Proliferative Characteristics of Intestinalized Mucosa in the Distal Esophagus and Gastroesophageal Junction (Short-Segment Barrett's Esophagus): A Case Control Study JAMES M. GULIZIA, MD, HELEN WANG, MD, DONALD ANTONIOLI, MD, STUARTJ. SPECHLER, MD, JOHN ZEROOGIAN, MD, RAJ GOYAL, MD, ALl SHAHSAFAEI,YEN YI CHEN, MD, AND ROBERT D. ODZE, MD, FRCPC Intestinalized epithelium in traditional long-segmeut Barrett's esophagus (BE) shows increased proliferative activity, which is postu- lated to be an early step in the metaplasia-dysplasia-carcinoma sequence. The aim of this study was to evaluate the proliferative activity of intestinalized epithelium of the distal esophagus and gastroesophagealjunction (IMEGEJ). Tissue sections from 78 consecu- tive patients (20 with IMEGEJ, 58 without IMEGEJ) who had elective upper gastrointestinal endoscopy over a 6-month period were immu- nohistochemically stained with MIB-1, the Ki-67 proliferation-antigen- associated marker, for evaluation of the crypt MIB-1 proliferation index (PI), size of the proliferative zone (PZ), and the presence of surface epithelial staining. Data from the IMEGEJ and non-IMEGEJ groups, and from 15 age-matched patients with traditional long- segment BE (>3.0 cm), were compared statistically. IMEGEJ patients showed a statistically significant increase in the mean crypt PI compared with non-IMEGEJ controls (21.9 -+ 19.5 v 14.3 -+ 9.3; P = .01). In addition, IMEGEJ cases showed an increase in the mean crypt PZ (52.3 -+ 16.4 v 45.2 -+ 17.2; P = .05), and a trend toward an increase in the percentage of cases with MIB-l-positive surface epithelial cells (50% v 33%, P = .18). Patients with IMEGEJ did not differ from patients without IMEGEJ with respect to any other clinical or histological feature, including signs or symptoms of gastroesopha- geal reflux disease and presence or absence of esophagitis or carditis. The MIB-I results of the patients with long-segment BE (MIB-1 PI = 22.6 -4- 20.5, MIB-1 PZ = 51.8 -+ 19.6, proportion of cases with MIB-l-positive surface cells = 66%) were similar to those with IMEGEJ. Intestinalized epithelium in the distal esophagus or gastro- esophageal junction shows increased proliferative activity in compari- son with patients without intestinalized epithelimn. This finding supports an increased risk of carcinogenesis in patients with IMEGEJ. HUM PATHOL 30:412-418, 1999. Copyright © 1999 by W.B. Saunders Company Key words: Barrett's esophagus, MIB-1, carditis, intestinal metapla- sia, gastroesophageal reflux. Abbreviations: BE, Barrett's esophagus; IMEGEJ, intestinal meta- plasia of the distal esophagus or gastroesophageal junction; GEJ, gastroesophageal junction; PI, proliferation index; PZ, proliferative zone; PCNA, proliferating cell nuclear antigen. Barrett's esophagus (BE) is a well-known premalig- nant condition and has been previously defined as greater than 2 to 3 cm of columnar epithelium in the distal esophagus. 14 Many studies have shown that carci- nogenesis occurs through a progressive sequence of cell cycle and proliferative abnormalities that eventually lead to dysplasia and adenocarcinoma. 4-8 Of the three common types of columnar metaplasia, cardia, fundic, and specialized (intestinal) type, the latter is the most common and clinically important, because dysplasia and carcinoma are invariably associated with intestinal type metaplasia. 1,2,9Consequently, the presence of intes- tinal metaplasia, characterized by goblet cells, has become the most recent definition of"Barrett's esopha- gus," regardless of the length of columnar epithe- lium. 2,1° However, most of our information regarding the neoplastic potential of BE is based on studies of patients who have endoscopically obvious long seg- From the Departments of Pathology, Brigham & Women's Hospi- tal and Beth Israel Deaconess Medical Center, the Department of Medicine, Beth Israel Deaconess Medical Center, and Harvard Medi- cal School, Boston, MA. Accepted for publication November 6, 1998. Presented in part at the 1998 Annual Meeting of the USCAP, Boston, MA. Address correspondence and reprint requests to Robert D. Odze, MD, FRCPC, Brigham & Women's Hospital, Department of Pathol- ogy, 75 Francis St, Boston, MA 02115. Copyright © 1999 by W.B. Saunders Company 0046-8177/99/3004-0009510.00/0 ments (>2 to 3 cm) of columnar epithelium lining the distal esophagus. 9 Intestinal metaplasia shown on microscopic sec- tions in patients with no or less than 3 cm of columnar epithelium in the distal esophagus are being recognized with increasing frequency. 2&aa,12 This condition has been referred to as short-segment BE. The prevalence rate for this condition varies between 7% and 20% of patient populations undergoing endoscopy. 2,3,n-1~ Be- cause the definition of short-segment BE varies among investigators, and strict endoscopic criteria to diagnose this condition have not been defined, some authors have recommended that the term "intestinal metapla- sia of the distal esophagus or gastroesophageal junc- tion" (IMEGEJ) be used to describe this condition. 6,1° Use of this term is also supported by the fact that it is still unclear weather IMEGEJ and intestinal metaplasia of the proximal gastric cardia are pathogenetically related entities. Regardless of the term used, evidence is accumulating to suggest that the pathological finding of IMEGEJ is associated with an increased risk of neoplas- tic change both in the distal esophagus and the gastro- esophageal junction (GEJ).14-20 Recent reports by Wes- ton et al 2° and Sharma et aP 7 suggest a prevalence rate of dysplasia in IMEGEJ of 8% to 9%. 17,2° Adenocarci- noma also can also develop in IMEGEJ. 14,16 In fact, some investigators believe that most GEJ adenocarcinomas, a tumor that is showing an alarming recent increase in incidence in the Western world, arise in a background 412