Journal of Pathology and Translational Medicine

Original Article

Progressive Familial Intrahepatic Cholestasis in Korea: A Clinicopathological Study of Five Patients: Hyo Jeong Kang, Soon Auck Hong, Seak Hee Oh, Kyung Mo Kim, Han-Wook Yoo, Gu-Hwan Kim, Eunsil Yu; J Pathol Transl Med. 2019;53(4):253-260. Published online May 16, 2019; DOI: https://doi.org/10.4132/jptm.2019.05.03

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Background
Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive liver diseases that present as neonatal cholestasis. Little is known of this disease in Korea.
Methods
The records of five patients histologically diagnosed with PFIC, one with PFIC1 and four with PFIC2, by liver biopsy or transplant were reviewed, and ATP8B1 and ABCB11 mutation status was analyzed by direct DNA sequencing. Clinicopathological characteristics were correlated with genetic mutations.
Results
The first symptom in all patients was jaundice. Histologically, lobular cholestasis with bile plugs was the main finding in all patients, whereas diffuse or periportal cholestasis was identified only in patients with PFIC2. Giant cells and ballooning of hepatocytes were observed in three and three patients with PFIC2, respectively, but not in the patient with PFIC1. Immunostaining showed total loss of bile salt export pump in two patients with PFIC2 and focal loss in two. Lobular and portal based fibrosis were more advanced in PFIC2 than in PFIC1. ATP8B1 and ABCB11 mutations were identified in one PFIC1 and two PFIC2 patients, respectively. One PFIC1 and three PFIC2 patients underwent liver transplantation (LT). At age 7 months, one PFIC2 patient was diagnosed with concurrent hepatocellular carcinoma and infantile hemangioma in an explanted liver. The patient with PFIC1 developed steatohepatitis after LT. One patient showed recurrence of PFIC2 after 10 years and underwent LT.
Conclusions
PFIC is not rare in patients with neonatal cholestasis of unknown origin. Proper clinicopathologic correlation and genetic testing can enable early detection and management.

Citations

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Progressive Familial Intrahepatic Cholestasis: A Descriptive Study in a Tertiary Care Center
Fahad I. Alsohaibani, Musthafa C. Peedikayil, Abdulaziz F. Alfadley, Mohamed K. Aboueissa, Faisal A. Abaalkhail, Saleh A. Alqahtani, Dirk Uhlmann
International Journal of Hepatology.2023; 2023: 1. CrossRef
Next-generation sequencing panel test results in pediatric patients with progressive familial intrahepatic cholestasis: a single-center experience
Ali TOPAK
The European Research Journal.2023; 9(6): 1438. CrossRef
Progressive Familial Intrahepatic Cholestasis: A Study in Children From a Liver Transplant Center in India
Sagar Mehta, Karunesh Kumar, Ravi Bhardwaj, Smita Malhotra, Neerav Goyal, Anupam Sibal
Journal of Clinical and Experimental Hepatology.2022; 12(2): 454. CrossRef
Liver transplantation in pediatric patients with progressive familial intrahepatic cholestasis: Single center experience of seven cases
Jung-Man Namgoong, Shin Hwang, Hyunhee Kwon, Suhyeon Ha, Kyung Mo Kim, Seak Hee Oh, Seung-Mo Hong
Annals of Hepato-Biliary-Pancreatic Surgery.2022; 26(1): 69. CrossRef
Liver Transplantation for Pediatric Hepatocellular Carcinoma: A Systematic Review
Christos D. Kakos, Ioannis A. Ziogas, Charikleia D. Demiri, Stepan M. Esagian, Konstantinos P. Economopoulos, Dimitrios Moris, Georgios Tsoulfas, Sophoclis P. Alexopoulos
Cancers.2022; 14(5): 1294. CrossRef
Morphology of transplanted liver in recurrent progressive familial intrahepatic cholestasis type 2
I. M. Iljinsky, N. P. Mozheiko, O. M. Tsirulnikova
Russian Journal of Transplantology and Artificial Organs.2021; 22(4): 192. CrossRef

