Little is known regarding the significance of esophageal biopsies that show dysplasia-like atypia limited to the bases of the crypts, without involvement of the surface epithelium in
Barrett's esophagus (BE). The aim of this study was to evaluate the clinical, pathologic, immunohistochemical, and molecular characteristics of basal crypt dysplasia-like atypia (
BCDA) with surface maturation in surveillance endoscopic mucosal biopsies to gain insight into its
biologic significance. The Seattle
Barrett's Esophagus Project is a prospective cohort study in which patients and their biopsies have been evaluated prospectively for clinical, pathologic, and molecular markers. As part of continued surveillance of the cohort, 206 consecutive BE patients were evaluated prospectively for
BCDA between July 1, 2001 and August 13, 2003; 15 patients had
BCDA (prevalence rate = 7.3%). These 15 patients were evaluated for clinical, pathologic, and immunohistochemical (p53 and MIB-1) features during the study period (2001-2003) as well as associations with clinical, pathologic, and molecular markers [17p(TP53) loss of heterozygosity (LOH), 9p(p16) LOH,
tetraploidy, and
aneuploidy] that were detected previously in the same patients in the cohort study (1983-2001). All BE patients with
BCDA (male-to female ratio, 12:3; mean age, 72 years; mean length of BE, 7.0 cm; mean duration of BE, 95.1 months), except 2 (87%), had dysplasia or
adenocarcinoma detected in biopsies either prior to or concurrent to the one that contained
BCDA. In contrast, only 112 of 191 (59%) controls had
neoplasia during the same time period (59%, P = 0.05). The difference between
BCDA and controls was particularly significant with regard to the association with high-grade dysplasia (P = 0.004). Compared with adjacent nonatypical and nondysplastic (metaplastic) BE, areas of
BCDA showed a significantly elevated prevalence rate of p53 positivity (60% vs. 13%, P<0.02) and a significantly elevated total crypt and basal crypt MIB-1 proliferation rate (P<0.001). Indeed, the MIB-1 proliferation rate in the basal portion of the crypts in
BCDA was similar to that detected in conventional low- or high-grade dysplasia. Patients with
BCDA showed a significantly increased rate of 17p(TP53) LOH (P = 0.016),
aneuploidy (P = 0.004), and a trend in increased 9p(p16) LOH (P = 0.08), compared with control patients without
BCDA. The clinical, pathologic, immunohistochemical, and molecular abnormalities were similar in
BCDA cases that were considered low-grade versus those considered high-grade by histologic evaluation, except that high-grade cases tended to be older (79 years vs. 68 years, P = 0.06).
BCDA with surface maturation, in mucosal biopsies from patients with BE, is an uncommon but significant pathologic change that shows a variety of proliferative and molecular abnormalities and has a high association with conventional dysplasia and/or
adenocarcinoma. Based on these findings,
BCDA warrants further investigation as a possible subtype of true dysplasia despite the morphologic appearance of surface maturation.