Soslow R A, Remotti H, Baergen R N, Altorki N K
Department of Pathology, New York Presbyterian Hospital-Weill Medical College of Cornell University, New York City 10021, USA.
Mod Pathol. 1999 Mar;12(3):239-50.
Esophageal adenocarcinoma often arises in association with metaplastic and dysplastic mucosa in Barrett's esophagus. Derangements in cell cycle control and apoptosis regulation might be responsible for the progression from metaplasia to dysplasia and adenocarcinoma We tested this hypothesis by performing cell cycle analysis, in situ detection of apoptosis, and evaluation for the immunohistochemical expression of proteins involved in proliferation (Ki-67), the control of apoptosis (bcl-2, bcl-x and bax), and cell cycle regulation (retinoblastoma and cyclin D1). We studied 17 randomly selected paraffin-embedded esophagectomy specimens that contained intestinal metaplasia without dysplasia, low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma Compared with gastric controls and intestinal metaplasia without dysplasia, high-grade dysplasia and esophageal adenocarcinoma demonstrated greater numbers of cells in S phase and G2 phase. Comparison of the proliferation index and the apoptotic rate in intestinal metaplasia without dysplasia, low-grade dysplasia, high-grade dysplasia, and esophageal adenocarcinoma showed a statistically significant trend that linked an increasing proliferation index and apoptotic rate with increasing histologic severity (P = .006 and P = .0002, respectively). A statistically significant linear association was found between bcl-x expression, bax expression, and the bcl-2-to-bax expression ratio versus increasing histologic severity (P = .0004, P = .007, and P = .03, respectively). These data support the hypothesis that neoplastic transformation of intestinal metaplastic epithelium in the esophagus might result from sequential changes in the expression of proteins involved in the control of apoptosis and the cell cycle. Furthermore, suppression of apoptosis does not seem to foster neoplastic growth in Barrett's esophagus. These observations will lead to a better understanding of the pathogenesis of esophageal adenocarcinoma and might contribute to enhancing the diagnostic accuracy when presented with dysplastic lesions.
食管腺癌常与巴雷特食管的化生和发育异常黏膜相关。细胞周期调控和凋亡调节的紊乱可能是化生发展为发育异常和腺癌的原因。我们通过进行细胞周期分析、凋亡的原位检测以及评估参与增殖（Ki-67）、凋亡控制（bcl-2、bcl-x和bax）和细胞周期调控（视网膜母细胞瘤和细胞周期蛋白D1）的蛋白质的免疫组化表达来验证这一假设。我们研究了17个随机选择的石蜡包埋食管切除标本，这些标本包含无发育异常的肠化生、低级别发育异常、高级别发育异常和食管腺癌。与胃对照和无发育异常的肠化生相比，高级别发育异常和食管腺癌在S期和G2期的细胞数量更多。比较无发育异常的肠化生、低级别发育异常、高级别发育异常和食管腺癌的增殖指数和凋亡率，发现随着组织学严重程度增加，增殖指数和凋亡率增加，具有统计学显著趋势（分别为P = 0.006和P = 0.0002）。发现bcl-x表达、bax表达以及bcl-2与bax表达比值与组织学严重程度增加之间存在统计学显著的线性关联（分别为P = 0.0004、P = 0.007和P = 0.03）。这些数据支持以下假设，即食管肠化生上皮的肿瘤转化可能是由于参与凋亡控制和细胞周期的蛋白质表达的顺序变化所致。此外，凋亡抑制似乎并未促进巴雷特食管中的肿瘤生长。这些观察结果将有助于更好地理解食管腺癌的发病机制，并可能有助于提高对发育异常病变诊断的准确性。