Case Studies

Bile Granuloma Mimicking Peritoneal Seeding: A Case Report: Hasong Jeong, Hye Won Lee, Hye Ra Jung, Ilseon Hwang, Sun Young Kwon, Yu Na Kang, Sang Pyo Kim, Misun Choe; J Pathol Transl Med. 2018;52(5):339-343. Published online July 16, 2018; DOI: https://doi.org/10.4132/jptm.2018.06.02

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Abstract PDF

Laparoscopic cholecystectomy is a widely used treatment method for most cholelithiasis and is a relatively safe procedure. Foreign body granulomatous reaction to bile or gallstone spillage during laparoscopic cholecystectomy has rarely been reported. We report a case of bile granuloma after laparoscopic cholecystectomy, which mimicked peritoneal seeding. A 59-year-old Korean man presented with right upper quadrant pain. He underwent laparoscopic cholecystectomy for acute cholecystitis with cholelithiasis. Pathologic examination revealed an incidental adenocarcinoma invading the lamina propria with acute cholecystitis and cholelithiasis. After 3 months, follow-up abdominal computed tomography revealed a subhepatic nodule, which showed hypermetabolism on positron emission tomography–computed tomography. Suspecting localized peritoneal seeding, wedge resection of the liver, wedge resection of the transverse colon, and omentectomy were performed. Pathologic examination of the resected specimens revealed multiple bile granulomas. Awareness of bile granuloma mimicking malignancy is noteworthy for patient management to reduce unnecessary procedure during postoperative surveillance.

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A mimic of peritoneal metastatic disease, multifocal intraabdominal foreign body granulomas secondary to feculent peritonitis
Damien Gibson, Christo Joseph, Diarmid P. Foulis, Christophe R. Berney
ANZ Journal of Surgery.2024;[Epub] CrossRef
Practices and Attitudes of Surgeons With Regard to Spilled Gallstones During Laparoscopic Cholecystectomy: A Cross-Sectional Study From Saudi Arabia
Mohammed Alfehaid, Moath Aljohani, Sajad A Salati , Shoug Alaodah, Wejdan Alresheedi, Raghad Almarshud
Cureus.2024;[Epub] CrossRef
Spilled gallstone mimicking intra-abdominal seeding of gallbladder adenocarcinoma: A case report
Cheng-Ken Huang, Ruey-Hwa Lu, Chien-Cheng Chen, Po-Chun Chen, Wen-Chang Hsu, Meng-Jui Tsai, Chin-Tsung Ting
World Journal of Gastrointestinal Surgery.2024; 16(2): 622. CrossRef
Biliary Granulomatous Peritoneal Reaction as Consequence of Cholecystectomy: Case Report and Literature Review
Giuseppe Tarantino, Denise Menghini, Maria Eva Argenziano, Miriam Palmieri, Alessandra Mandolesi, Enrico Dalla Bona, Antonio Benedetti, Mario Guerrieri, Maria Giovanna Danieli
SN Comprehensive Clinical Medicine.2023;[Epub] CrossRef
Foreign body reaction mimicking local recurrence from polyactide adhesion barrier film after laparoscopic colorectal cancer surgery
Tien-Chan Hsieh, Chao-Wen Hsu
Medicine.2022; 101(5): e28692. CrossRef
Spilled gallstones after laparoscopic cholecystectomy: a systematic review
Sajad Ahmad Salati, Mohammed Alfehaid, Saleh Alsuwaydani, Lamees AlSulaim
Polish Journal of Surgery.2022; 94(4): 1. CrossRef
Foreign body granulomas mimic peritoneal dissemination caused by incarcerated femoral hernia perforation: A case report
Shinpei Ogino, Tatsuya Matsumoto, Yosuke Kamada, Noriaki Koizumi, Hiroshi Fujiki, Kenji Nakamura, Takeshi Yamano, Chouhei Sakakura
World Journal of Clinical Oncology.2021; 12(11): 1083. CrossRef

