Preoperative Chemoradiotherapy Alters the Expression and Prognostic Significance of Adhesion Molecules in Barrett' s-Associated Adenocarcinoma JERROLD R. TURNER, MD, PHD, CARLOS M. TORRES, MD, HELEN H. WANG, MD, MPH, ALl SHAHSAFAEI, WILLIAM G. RICHARDS, PHD, DAVID SUGARBAKER, MD, AND ROBERT D. ODZE, MD, FRCPC A variety of prognostic markers have been related to decreased patient survival in patients with epithelial nmfignancies. These include expression of the homotypic adhesion molecule E-cadherin (ECAD) and the hyalu~onlc acid receptor CD44. Expression of ECAD and CD44 was evaluated in Barrett's-associated adenocarcinoma (BAd) from 67 patients. Expression was determined by immunoperoxidase staining and graded semiquantitatively based on the proportion of positively stained cells. These data were then correlated with clinical and pathological parameters, including the presence or absence of chemoradiotherapy (chemrad) and patient survival. There were 56 men and 11 women (mean age, 62 years). Thirty-nine (58%) patients received preoperative chemrad. ECAD expression was detected in all (100%) tumors. The ECAD staining grade did not correlate with other pathological features of the tumors. However, ECAD staining was significantly increased in BAd of patients who received chemrad (P = .003)i in comparison with those who did not, and in individual patients when prechemrad biopsies and postchemrad resection speci- mens were compared (P = .04). In terms of prognosis, increased ECAD expression was associated with shortened patient survival only in BAd patients who had received chemrad (univariate analysis of chemrad patients with stage I and II BAd, P = .02). ECAD expression was not significantly associated with survival in BAd patients who did not receive chemrad. CD44 expression was detected in 88% of cases. CD44 expression did not correlate with any of the pathological features of the tumors or with chemrad status. Increased expression of CD44 was significantly associated with shortened patient survival in chemrad patients only lunivariate analysis P = .03, multivan'ate analy- sis P = .04), although a strong trend was observed when all patients were analyzed regardless of chemrad status (P = .07). The results of this study indicate that chemrad alters the expression of ECAD in BAd. Thus, the prognostic utility of ECAD expression must be evaluated in the context of chemrad status. CD44 also may be a valuable prognostic marker in BAd. HUM PATHOL 31:347-353. Copyright © 2000 byW.B. Saunders Company Key words: esophagus, adhesion proteins, preoperative chemora- diotherapy, prognostic factors, survival. Abbreviations: BAd, Barrett's-associated adenocarcinoma; chem- rad, chemoradiotherapy; ECAD, E-cadherin. Tumor metastases occur via a progressive stepwise process. To metastasize, neoplastic cells must detach from adjacent cells, enter and exit the circulation, and grow at distant tissue sites. Regulation of cell adhesion via surface membrane adhesion molecules is integral to this process. Well-characterized adhesion molecules that have been implicated in tumor metastasis include proteins of the cadherin family, such as E-cadherin (ECAD), and the hyaluronic acid receptor CD44. Cal- cium-dependent adhesion between extracellular do= mains of ECAD on the surface of epithelial cells form homotypic intercellular adherens junctions) The cyto- plasmic domain of ECAD associates with 0t-, [3-, and From the Departments of Pathology and Surgery, Brigham and Women's Hospital, Boston. MA: the Department of Pathology, Beth Israel Deaconess Medical Center, Boston. MA; Harvard Medical School. Boston. MA: and the Department of Pathology, Wayne State University School of Medicine, Detroit, ML Accepted for publication November 22, 1999. Supported by the National Institutes of Health (NIDDK) DK02503 (J.R.T.). Presented in part at the 1998 annual meeting of the United States and Canadian Academv of Pathology, Boston, MA. Address correspondence and reprint requests to Jerrold R. Turner. Wayne State University School of Medicine• 9245 Scott Hall, 540 E Canfield. Detroit. MI 48201. Copyright © 2000 by W.B. Saunders Company 0046-8177/00/3103-0013510.00/0 doi: 10.1053/hp.2000.5210 y-catenins. 2 This links the adherens junction to the actin cytoskeleton and is the likely mechanism of signal transduction via the ECAD pathway. Increased ECAD expression has been associated with improved survival in several epithelial malignancies)a and germline muta- tion of ECAD has been associated with familial gastric cancer. 5 The transmembrane glycoprotein CD44 is one of the primary cell-matrix adhesion proteins. 6 The extracel- lular domain of CD44 interacts with hyaluronic acid and collagen,7,8 whereas the cytoplasmic domain interacts with microfilaments through a variety of linker proteins that may modulate both CD44 surface expression and function. Several variant CD44 isoforms are formed as a result of differential mRNA splicing of specific exons. However, the in vivo biological significance and differen- tial functions of these is0fOrms are unknown. Increased expression of both total CD44 and various CD44 iso- forms has been associated with decreased patient sur- vival in lymphomas and epithelial malignancies.9-1° The prognostic significance of ECAD and CD44 expression in Barrett's-associated esophageal adenocar- cinoma (BAd) is controversial. Furthermore, the signifi- cance of ECAD and CD44 expression in BAd patients who have received preoperative chemoradiotherapy (chemrad), an increasingly common form of neoadju- rant therapy, has not been critically evaluated. There- 347