Proliferative potential and K-ras mutation in epithelial hyperplasia of the gallbladder in patients with anomalous pancreaticobiliary ductal union.
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.
Tanno
S
S
Third Department of Internal Medicine, Asahikawa Medical College, Hokkaido, Japan.
Obara
T
T
Fujii
T
T
Mizukami
Y
Y
Shudo
R
R
Nishino
N
N
Ura
H
H
Klein-Szanto
A J
AJ
Kohgo
Y
Y
D000293:Adolescent; D000328:Adult; D000368:Aged; D001652:Bile Ducts / Q000002:abnormalities*; D002277:Carcinoma / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D004847:Epithelial Cells / Q000166:cytology; D005260:Female; D005704:Gallbladder / Q000473:pathology*; D005706:Gallbladder Neoplasms / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D006965:Hyperplasia; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010183:Pancreatic Ducts / Q000002:abnormalities*; D011379:Prognosis; D012307:Risk Factors