Isolated Mass-Forming IgG4-Related Cholangitis as an Initial Clinical Presentation of Systemic IgG4-Related Disease: Seokhwi Kim, Hyunsik Bae, Misun Choi, Binnari Kim, Jin Seok Heo, Ho Seong Kim, Seung Hee Choi, Kee-Taek Jang; J Pathol Transl Med. 2016;50(4):300-305. Published online January 11, 2016; DOI: https://doi.org/10.4132/jptm.2015.12.01

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Abstract PDF

IgG4-related disease (IgG4-RD) may involve multiple organs. Although it usually presents as diffuse organ involvement, localized mass-forming lesions have been occasionally encountered in pancreas. However, the same pattern has been seldom reported in biliary tract. A 61-year-old male showed a hilar bile duct mass with multiple enlarged lymph nodes in imaging studies and he underwent trisectionectomy under impression of cholangiocarcinoma. Gross examination revealed a mass-like lesion around hilar bile duct. Histopathologically, dense lymphoplasmacytic infiltration and storiform fibrosis were identified without evidence of malignancy. Immunohistochemical stain demonstrated rich IgG4-positive plasma cell infiltration. Follow-up imaging studies disclosed multiple enlarged lymph nodes with involvement of pancreas and perisplenic soft tissue. The lesions have been significantly reduced after steroid treatment, which suggests multi-organ involvement of systemic IgG4-RD. Here, we report an unusual localized mass-forming IgG4-related cholangitis as an initial presentation of IgG4-RD, which was biliary manifestation of systemic IgG4-related autoimmune disease.

Citations

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Pathologic interpretation of endoscopic ultrasound–guided fine needle aspiration cytology/biopsy for pancreatic lesions
Haeryoung Kim, Kee-Taek Jang
Journal of Pathology and Translational Medicine.2020; 54(5): 367. CrossRef
Multivisceral IgG4-related disease presenting as recurrent massive gastrointestinal bleeding: a case report and literature review
Xuexue Deng, Ronghua Fang, Jianshu Zhang, Rongqiong Li
BMC Gastroenterology.2018;[Epub] CrossRef
Recent advances in understanding and managing IgG4-related disease
Anna R. Wolfson, Daniel L. Hamilos
F1000Research.2017; 6: 185. CrossRef

Original Article

Expression of Raf-1 Kinase Inhibitory Protein in Extrahepatic Bile Duct Carcinoma.: Hyun Soo Kim, Gou Young Kim, Sung Jig Lim, Youn Wha Kim; Korean J Pathol. 2010;44(3):234-242.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.3.234

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Abstract PDF

BACKGROUND
Raf-1 kinase inhibitory protein (RKIP) recently has been identified as a metastasis suppressor in a variety of human carcinomas. The prognostic significance of RKIP expression in extrahepatic bile duct (EBD) carcinoma has not been studied. The aims of the current study were to evaluate RKIP expression and to determine the prognostic significance of RKIP expression in EBD carcinoma.
METHODS
Immunohistochemical staining for RKIP was performed for 131 cases of EBD carcinoma. The associations of RKIP expression with clinicopathologic parameters and patient outcomes were examined. Multivariate logistic regression analysis was used to identify independent predictive parameters for lymphovascular invasion and nodal and distant metastases.
RESULTS
Loss of RKIP expression was observed in 55.0% (72/131) of cases. EBD carcinoma had significantly lower RKIP immunoreactivity than normal EBD (p < 0.001). Loss of RKIP expression was significantly associated with lymphatic invasion (p = 0.030) and nodal metastasis (p = 0.036), but it was not found to be a significant prognostic predictor for overall, disease-free or distant metastasis-free survival. In addition, loss of RKIP expression was an independent predictor for lymphatic invasion (p = 0.027).
CONCLUSIONS
These results suggest that RKIP may play a role in the suppression of lymphatic invasion and nodal metastasis in EBD carcinoma.

