K- ras and p53 gene mutations in noncancerous biliary lesions of patients with pancreaticobiliary maljunction

Matsubara, Toshiki; Sakurai, Yoshinori; Zhi, Lizhu; Miura, Hirotake; Ochiai, Masahiro; Funabiki, Takuzo

doi:10.1007/s005340200035

Cited by 56 publications

(53 citation statements)

References 22 publications

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“…Prophylactic cholecystectomy is performed in many institutes, as most biliary cancers that develop in PBM patients without biliary dilatation are gallbladder cancers [38,39]. However, some surgeons propose excision of the extrahepatic bile duct together with the gallbladder for PBM patients without biliary dilatation [23], because the frequency of bile duct cancer in PBM patients without biliary dilatation is higher compared to that in the general population [2], and K-ras and/or p53 gene mutations are also reportedly seen in the bile duct of PBM patients without biliary dilatation [23,40].…”

Section: Treatment Of Pbmmentioning

confidence: 99%

Pancreaticobiliary maljunction and biliary cancer

et al. 2014

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Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Japanese clinical practice guidelines on how to deal with PBM were made in 2012, representing a world first. According to the 2013 revision to the diagnostic criteria for PBM, in addition to direct cholangiography, diagnosis can be made by magnetic resonance cholangiopancreatography (MRCP), 3-dimensional drip infusion cholangiography computed tomography, endoscopic ultrasonography (US), or multiplanar reconstruction images by multidetector row computed tomography. In PBM, the common channel is so long that sphincter action does not affect the pancreaticobiliary junction, and pancreatic juice frequently refluxes into the biliary tract. Persistence of refluxed pancreatic juice injures epithelium of the biliary tract and promotes cancer development, resulting in higher rates of carcinogenesis in the biliary tract. In a nationwide survey, biliary cancer was detected in 21.6 % of adult patients with congenital biliary dilatation (bile duct cancer, 32.1 % vs. gallbladder cancer, 62.3 %) and in 42.4 % of PBM patients without biliary dilatation (bile duct cancer, 7.3 % vs. gallbladder cancer, 88.1 %). Pathophysiological conditions due to pancreatobiliary reflux occur in patients with high confluence of pancreaticobiliary ducts, a common channel C6 mm long, and occlusion of communication during contraction of the sphincter. Once the diagnosis of PBM is established, immediate prophylactic surgery is recommended. However, the surgical strategy for PBM without biliary dilatation remains controversial. To detect PBM without biliary dilatation early, MRCP is recommended for patients showing gallbladder wall thickening on screening US under suspicion of PBM.

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Section: Treatment Of Pbmmentioning

confidence: 99%

Pancreaticobiliary maljunction and biliary cancer

et al. 2014

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“…However, in PBM patients, in addition to biliary tract cancers, K-ras mutation is detected in the noncancerous epithelium of the gallbladder and bile duct. Matsubara et al reported that in PBM patients without biliary carcinoma, K-ras mutation was detected in 33 and 40 % of the gallbladder and bile duct epithelium, respectively [29]. Iwase et al reported that K-ras mutation was detected in 36 % of hyperplastic gallbladder lesions in PBM patients [30].…”

Section: Gene Mutationmentioning

confidence: 99%

Biliary carcinogenesis in pancreaticobiliary maljunction

et al. 2016

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Pancreaticobiliary maljunction (PBM) is a congenital malformation in which the pancreatic and bile ducts join anatomically outside the duodenal wall. Because of the excessive length of the common channel in PBM, sphincter action does not directly affect the pancreaticobiliary junction, which allows pancreatic juice to reflux into the biliary tract. According to the results of a nationwide survey, bile duct and gallbladder cancers were found in 6.9 and 13.4 % of adult patients with congenital biliary dilatation, respectively, and in 3.1 and 37.4 % of those with PBM without biliary dilatation, respectively. Biliary tract cancers develop about 15-20 years earlier in patients with PBM than in individuals without PBM; they sometimes develop as double cancers. Carcinogenesis is strongly associated with stasis of bile intermingled with refluxed pancreatic juice. Epithelial cells in the biliary tract of PBM patients are under constant attack from activated pancreatic enzymes, increased secondary bile acids, or other mutagens. This can result in hyperplastic change with increased cell proliferation activity, and in turn, oncogene and/or tumor suppressor gene mutations in the epithelia, leading to the biliary tract carcinogenesis. The carcinogenesis of biliary tract cancer accompanying PBM is considered to involve a hyperplasia-dysplasia-carcinoma sequence induced by chronic inflammation caused by the reflux of pancreatic juice into the biliary tract, which differs from the adenoma-carcinoma sequence or the de novo carcinogenesis associated with biliary tract cancers in the population without PBM. Patients with a relatively long common channel have a similar, albeit slightly lower, risk for gallbladder cancer compared with PBM patients.

