an adequate mediastinal and abdominal lymphadenectomy, the chance of cure for node-positive patients is limited to cases with a small number of perigastric metastatic lymph nodes.3 If we assume that in Korea, AEJ shares with GC long-term results, clinicopathological characteristics, and causative/causal factors, the differences in long-term results observed in Western series may be related to the already described geographic variability in incidence, histological features, and prognosis of GC.4 Positive H. pylori status has been demonstrated to be extremely high in patients with GC in Far Eastern countries (>90%). We recently confirmed the results reported by Meimarakis and colleagues5 that negative H. pylori status correlates with a poor prognosis and is more frequently observed in type II and III AEJ.6 These features together with the possible different cause(s) of “certain” type II tumors may partly explain the huge difference in survival observed for AEJ between Eastern and Western series.
SURGICAL APPROACH It is almost accepted that type I AEJ is treated as a distal esophageal carcinoma and type III AEJ as a gastric carcinoma, whereas the treatment of type II AEJ is still greatly debated. No differences in long-term results have been demonstrated for type II AEJ in 2 randomized, multicenter, controlled studies; the first comparing extended transthoracic versus transhiatal esophagegtomy in a Dutch trial,7 the second comparing total gastrectomy plus distal esophagectomy performed through a left thoracoabdominal approach versus an abdominal transhiatal approach in a Japanese trial.8 The possibility of achieving a potentially curative resection with adequate clear proximal margins in type III and type II AEJ with no evidence of Barrett’s esophagus has been demonstrated to be quite high through an abdominal transhiatal approach.9 Unfortunately, the study by Suh and colleagues did not analyze the extent of gastric and esophageal resection or the extent of esophageal involvement that required a transthoracic approach to be clearly resected. Seemingly, the extent of mediastinal lymph node dissection was not specified. Probably, the surgical approach in type II AEJ should be based on the stage of the disease, the length of invasion of the esophagus and stomach, and the probable origin of the tumor (ie, esophageal vs gastric).
CONCLUSIONS Tumors arising in proximity of the EGJ show peculiar cause(s), clinicopathological www.annalsofsurgery.com | e107
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
Annals of Surgery r Volume 261, Number 4, April 2015
Letter to the Editor
characteristics, and long-term results, with type II AEJ representing the most complex and composite type. These figures seem to vary greatly between Eastern and Western series. The aforementioned hypothesis on 2 possible origins of type II AEJ may help explain this difference. The adoption of a specific classification and staging system for tumors involving the EGJ should be encouraged with the aim of reaching a clear and final definition. Corrado Pedrazzani, MD Divisione di Chirurgia Generale Ospedale S. Maria del Carmine APSS Trento, Italy [email protected] [email protected]
e108 | www.annalsofsurgery.com
REFERENCES 1. Suh YS, Han DS, Kong SH, et al. Should adenocarcinoma of the esophagogastric junction be classified as esophageal cancer? A comparative analysis according to the seventh AJCC TNM classification. Ann Surg. 2012;255: 908–915. 2. Gertler R, Stein HJ, Langer R, et al. Long-term outcome of 2920 patients with cancers of the esophagus and esophagogastric junction. Evaluation of the new Union Internationale Contre le Cancer/American Joint Cancer Committee staging system. Ann Surg. 2011;253:689–698. 3. Pedrazzani C, de Manzoni G, Marrelli D, et al. Lymph node involvement in advanced gastroesophageal junction adenocarcinoma. J Thorac Cardiovasc Surg. 2007;134:378–385. 4. Marrelli D, Pedrazzani C, Corso G, et al. Different pathological features and prognosis in gastric cancer patients from high-risk and low-risk areas of Italy. Ann Surg. 2009;250:43–50.
5. Meimarakis G, Winter H, Assmann I, et al. Helicobacter pylori as a prognostic indicator after curative resection of gastric carcinoma: a prospective study. Lancet Oncol. 2006;7:211–222. 6. Marrelli D, Pedrazzani C, Berardi A, et al. Negative Helicobacter pylori status is associated with poor prognosis in patients with gastric cancer. Cancer. 2009;115:2071–2080. 7. Hulscher JB, van Sandick JW, de Boer AG, et al. Extended transthoracic resection compared with limited transhiatal resection for adenocarcinoma of the esophagus. N Engl J Med. 2002;347:1162–1169. 8. Sasako M, Sano T, Yamamoto S, et al. Left thoracoabdominal approach versus abdominaltranshiatal approach for gastric cancer of the cardia or subcardia: a randomized controlled trial. Lancet Oncol. 2006;7:644–651. 9. Barbour AP, Rizk NP, Gonen M, et al. Adenocarcinoma of the gastroesophageal junction. Influence of esophageal resection margin and operative approach on outcome. Ann Surg. 2009;246:1–8.
C 2014 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2014 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