Citations

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Down-regulation of osteoprotegerin expression as a novel biomarker for colorectal carcinoma
Hyun-Soo Kim, Gun Yoon, Sung-Im Do, Sung-Joo Kim, Youn-Wha Kim
Oncotarget.2016; 7(12): 15187. CrossRef
Expression of phosphorylated extracellular signal-regulated kinase at the invasive front of hepatic colorectal metastasis
HYUN-SOO KIM, SUNG-IM DO, BYEONG-JOO NOH, YOUNG IN JEONG, SUN JIN PARK, YOUN WHA KIM
Oncology Letters.2015; 9(3): 1261. CrossRef
Reduced expression of Raf-1 kinase inhibitory protein predicts regional lymph node metastasis and shorter survival in esophageal squamous cell carcinoma
Hyun-Soo Kim, Kyu Yeoun Won, Gou Young Kim, Soo Cheol Kim, Yong-Koo Park, Youn Wha Kim
Pathology - Research and Practice.2012; 208(5): 292. CrossRef
Expression of Raf-1 kinase inhibitory protein in carcinoma of the ampulla of Vater
Hyun-Soo Kim, Sun Ho Lee, Kyu Yeoun Won, Gou Young Kim, Yong-Koo Park, Youn Wha Kim
Virchows Archiv.2012; 460(1): 61. CrossRef
Raf-1 Kinase Inhibitory Protein Expression in Thyroid Carcinomas
Hyun-Soo Kim, Gou Young Kim, Sung-Jig Lim, Youn Wha Kim
Endocrine Pathology.2010; 21(4): 253. CrossRef
Loss of Raf-1 kinase inhibitory protein in pancreatic ductal adenocarcinoma
Hyun-Soo Kim, Gou Young Kim, Sung-Jig Lim, Youn Wha Kim
Pathology.2010; 42(7): 655. CrossRef

Case Report

Intraductal Papillary Mucinous Tumor Simultaneously Involving the Liver and Pancreas: A Case Report.: Bong Hee Park, Jae Hee Suh, Hee Jeong Cha, Young Min Kim, Hye Jeong Choi; Korean J Pathol. 2010;44(1):83-86.; DOI: https://doi.org/10.4132/KoreanJPathol.2010.44.1.83

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Abstract PDF

We describe here a 67-year-old man who was diagnosed with a rare case of intraductal papillary mucinous tumors that occurred simultaneously in the liver and pancreas. Abdominal computed tomography showed a tubular and cystic dilatation of the pancreatic duct in the pancreas tail, which suggested an intraductal papillary mucinous tumor (IPMT), and multiple intrahepatic duct stones. The patient underwent a distal pancreatectomy with splenectomy and a lateral segmentectomy of the liver. Microscopic examination showed an intraductal papillary mucinous neoplasms of borderline malignancy in the pancreas and a non-invasive intraductal papillary mucinous tumor with moderate dysplasia of the bile duct. Although several cases of intraductal papillary mucinous neoplasm of the liver (IPNL) without any pancreatic association have been described, the simultaneous presentation of both IPMT of the pancreas and IPNL is very rare. The patient has been doing well for 10 months postoperatively.

