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Pathological classification of intrahepatic cholangiocarcinoma based on a new concept

World Journal of Hepatology 2010年第12期2卷 419-427页

作者： Yasuni Nakanuma Yasunori Sato kenichi harada Mokoto Sasaski Hiroko Ikeda Department of Human Pathology Kanazawa University Graduate School of Medicine Pathology Diagnosis Section Kanazawa University Hospital

Intrahepatic cholangiocarcinoma (ICC) arises from the lining epithelium and peribiliary glands of the intrahepatic biliary tree and shows variable cholangiocytic dif-f-e-re-ntiation. To date-,ICC was large-ly classifie-d into adenocarcinoma and rare variants. Herein,we propose to subclassify the former,based on recent progress in the-study of-ICC including the-gross classification and hepatic progenitor/stem cells and on the pathological similarities between biliary and pancreatic neoplasms. That is,ICC is classifiable into the conventional (bile duct) type,the bile ductular type,the intraductal neoplasm type and rare variants. The conventional type is further divided into the small duct type (peripheral type) and large bile duct type (perihilar type). The former is a tubular or micropapillary adenocarcinoma while the latter involves the intrahepatic large bile duct. Bile ductular type resembles proliferated bile ductules and shows a replacing growth of the hepatic *** progenitor cell or stem cell phenotypes such as neural cell adhesion molecule expression are frequently expressed in the bile ductular type. Intraductal type includes papillary and tubular neoplasms of the bile duct (IPNBs and ITNBs) and a superficial spreading type. IPNB and ITNB show a spectrum from a preneoplastic borderline lesion to carcinoma and may have pancreatic counterparts. At invasive sites,IPNB is associated with the conventional bile duct ICC and mucinous carcinoma. Biliary mucinous cystic neoplasm with ovarian-like stroma in its wall is different from IPNB,particularly IPNB showing cystic dilatation of the affected ducts. Rare variants of ICC include squamous/adenosquamous cell carcinoma,mucinous/signet ring cell carcinoma,clear cell type,undifferentiated type,neuroendocrine carcinoma and so on. This classification of-ICC may ope-n up a ne-w fie-ld of-re-se-arch of-ICC and contribute-to the-clini cal approach to ICC.

关键词： Intrahepatic cholangiocarcinoma Adenocarcinoma Bile duct Bile ductule Intraductal neoplasm

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Metachronous intracystic and intraductal papillary neoplasms of the biliary tree

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World Journal of Gastroenterology 2013年第36期19卷 6125-6126页

作者： Hirohide Sato Yasunori Sato kenichi harada Motoko Sasaki Katsuyasu Hirano Yasuni Nakanuma Department of Human Pathology Kanazawa University Graduate School of Medicine Department of Surgery Wajima Hospital

A 77-year-old woman complained of epigastralgia,and a tumor(5 cm in diameter)of the gallbladder neck was detected by image *** cholecystectomy,the tumor was pathologically diagnosed as intraductal papillary neoplasm(IPN),gastric type,with associated invasive *** 10 mo later,intraluminal multiple masses(3 foci,up to 1.8 cm)were noted in the extrahepatic bile duct,and the resected specimen showed that all tumors had similar gross and microscopic features as seen in gallbladder IPN without invasion,and they were synchronous multiple *** case showed a papillary tumor of the gallbladder of gastric phenotype,and confirmed that the gallbladder is a target of IPN in addition to the bile ducts.

关键词： Intraductal papillary neoplasm Intracystic papillary neoplasm Gastric type Metachronous occurrence Synchronous occurrence

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Participation of peribiliary glands in biliary tract pathophysiologies

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World Journal of Hepatology 2013年第8期5卷 425-432页

作者： Saya Igarashi Yasunori Sato Xiang Shan Ren kenichi harada Motoko Sasaki Yasuni Nakanuma Department of Human Pathology Kanazawa University Graduate School of Medicine

