Clinicopathology of pancreaticobiliary maljunction: relationship between alterations in background biliary epithelium and neoplastic development

Seki, Makoto; Yanagisawa, Akio; Ninomiya, Eiji; Ninomiya, Yasuo; Ohta, Hiroyuki; Saiura, Akio; Yamamoto, Junji; Yamaguchi, Toshiharu; Aruga, Akiko; Yamada, Keiko; Takano, Koichi; Fujita, Rikiya; Ikeda, Masayuki; Sasaki, Keiko; Kato, Yukio

doi:10.1007/s00534-004-0966-8

Cited by 35 publications

(44 citation statements)

References 11 publications

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“…LL and other altered bile components may be responsible for the development of PHP and also carcinoma of the gallbladder in PBM. [3][4][5][6][7] Although gallstones seem to be closely associated with gallbladder carcinoma, there is no evidence of direct causal relationship between them. Lining epithelia of the biliary tract including the gallbladder are known to show intraepithelial atypical/proliferative lesions closely associated with the development of carcinoma.…”

mentioning

confidence: 99%

“…[3][4][5] It has been postulated in PBM that the reflex of pancreatic juice into the common bile duct and the stagnation of pancreatic juice mixed with bile have been considered to play an important role in the pathophysiology of PBM, including biliary tract carcinoma. [3][4][5][6][7][8][9][10] A high concentration of lysolecithin (LL) was reported in the gallbladder bile of PBM, [3][4][5][6][7] and LL is produced from lecithin by activated phospholipase A2 in the refluxing pancreatic juice in PBM. LL and other altered bile components may be responsible for the development of PHP and also carcinoma of the gallbladder in PBM.…”

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confidence: 99%

“…PBM patients are known to be associated with bile duct dilatation and also biliary tract carcinoma, especially in the Far East. [3][4][5][6][7] Patients who develop gallbladder carcinoma in association with PBM are usually 10 years younger than those without PBM. Synchronous primary cancers of the gallbladder and common bile duct have also been associated with PBM.…”

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confidence: 99%

“…[1][2][3] PBM is defined as the union of the pancreatic and common bile ducts outside the wall of the duodenum, beyond the influence of the sphincter of Oddi. [3][4][5][6][7] Normally, the pancreaticobiliary duct and junction are governed by sphincter, but as a result of the anomaly, pancreatic juice can reflex into the common bile duct. PBM patients are known to be associated with bile duct dilatation and also biliary tract carcinoma, especially in the Far East.…”

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confidence: 99%

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Papillary hyperplasia of the gallbladder in pancreaticobiliary maljunction represents a senescence-related lesion induced by lysolecithin

Yamaguchi

Sasaki

Harada

et al. 2009

Laboratory Investigation

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Cellular senescence, an irreversible growth arrest, is considered to play as safeguard against malignant progression, though such a mechanism is speculative in human carcinogenesis. In gallbladder carcinoma, cholecystolithiasis and pancreaticobiliary maljunction (PBM) are major risk factors. Here, by using 113 surgically resected gallbladders and cultures of human gallbladder epithelial cells (HGECs) and gallbladder carcinoma cell line (TGBC2TKB), we examined carcinogenesis with respect to cellular senescence. Among 15 cases of PBM in which carcinoma was found in 4 cases, nonneoplastic gallbladder mucosa showed diffuse papillary hyperplasia (PHP). PHP was not found in gallbladders with cholecystolithiasis. Interestingly, PHP exhibited senescent features such as expression of p16INK4A and low cell proliferative activity. In contrast, EZH2, a polycomb group protein, was overexpressed in intraepithelial neoplasm and carcinoma in gallbladders with cholecystolithiasis. In PBM, EZH2 was expressed only in carcinoma foci but not in PHP. Cultured HGECs treated with lysolecithin, the level of which is elevated in gallbladder bile of PBM, showed increased expression of p16INK4A and senescence-associated b-galactosidase. Conversely, enforced overexpression of EZH2 in senescent HGECs reduced p16 INK4A expression. A knockdown of EZH2 in cultured TGBC2TKB cells increased p16 INK4aexpression. In conclusion, PHP in PBM may act as a barrier to malignant transformation for decades. EZH2 may be responsible for the escape from cellular senescence followed by malignant transformation in the gallbladder of PBM.