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Reoperation for heterochronic intraductal papillary mucinous neoplasm of the pancreas after bile duct neoplasm resection: A case report
Gang Xiao, Tao Xia, Yi-Ping Mou, Yu-Cheng Zhou
World Journal of Gastrointestinal Surgery.2023; 15(7): 1542. CrossRef
Intraductal papillary neoplasm of the bile duct: The new frontier of biliary pathology
Federico Mocchegiani, Paolo Vincenzi, Grazia Conte, Daniele Nicolini, Roberta Rossi, Andrea Benedetti Cacciaguerra, Marco Vivarelli
World Journal of Gastroenterology.2023; 29(38): 5361. CrossRef
Multicentric recurrence of intraductal papillary neoplasm of bile duct after spontaneous detachment of primary tumor: A case report
Hiroki Fukuya, Akifumi Kuwano, Shigehiro Nagasawa, Yusuke Morita, Kosuke Tanaka, Masayoshi Yada, Akihide Masumoto, Kenta Motomura
World Journal of Clinical Cases.2022; 10(3): 1000. CrossRef
Co-occurrence of IPMN and malignant IPNB complicated by a pancreatobiliary fistula: A case report and review of the literature
Xu Ren, Chun-Lan Zhu, Xu-Fu Qin, Hong Jiang, Tian Xia, Yong-Ping Qu
World Journal of Clinical Cases.2019; 7(1): 102. CrossRef
Synchronous pancreatic adenocarcinoma and intrahepatic cholangiocarcinoma arising in the context of intraductal papillary neoplasms
Anmol Bansal, Swan N. Thung, Hongfa Zhu, Myron Schwartz, Sara Lewis
Clinical Imaging.2016; 40(5): 897. CrossRef

Original Articles

Immunohistochemical Study about the Origin of Bile Ductules Proliferation in Obstructive Liver Disease.: Hyun Jung Sung, Byung Chul Ann, Jae Tae Lee, Yoon Seup Kum, Jae Bok Park, Kwan Kyu Park; Korean J Pathol. 2009;43(2):126-132.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.2.126

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Abstract PDF: BACKGROUND
The relationship between bile duct proliferation and portal fibrosis in obstructive liver diseases remains unclear. The purpose of this study is to analyze the relationship between hepatic stellate cells (HSC), hepatocytes and bile ductule proliferation in obstructive liver disease using immunoreactivity for alpha-SMA (alpha-smooth muscle actin), CK7, and CK19.
METHODS
We used 20 human tissue samples with hepatic fibrosis due to intrahepatic stones and liver cirrhosis. Immunohistochemical staining was performed using the streptavidin-biotin method.
RESULTS
Proliferations of bile ductules at the periphery of the hepatic lobules, and diffuse HSC activation in the perisinusoidal spaces were observed in all cases. Immunoreactivity of the hepatocytes for CK7 and CK19 suggested a possible phenotypic transformation into bile duct epithelium during fibrogenesis. Immunohistochemical-analyses of alpha-SMA expression profiles showed that intralobular HSCs and some hepatocytes underwent early phenotypic changes, and that the accumulation of collagen coincides with that of alpha-SMA-labeled myofibroblasts around portal/septal ductular structures.
CONCLUSIONS
Our results showed the possibility of a phenotypic transformation of hepatocytes into bile ductular epithelium. It is suggested that hepatocytes might play a role in bile ductule proliferation in obstructive liver disease.

Alteration of Bile Acid Transporter Expression in Patients with Early Cholestasis Following Living Donor Liver Transplantation.: Eun Sun Jung, Byung Kee Kim, So Youn Kim, Youn Soo Lee, Si Hyun Bae, Seung Kew Yoon, Jong Young Choi, Young Min Park, Dong Goo Kim; Korean J Pathol. 2009;43(1):48-55.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.1.48

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Abstract PDF: BACKGROUND
Intrahepatic cholestasis can occur early after living donor liver transplantation (LDLT). We investigated the changes in the expressions of the bile acid transporters and the liver histology in the patients who suffered with early cholestasis (EC) following LDLT.
METHODS
The histological differences between 15 graft livers with EC after LDLT and 5 graft livers with biliary stricture following LDLT were evaluated. The hepatic mRNA levels of the bile canaliculi transporters (BSEP, MRP2, MRP3, MDR1, MDR3, NTCP) in 40 (20 graft livers, 20 matched donor livers) liver biopsy tissues were analyzed by performing real-time reverse-transcription polymerase chain reaction (RT-PCR).
RESULTS
Microscopic examination revealed hepatocellular and/or bile canalicular cholestasis around acinar zone 3 in the livers of the patients with EC. In the livers with biliary stricture, the cholestasis was dominantly observed in the hepatocytic cytoplasm and in the bile ductules around the portal area rather than around acinar zone 3. The BSEP and MRP2 mRNA levels in the EC livers were significantly reduced by 44% and 23%, respectively (p=0.000), compared to the matched donor livers. The levels of MDR3 and NTCP mRNA in the EC livers increased by 738% (p=0.000) and 281% (p<0.01), respectively. The change of the expressions of the bile acid transporters in the patients with biliary stricture was less significant than that in the EC group.
CONCLUSIONS
These results suggest that the altered expressions of the bile acid transporters may play a role in the pathogenesis of EC following LDLT.