AIM:To investigate the roles of peribiliary glands around the bile ducts in the pathophysiology of the biliary ***:The expression of fetal pancreatic markers,pancreatic duodenal homeobox factor 1(PDX1)and hairy and enhancer of split 1(HES1)and endodermal stem/progenitor(S/P)cell markers[CD44s,chemokine receptor type 4(CXCR4),SOX9 and epithelial cell adhesion molecule(EpCAM)]were examined immunohistochemically in 32 normal adult livers(autopsy livers)and 22 hepatolithiatic livers(surgically resected livers).The latter was characterized by the proliferation of the peribiliary *** was performed using formalin-fixed,paraffin-embedded tissue sections after *** PDX1and HES1 were expressed in both the nucleus and cytoplasm of epithelial cells,only nuclear staining was ***9 was expressed in the nucleus,while CD44s,CXCR4 and EpCAM were expressed in the cell *** frequency and extent of the expression of these molecules in the lining epithelia and peribiliary glands were evaluated semi-quantitatively based on the percentage of positive cells:0,1+(focal),2+(moderate)and 3+(extensive).RESULTS:In normal livers,PDX1 was infrequently expressed in the lining epithelia,but was frequently expressed in the peribiliary *** contrast,HES1was frequently expressed in the lining epithelia,but its expression in the peribiliary glands was focal,suggesting that the peribiliary glands retain the potential of differentiation toward the pancreas and the lining epithelia exhibit properties to inhibit such *** unique combination was also seen in hepatolithiatic *** expression of endodermal S/P cell markers varied in the peribiliary glands in normal livers:SOX9 and EpCAM were frequently expressed,CD44s infrequently,and CXCR4 almost not at *** expression of these markers,particularly CD44s and CXCR4,increased in the peribiliary glands and lining epithelia in hepatolithiatic *** increa

关键词： Biliary tree Peribiliary glands Pancreatic duodenal homeobox factor 1 Stem cells Differentiation Pancreas

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Expression of AID, P53, and Mlh1 proteins in endoscopically resected differentiated-type early gastric cancer

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World Journal of Gastrointestinal Oncology 2012年第6期4卷 131-137页

作者： Yohei Takeda Kazuo Yashima Akihiro Hayashi Shuji Sasaki Koichiro Kawaguchi kenichi harada Yoshikazu Murawaki Hisao Ito Division of Medicine and Clinical Science Faculty of Medicine Tottori University Division of Organ Pathology Faculty of Medicine Tottori University

AIM: To analyze the expression of the tumor-related proteins in differentiated-type early gastric carcinoma (DEGC) samples. METHODS: Tumor specimens were obtained from 102 patients (75 males and 27 females) who had received an endoscopic tumor resection at Tottori University Hospital between 2007 and 2009. Ninety-one cancer samples corresponded to noninvasive or intramucosal carcinoma according to the Vienna classification system, and 11 samples were submucosal invasive carcinomas. All of the EGCs were histologically differentiated carcinomas. All patients were classified as having Helicobacter pylori (H. pylori) infections by endoscopic atrophic changes or by testing seropositive for H. pylori IgG. All of the samples were histopathologically classified as either tubular or papillary adenocarcinoma according to their structure. The immunohistochemical staining was performed in a blinded manner with respect to the clinical information. Two independent observers evaluated protein expression. All data were statistically analyzed then. RESULTS: The rates of aberrant activation-induced cytidine deaminase (AID) expression and P53 overexpression were both 34.3% in DEGCs. The expression of Mlh1 was lost in 18.6% of DEGCs. Aberrant AID expression was not significantly associated with P53 overexpression in DEGCs. However, AID expression was associated with the severity of mononuclear cell activity in the non-cancerous mucosa adjacent to the tumor (P = 0.064). The rate of P53 expression was significantly greater in flat or depressed tumors than in elevated tumors. The frequency of Mlh1 loss was significantly increased in distal tumors, elevated gross-type tumors, papillary histological-type tumors, and tumors with a severe degree of endoscopic atrophic gastritis (P < 0.05). CONCLUSION: Aberrant AID expression, P53 overexpression, and the loss of Mlh1 were all associated with clinicopathological features and gastric mucosal alterations in DEGCs. The aberrant expression of AID p

