High Goblet Cell Density Protects Against Progression to Adenocarcinoma in Patients with Barrett's Esophagus.
Kevin Golden, Amitabh Srivastava, Carissa A Sanchez, Pui Y Fong, Xiaohong Li, David S Cowan, Carlo Maley, Patricia L Blount, Brian J Reid, Robert D Odze. Brigham & Women's Hospital, Boston; Dartmouth Hitchcock Medical Center, Lebanon; Fred Hutchinson Cancer Center, Seattle; UCSF, San Francisco
Background: Most Barrett's esophagus (BE)-associated adenocarcinomas (BEA) develop in columnar mucosa with goblet cells (GC). However, 95% of BE patients never develop BEA. One recently proposed hypothesis states that GCs represent a potentially successful adaptive response by producing a thick mucous barrier to acidic reflux which may protect against cancer development, but this has never been tested. The aim of this study was to determine the association of GC density with risk of progression to BEA, and DNA content abnormalities, the latter of which represents a major step in the BE carcinogenic pathway.
Design: 3970 baseline mucosal biopsies from 214 BE patients enrolled in a large prospective surveillance cohort (M/F ratio:170/44, mean age: 63 yrs, mean BE segment length: 5.7 cm) all of whom had a baseline endoscopy and at least one follow-up endoscopy (mean follow up: 90.4 months), were scored in a blinded fashion, for the total # of GCs and crypts, and the # of crypts with ≥1 GC, in both dysplastic and non-dysplastic epithelium, to determine the mean # GC/crypt and the % crypts with ≥1 GC. The relationship between the GC parameters and flow cytometric abnormalities (aneuploidy, tetraploidy) was compared using Wilcoxon rank sum test, and a weighted Cox regression model was used to assess BEA risk, after adjustment for age, gender, and BE segment length.
Results: 32 patients progressed to cancer during follow up. Increased GCs in baseline biopsies were significantly associated with protection from BEA when analyzed for total # of GCs, mean # GC/crypt, # crypts ≥1 GC and % crypts ≥1 GC (p<0.0001 for each comparison). GCs in non-dysplastic biopsies were similarly significant for a protective association in all comparisons (p= 0.007, 0.016, 0.0070 and 0.016, respectively). High GC values in all crypts showed a significantly lower association with aneuploidy (p=0.0016), ploidies (>2.7N; p=0.0061), and tetraploidy (elevated 4N≥6%; p=0.0015).
Conclusions: The results of this study show, for the first time, that GC have a protective effect on progression to BEA, and on the development of flow cytometric DNA content abnormalities. GC may participate in mucosal defense and represent a successful adaptative response to carcinogenesis in BE.
Tuesday, March 1, 2011 8:30 AM
Platform Session: Section E, Tuesday Morning