Proliferative potential and K-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union

Abstract

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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. Cancer 1998;83:267‐275. © 1998 American Cancer Society.

Long-term follow-up may be needed for pancreaticobiliary reflux in healthy adults

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“…The Ki-67 labeling index is usually substantially greater in dysplastic lesions and increases in quantity with increasing degrees of dysplasia. It can also be marked in areas of regenerative change as well [8,12]. We found that high amylase level in the gallbladder was an important risk factor which causes inflammation and degeneration of the gallbladder mucosa.…”

Early Diagnosis of Gallbladder Carcinoma: An Algorithm Approach

“…The incidence of epithelial hyperplasia of the gallbladder of PBM patients without biliary dilatation was reported to be 72% to 91%. Tanno et al [32] reported that the Ki-67 labeling index of epithelial hyperplasia of PBM patients was elevated to 6.1%  ± 1.5% and K-ras mutation was detected in 2 (13%) of 15 patients. To detect PBM without biliary dilatation before onset of gallbladder cancer, we should perform MRCP for individuals showing gallbladder wall thickness on US [33].…”

Imaging findings in 75 pediatric patients with pancreaticobiliary maljunction: a retrospective case study

“…Under this condition, the sphincter of Oddi can not regulate the outflow of bile and pancreatic juice, leading to two-way regurgitation [1, 2]. Frequent passage of pancreatic juice into the bile duct damages the epithelium of the biliary tract [3]. Bile reflux into the pancreatic duct could lead to pancreatitis.…”