关键词： Gastric cancer Activation-induced cytidine deaminase P53 Mlh1 Endoscopic resection

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Clinicopathological study of primary biliary cirrhosis with interface hepatitis compared to autoimmune hepatitis

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World Journal of Gastroenterology 2014年第13期20卷 3597-3608页

作者： Mio Kobayashi Yuko Kakuda kenichi harada Yasunori Sato Motoko Sasaki Hiroko Ikeda Mitsuhiro Terada Munenori Mukai Shuichi Kaneko Yasuni Nakanuma Department of Human Pathology Kanazawa University Graduate School of MedicineKanazawa 920-8640Japan Division of Pathology Kanazawa University HospitalKanazawa 920-8641Japan Department of Gastroenterology Kouseiren Takaoka HospitalTakaoka 933-8555Japan Department of Pathology Kouseiren Takaoka HospitalTakaoka 933-8555Japan Department of Gastroenterology Kanazawa University Graduate School of MedicineKanazawa 920-8640 Japan

AIM:To investigate histological and immunohistochemical differences in hepatitis between autoimmune hepatitis(AIH)and primary biliary cirrhosis(PBC)with AIH ***:Liver needle biopsies of 41 PBC with AIH features and 43 AIH patients were *** activity of periportal and lobular inflammation was scored0(none or minimal activity)to 4(severe),and the degree of hepatitic rosette formation and emperipolesis was semiquantatively scored *** infiltration of mononuclear cells positive for CD20,CD38,CD3,CD4,and CD8 and positive for immunoglobulins(IgG,IgM,and IgA)at the periportal areas(interface hepatitis)and in the hepatic lobules(lobular hepatitis)were semiquantitatively scored in immunostained liver sections(score 0-6).Serum aspartate aminotransferase(AST),immunoglobulins,and autoantibodies at the time of liver biopsy were correlated with the histological and immunohistochemical scores of individual ***:Lobular hepatitis,hepatitic rosette formation,and emperipolesis were more extensive and frequent in AIH than in ***3+,CD4+,and CD8+cell infiltration scores were higher in the hepatic lobules and at the interface in AIH but were also found in *** degree of mononuclear cell infiltration correlated well with the degree of interface and lobular hepatitis in PBC,but to a lesser degree in ***20+cells were mainly found in the portal tracts and,occasionally,at the interface in both *** AST correlated well with the hepatocyte necroinflammation and mononuclear cell infiltration,specifically CD38+cells in *** correlation existed between autoantibodies and inflammatory cell infiltration in PBC or *** most AIH cases were IgG-predominant at the interface,PBC cases were divided into IgM-predominant,IgM/IgGequal,and IgG-predominant types,with the latter sharing several features with ***:These results suggest that the hepatocellular injuries associated with interface and lobular hepatitis in AIH and PBC with inte

关键词： Primary biliary cirrhosis Autoimmune hepa-titis Interface hepatitis Lobular hepatitis Plasma cell subclass

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Intraductal papillary neoplasm of the bile duct in liver cirrhosis with hepatocellular carcinoma

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World Journal of Gastroenterology 2011年第14期17卷 1923-1926页

作者： Jing Xu Yasunori Sato kenichi harada Norihide Yoneda Yasuni Nakanuma Teruyuki Ueda Atsushi Kawashima Akishi Ooi Department of Human Pathology Kanazawa University Graduate School of Medicine Kanazawa 920-8640 Japan Department of Pathology Shanxi Medical University Taiyuan 030001 Shanxi Province China Internal Medicine for Digestive Organs Kanazawa University Graduate School of Medicine Kanazawa 920-8640 Japan Department of Molecular Pathology Kanazawa University Graduate School of Medicine Kanazawa 920-8640 Japan