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confidence: 99%

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confidence: 99%

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confidence: 99%

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confidence: 99%

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Papillary hyperplasia of the gallbladder in pancreaticobiliary maljunction represents a senescence-related lesion induced by lysolecithin

Yamaguchi

Sasaki

Harada

et al. 2009

Laboratory Investigation

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“…Intra-and extrahepatic bile duct carcinomas represent a rare but significant complication of long-standing ulcerative colitis and are commonly preceded by sclerosing cholangitis and epithelial dysplasia (Anthony 2002). The biliary epithelium in patients with pancreaticobiliary maljunction demonstrates chronic injury and repeated regeneration that progresses to papillary hyperplasia and metaplasia or dysplasia, eventually resulting in carcinoma (Seki et al 2005).…”

Section: Bile Duct Hyperplasia (Atypical)mentioning

confidence: 99%

Biliary Proliferative Lesions in the Sprague-Dawley Rat

Hailey

Nold²,

Brown

et al. 2013

Toxicol Pathol

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Whether biliary proliferative lesions in nonclinical species are predictive of potential hepatotoxicity in humans depends, at least in part, on the nature and severity of such changes in the nonclinical species. We reviewed published literature (clinical and nonclinical) and experimental data from rat toxicology studies conducted by GlaxoSmithKline and the National Institute of Environmental Health Sciences' National Toxicology Program in an effort to better characterize the relative risk of hepatobiliary effects in humans. Available evidence supports the interpretation that minimal ''typical'' appearing bile duct hyperplasia limited to the portal triads may be considered non-adverse in the rat and is of little to no concern to humans. The toxicological relevance of mild to moderate ''typical'' hyperplasia is less certain, and may be considered adverse in the rat and potentially pose a risk for humans, particularly if accompanied by evidence of hepatobiliary injury or functional compromise. In addition, any proliferative lesion that includes atypical or dysplastic epithelial changes, oval cell proliferation, and/or significant extension beyond the portal tracts is considered more ominous and may be considered adverse in the rat.

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Recent advances and problems in the management of pancreaticobiliary maljunction: feedback from the guidelines committee

Kamisawa

Ando

Shimada

et al. 2013

J Hepato Biliary Pancreat

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Clinical practice guidelines on how to deal with pancreaticobiliary maljunction (PBM) were made in Japan in 2012, representing a world first. Using a narrow definition, congenital biliary dilatation involves only Todani type I (except type Ib) and type IV-A, both of which are accompanied by PBM in almost all cases. Prospective ultrasonographic study revealed that the maximum diameter of the common bile duct increased with age. Pathophysiological conditions due to pancreatobiliary reflux occur in patients with high confluence of the pancreaticobiliary ducts, a common channel ≥ 6 mm long and occlusion of communication during contraction of the sphincter of Oddi. Since PBM can be diagnosed by magnetic resonance cholangiopancreatography, multi-planar reconstruction multi-detector row computed tomography and endoscopic ultrasonography, the current diagnostic criteria should be revised to take these diagnostic imaging modalities into consideration. According to a nationwide survey, biliary cancer occurred in 21.6% of adult patients with PBM with biliary dilatation and 42.2% of patients with PBM without biliary dilatation. In biliary cancer associated with PBM without biliary dilatation, 88.1% were gallbladder cancer. Treatment for PBM with biliary dilatation is prophylactic flow-diversion surgery, but further investigations and surveillance studies are needed to clarify the appropriate surgical strategy for PBM without biliary dilatation.

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Clinicopathology of pancreaticobiliary maljunction: relationship between alterations in background biliary epithelium and neoplastic development

Abstract: PHP of the biliary epithelium in PBM patients is an important precursor lesion, especially for gallbladder cancer, and the risk becomes greater with age, regardless of the type of pancreatobiliary junction (PBJ) and its location in the biliary tract.

Cited by 35 publications

References 11 publications

Papillary hyperplasia of the gallbladder in pancreaticobiliary maljunction represents a senescence-related lesion induced by lysolecithin

Papillary hyperplasia of the gallbladder in pancreaticobiliary maljunction represents a senescence-related lesion induced by lysolecithin

Biliary Proliferative Lesions in the Sprague-Dawley Rat

Recent advances and problems in the management of pancreaticobiliary maljunction: feedback from the guidelines committee

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