title: The dichotomy in carcinogenesis of the distal esophagus and esophagogastric junction: intestinal-type vs cardiac-type mucosa-associated adenocarcinoma.
abstract: Adenocarcinoma of the distal esophagus and esophagogastric junction continues to rise in incidence. An intestinal metaplasia (Barrett esophagus)-dysplasia-carcinoma sequence induced by gastroesophageal reflux disease is well established. However, a significant number of adenocarcinomas in the vicinity of the esophagogastric junction are seen in the background of gastric/cardiac-type mucosa without intestinal metaplasia. Thus, the aim of this study was to investigate the role of Barrett esophagus (intestinal-type mucosa) in the classification and prognosis of tumors of the distal esophagus and esophagogastric junction. Clinicopathological and molecular characteristics were examined in 157 consecutively resected adenocarcinomas of the distal esophagus and esophagogastric junction and were compared between tumors arising in association with intestinal-type and cardiac-type mucosa. Intestinal-type mucosa-associated adenocarcinomas were more likely to be associated with younger age (P=0.0057), reflux symptoms (P<0.0001), proximal location (P=0.0009), lower T stage (P<0.0001), fewer nodal metastases (P=0.0001), absence of lymphatic (P<0.0001), venous (P=0.0060) or perineural (P<0.0001) invasion. Histologically, intestinal-type mucosa-associated tumors were more likely to be low-grade glandular tumors (P=0.0095) of intestinal or mixed immunophenotype (P=0.015) and express nuclear β-catenin (P=0.0080), whereas tumors arising in a background of cardiac-type mucosa were more frequently associated with EGFR amplification (P=0.0051). Five-year overall survival rate was significantly higher in patients with intestinal-type mucosa-associated tumors (28 vs 9%, P=0.0015), although no survival benefit was seen after adjusting for potential confounders. Our findings support the theory that multiple distinct pathways of tumorigenesis exist in the vicinity of the esophagogastric junction, including one in which tumors arise from dysplastic intestinal metaplasia (intestinal pathway), and one potentially involving dysplasia of the cardiac-type mucosa (non-intestinal pathway). Additional studies are warranted to further clarify their pathogenesis and the molecular mechanisms involved.
authors.affiliation: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Demicco
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.forename: Yoshifumi
authors.initials: Y
authors.lastname: Baba
authors.forename: Brian
authors.initials: B
authors.lastname: Agbor-Etang
authors.forename: Kristin
authors.initials: K
authors.lastname: Bergethon
authors.forename: Rajni
authors.initials: R
authors.lastname: Mandal
authors.forename: Diane
authors.initials: D
authors.lastname: Daives
authors.forename: Junya
authors.initials: J
authors.lastname: Fukuoka
authors.forename: Michio
authors.initials: M
authors.lastname: Shimizu
authors.forename: Dora
authors.initials: D
authors.lastname: Dias-Santagata
authors.forename: Shuji
authors.initials: S
authors.lastname: Ogino
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Henning A
authors.initials: HA
authors.lastname: Gaissert
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001471:Barrett Esophagus / Q000150:complications / Q000401:mortality / Q000473:pathology*; D002299:Cardia / Q000473:pathology; D004938:Esophageal Neoplasms / Q000401:mortality / Q000473:pathology*; D004943:Esophagogastric Junction / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000473:pathology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions / Q000150:complications / Q000401:mortality / Q000473:pathology; D013274:Stomach Neoplasms / Q000401:mortality / Q000473:pathology*; D046888:Tissue Array Analysis