A case of intraductal papillary neoplasm of the bile duct (IPNB) arising in a patient with hepatitis B-related liver cirrhosis with hepatocellular carcinoma (HCC) is reported. A 76-year-old man was admitted to our hospital with recurrent HCC. Laboratory data showed that levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were elevated. He died of progressive hepatic failure. At autopsy,in addition to HCCs,an intraductal papillary proliferation of malignant cholangiocytes with fibrovascular cores was found in the dilated large bile ducts in the left lobe,and this papillary carcinoma was associated with an invasive mucinous carcinoma (invasive IPNB). Interestingly,extensive intraductal spread of the cholangiocarcinoma was found from the reactive bile ductular level to the interlobular bile ducts and septal bile ducts and to the large bile ducts in the left lobe. Neural cell adhesion molecule,a hepatic progenitor cell marker,was detected in IPNB cells. It seems possible in this case that hepatic progenitor cells located in reactive bile ductules in liver cirrhosis may have been responsible for the development of the cholangiocarcinoma and HCC,and that the former could have spread in the intrahepatic bile ducts and eventually formed grossly visible IPNB.

关键词： Papillary carcinoma Bile duct neoplasms Liver cirrhosis Progenitor cells Hepatocellular carcinoma Neural cell adhesion molecules

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Intraductal papillary neoplasm of the bile duct accompanying biliary mixed adenoneuroendocrine carcinoma

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World Journal of Gastroenterology 2013年第20期19卷 3161-3164页

作者： Ichiro Onishi Hirohisa Kitagawa kenichi harada Syogo Maruzen Seisyo Sakai Isamu Makino Hironori Hayashi Hisatoshi Nakagawara Hidehiro Tajima Hiroyuki Takamura Takashi Tani Masato Kayahara Hiroko Ikeda Tetsuo Ohta Yasuni Nakanuma Department of Gastroenterologic Surgery Graduate School of Medical ScienceKanazawa UniversityKanazawa 920-8641Japan Department of Human Pathology Graduate School of Medical ScienceKanazawa UniversityKanazawa 920-8650Japan Pathology Division Kanazawa University HospitalKanazawa 920-8650Japan

We present the first case of an intraductal papillary neoplasm of the bile duct(IPNB) accompanying a mixed adenoneuroendocrine carcinoma(MANEC).A 74-yearold woman presented with fever of unknown *** data revealed jaundice and liver ***-enhanced computed tomography revealed a 20 mm polypoid tumor in the dilated distal bile duct,which exhibited early enhancement and papillary *** gastrointestinal endoscopy revealed mucus production from the papilla of Vater,characterized by its protruding and dilated *** ultrasonography visualized the polypoid tumor in the distal bile duct,but no invasive region was suggested by diagnostic ***,the initial diagnosis was *** endoscopic nasobiliary drainage,a pylorus-preserving pancreaticoduodenectomy was *** examination of the resected bile duct revealed papillary proliferation of biliary-type cells with nuclear atypia,indicating pancreaticobiliary-type *** addition,solid portions comprised of tumor cells with characteristic salt-and-pepper nuclei were *** revealed expression of the neuroendocrine marker synaptophysin in this solid component,diagnosing it as a neuroendocrine tumor(NET).Furthermore,the MIB-1 proliferation index of NET was higher than that of IPNB,and microinvasion of the NET component was found,indicating neuroendocrine carcinoma(NET G3).This unique case of MANEC,comprising IPNB and NET,provides insight into the pathogenesis of biliary NET.

关键词： Neuroendocrine tumor Intraductal papillary neoplasm of bile duct Intraductal papillary neoplasm of the bile duct Bile duct

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PP242诱导多囊肾大鼠胆管上皮细胞自噬和凋亡的机制研究

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中国药理学通报 2018年第9期34卷 1218-1225页

作者：闫文帝李珍玲刘特思李玉姬原田宪一任香善延边大学肿瘤研究中心吉林延边133002 金泽大学医学部病理学教研室日本金泽9208640 延边大学医学院病理学教研室吉林延边133002