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“…Iwase et al [23] reported detecting Kras mutations in 36% of cases with hyperplasia. Matsubara et al [25] reported mutations in 31.6% of inflammatory epithelium, and in 47.6% with both hyperplasia and metaplasia. We detected Kras mutations in 64% of cases with hyperplasia, in 28% with metaplasia, and in 17% with dysplasia [22] .…”

Section: Gene Mutationmentioning

confidence: 99%

“…Hanada et al [27] analyzed exon 58 of p53 using PCRSSCP and reported the detection of an abnormal band on exon 7, 8 in 3 of the 6 cases (50%) of stage Ⅰ gallbladder cancer with coexisting PBM. Matsubara et al [25] detected p53 gene mutation in 34.8% of cases with an inflammatory epithelium, in 47.6% with both hyperplasia and metaplasia, and in 60% with cancer, stating that these were mainly exon 5, 6, 8. However, Nagai et al [28] reported that p53 gene mutation was not detected in cases of hyperplasia and dysplasia, but that the gene mutation was observed in 4 of 26 cases (16%) of cancer.…”

Section: Gene Mutationmentioning

confidence: 99%

Carcinogenesis and chemoprevention of biliary tract cancer in pancreaticobiliary maljunction

Tsuchida

Itoi²

2010

WJGO

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Pancreaticobiliary maljunction (PBM) is a high risk factor for biliary tract cancer. In PBM, since the pancreatic duct and bile duct converge outside the duodenal wall beyond the influence of the sphincter of Oddi, pancreatic juice and bile are constantly mixed, producing a variety of harmful substances. Because of this, the biliary mucosa is repeatedly damaged and repaired, which causes an acceleration of cell proliferative activity and multiple gene mutations. Histological changes such as hyperplasia, metaplasia, and dysplasia ultimately result in a high incidence of carcinogenesis. In a nationwide survey by the Japanese Study Group on PBM, coexisting biliary tract cancer was detected in 278 of the 1627 registered cases of PBM (17.1%). Of these cases, in those with dilatation of the extrahepatic bile duct, cancer was often detected not only in the gallbladder but also in the bile ducts. More than 90% of cancer cases without dilatation of the extrahepatic bile duct develop in the gallbladder. Standard treatment for PBM is a cholecystectomy and resection of the extrahepatic bile duct. However, cholecystectomy alone is performed at nearly half of institutions in Japan. Conversely, reports of carcinogenesis in the remnant bile duct or pancreas after diversion surgery are steadily increasing. One of the causes for this is believed to be an accumulation of gene mutations which were present before surgery. Anticancer drugs are ineffective in preventing such carcinogenesis following surgery, thus the postoperative administration of chemopreventive agents may be necessary.

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K- ras and p53 gene mutations in noncancerous biliary lesions of patients with pancreaticobiliary maljunction

Abstract: These results suggest that noncancerous lesions of the biliary epithelium in patients with pancreaticobiliary maljunction have mutations of the K- ras gene and/or the p53 gene, which provides genetic evidence that biliary epithelium has high carcinogenic potential.

Cited by 56 publications

References 22 publications

Pancreaticobiliary maljunction and biliary cancer

Pancreaticobiliary maljunction and biliary cancer

Biliary carcinogenesis in pancreaticobiliary maljunction

Carcinogenesis and chemoprevention of biliary tract cancer in pancreaticobiliary maljunction

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