Tanno S, Obara T, Fujii T, Mizukami Y, Shudo R, Nishino N, Ura H, Klein-Szanto A J, Kohgo Y
Third Department of Internal Medicine, Asahikawa Medical College, Hokkaido, Japan.
Cancer. 1998 Jul 15;83(2):267-75.
Recent studies have shown that anomalous pancreaticobiliary ductal union (APBD) is an important risk factor for the development of gallbladder carcinoma. Epithelial hyperplasia of the gallbladder is one of the characteristic changes, but it is not clear whether epithelial hyperplasia is a premalignant lesion that could lead to cancer in APBD patients.
Twenty-four APBD patients were classified into two types: patients with bile duct dilation (dilated type) (n 13) and patients without dilation (undilated type) (n = 11). Resected gallbladders obtained from APBD patients and control patients without APBD were examined histologically and with immunohistochemical techniques for the detection of p53 and Ki-67 (as a cell proliferation marker). K-ras mutations were examined using polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequence analysis. The patients were also classified, according to extent of epithelial hyperplasia, as having high grade or low grade hyperplasia.
Fifteen (63%) of 24 APBD patients had epithelial hyperplasia of the gallbladder, whereas no patients without APBD exhibited this lesion. The incidence of epithelial hyperplasia was significantly higher in the gallbladders of undilated-type APBD patients (91%) than in those of dilated-type patients (38%) (P < 0.01). Three of 24 APBD patients (13%) had gallbladder carcinoma, and 2 of the 3 gallbladder carcinomas (67%) were accompanied by diffuse epithelial hyperplasia of the gallbladder. Among 21 nonneoplastic gallbladders, diffuse epithelial hyperplasia was observed in all (100%) of the undilated-type APBD and in 4 (33%) of 12 dilated-type APBD (P < 0.001). High grade hyperplasia was observed in 7 of 11 patients (64%) with undilated-type APBD and 2 of 13 patients (15%) with dilated-type APBD (P < 0.05). The incidence of high grade hyperplasia increased with age among patients older than 35 years. Ki-67 labeling index (LI) was significantly higher in hyperplastic mucosa than in control gallbladder mucosa. High grade hyperplasia had a significantly higher Ki-67 LI than low grade hyperplasia (P < 0.001). Two (22%) of 9 high grade hyperplasia cases had K-ras mutations, whereas none of 6 low grade hyperplasia cases had. The types of K-ras mutations in codon 12 were GTT (Val) and GAT (Asp) in each case of hyperplasia; these were identical to those of concomitant carcinomas. Neither hyperplastic nor normal mucosa exhibited p53 overexpression.
The results of this study suggest that hyperplasia of the gallbladder mucosa in APBD patients is an early change that, because of the increased proliferative activity and presence of K-ras mutations, could be considered a premalignant lesion of the gallbladder. An increased cell population of epithelial hyperplasia may predispose the mucosa to mutational events, resulting in an increased risk for the development of gallbladder carcinoma in APBD patients.
近期研究表明，胰胆管汇合异常（APBD）是胆囊癌发生的重要危险因素。胆囊上皮增生是其特征性改变之一，但尚不清楚上皮增生是否为APBD患者中可导致癌症的癌前病变。
24例APBD患者分为两种类型：胆管扩张患者（扩张型）（n = 13）和无扩张患者（非扩张型）（n = 11）。对从APBD患者及无APBD的对照患者切除的胆囊进行组织学检查及免疫组化检测，以检测p53和Ki-67（作为细胞增殖标志物）。采用聚合酶链反应-限制性片段长度多态性及直接DNA序列分析检测K-ras突变。患者还根据上皮增生程度分为高级别或低级别增生。
24例APBD患者中有15例（63%）出现胆囊上皮增生，而无APBD的患者未出现此病变。非扩张型APBD患者胆囊上皮增生的发生率（91%）显著高于扩张型患者（38%）（P < 0.01）。24例APBD患者中有3例（13%）发生胆囊癌，3例胆囊癌中有2例（67%）伴有胆囊弥漫性上皮增生。在21个非肿瘤性胆囊中，非扩张型APBD的所有胆囊（100%）及12个扩张型APBD中的4个（33%）观察到弥漫性上皮增生（P < 0.001）。11例非扩张型APBD患者中有7例（64%）及13例扩张型APBD患者中有2例（15%）观察到高级别增生（P < 0.05）。35岁以上患者中高级别增生的发生率随年龄增加。增生黏膜中的Ki-67标记指数（LI）显著高于对照胆囊黏膜。高级别增生的Ki-67 LI显著高于低级别增生（P < 0.001）。9例高级别增生病例中有2例（22%）发生K-ras突变，而6例低级别增生病例均未发生。增生病例中第12密码子的K-ras突变类型均为GTT（Val）和GAT（Asp）；这些与伴发癌的突变类型相同。增生及正常黏膜均未表现出p53过表达。
本研究结果提示，APBD患者胆囊黏膜增生是一种早期改变，由于增殖活性增加及存在K-ras突变，可被视为胆囊的癌前病变。上皮增生细胞数量增加可能使黏膜易发生突变事件，导致APBD患者发生胆囊癌的风险增加。