目的探讨mTORC1/2抑制剂PP242诱导多囊肾(polycystic kidney,PCK)大鼠胆管上皮细胞凋亡和自噬、抑制细胞增殖及胆管囊性扩张的分子机制。方法免疫组织化学染色法检测PCK大鼠胆管上皮细胞中p-mTOR和p-Akt的表达;WST-1比色法检测雷帕霉素... 详细信息

目的探讨mTORC1/2抑制剂PP242诱导多囊肾(polycystic kidney,PCK)大鼠胆管上皮细胞凋亡和自噬、抑制细胞增殖及胆管囊性扩张的分子机制。方法免疫组织化学染色法检测PCK大鼠胆管上皮细胞中p-mTOR和p-Akt的表达;WST-1比色法检测雷帕霉素和PP242对胆管上皮细胞增殖活性的抑制作用,以及LC3、Beclin-1基因沉默和自噬特异性抑制剂3-甲基腺嘌呤(3-methyladenine,3-MA)对细胞增殖的影响;蛋白免疫印迹法检测PP242对PI3K/Akt信号通路相关蛋白、自噬标识蛋白LC3和Beclin-1、cleaved caspase-3表达的影响;流式细胞术和ELISA法检测PP242对细胞凋亡的影响;免疫荧光染色法检测LC3在细胞质中的表达情况;3D细胞培养检测Rictor基因沉默和雷帕霉素联用及雷帕霉素单独应用时对大鼠胆管上皮细胞成球能力的影响。结果 p-mTOR和p-Akt在PCK大鼠胆管上皮细胞中呈过表达,PP242比雷帕霉素抑制胆管上皮细胞增殖效果更为明显,且呈浓度和时间依赖性改变(P <0. 05); PP242明显抑制PI3K/Akt信号通路相关蛋白的表达; PP242可诱导细胞凋亡和自噬,上调cleaved caspase-3、Beclin-1和LC3-Ⅱ/LC3-Ⅰ比值。Rictor基因沉默和雷帕霉素联用比雷帕霉素单独应用对大鼠胆管上皮细胞的抑制作用更为明显; LC3、Beclin-1基因沉默和3-MA均可明显减弱PP242对细胞增殖的抑制作用(P <0. 05)。结论 PP242可通过PI3K/Akt/mTOR信号通路抑制PCK大鼠胆管上皮细胞的增殖,其机制与细胞凋亡和自噬密切相关。

关键词：自噬凋亡 PI3K/Akt/mTOR信号通路多囊肾大鼠 PP242 Caroli病

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Adult case of an omphalomesenteric cyst resected by laparoscopic-assisted surgery

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World Journal of Gastroenterology 2006年第5期12卷 825-827页

作者： Fumi Sawada Rie Yoshimura kenichi Ito Kazuhiko Nakamura Hajime Nawata Kazuhiro Mizumoto Shuji Shimizu Takahiro Inoue Takashi Yao Masazumi Tsuneyoshi Atushi Kondo Naohiko harada Department of Medicine and Bioregulatory Science Department of Surgery and Oncology Department of Anatomic Pathology Graduate School of Medical SciencesKyushu UniversityFukuoka 812-8582FukuokaJapan Department of Gastroenterology Aso Iizuka HospitalIizuka 820-8505FukuokaJapan Department of Gastroenterology Fukuoka Higashi Medical CenterKoga 811-3195FukuokaJapan

This report describes an extremely rare adult case of an omphalomesenteric cyst resected by laparoscopicassisted surgery. A 29-years-old Japanese man was referred and admitted to Kyushu University Hospital because of an abdominal mass and an elevated serum CEA （carcinoembryonic antigen） level （21.3 ng/mL） in August 2001. Abdominal CT and US demonstrated a cystic mass with septum and calcification. Laparoscopy showed a large mass to be attached to his abdominal wall, measuring 110 mm × 70 mm× 50 mm and filled with mucus. The mass was resected by laparoscopicassisted surgery. The histological findings of its wall showed fibromuscular tissue, adipose tissue, calcification, and an intestinal structure. It was finally diagnosed to be an omphalomesenteric cyst.

关键词： Omphalomesenteric cyst Laparoscopicassisted surgery

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