The Clinicopathological Parameters for Making the Differential Diagnosis of Neonatal Cholestasis.: Heejin Lee, Jun Kang, Kyung Mo Kim, Joo Young Jang, Se Jin Jang, Eunsil Yu; Korean J Pathol. 2009;43(1):43-47.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.1.43

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Abstract PDF

BACKGROUND
The diseases that cause neonatal cholestasis display several overlapping clinical feature. Making the differential diagnosis using liver biopsy specimens from infants with neonatal cholestasis is important for delivering the proper treatment.
METHODS
We assessed the clinical manifestations, laboratory data, and histopathologic features of the pretreatment liver biopsy specimens from patients suffering with biliary atresia (n=66), intrahepatic bile duct paucity (n=15), and neonatal hepatitis (n=21).
RESULTS
The gender distribution was nearly equal for the patients with biliary atresia and intrahepatic bile duct paucity, whereas males predominated for the cases of neonatal hepatitis. Only the gamma-glutamyl transferase level differed significantly amongst the groups. The diagnostic features for making the differential diagnosis of bile duct lesions included marked bile ductular proliferation, severe fibrosis, and bile duct loss. The difference of the average percentage of portal tracts with bile duct loss was statistically significant between the patients with intrahepatic bile duct paucity (73.9%) and those patients with neonatal hepatitis (39.1%) (p<0.001).
CONCLUSIONS
Bile ductular proliferation, bile duct loss, and advanced fibrosis are useful for the differential diagnosis of neonatal cholestasis. Moreover, stricter diagnostic criteria for bile duct loss (more than 2/3 of bile ducts) should be applied for the definitive diagnosis of intrahepatic bile duct paucity, because bile duct loss also frequently occurs in infants suffering with neonatal hepatitis.

Citations

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False-negative Hepatobiliary Scintigraphy for Biliary Atresia
Hyunji Kim, Sujin Park, Sejin Ha, Jae Seung Kim, Dae Yeon Kim, Minyoung Oh
Nuclear Medicine and Molecular Imaging.2019; 53(5): 356. CrossRef
Morphometric assessment of liver fibrosis may enhance early diagnosis of biliary atresia
Ahmed F. Abdalla, Abeer Fathy, Khaled R. Zalata, Ahmed Megahed, Ahmed Abo-Alyazeed, Mohammed Ezz El regal
World Journal of Pediatrics.2013; 9(4): 330. CrossRef
Differential hepatic expression of CD56 can discriminate biliary atresia from other neonatal cholestatic disorders
Mostafa Mohamed Sira, Mohamed Abdel-Salam El-Guindi, Magdy Anwar Saber, Nermin Ahmad Ehsan, Marwa Sabry Rizk
European Journal of Gastroenterology & Hepatology.2012; 24(10): 1227. CrossRef
Biliary Atresia: A Multidisciplinary Approach to Diagnosis and Management
Roger Klein Moreira, Rodrigo Cabral, Robert A. Cowles, Steven J. Lobritto
Archives of Pathology & Laboratory Medicine.2012; 136(7): 746. CrossRef
Tentative Proposal of Optimal Timing of Kasai Operation for Biliary Atresia Based on Fibroscan Results
Hwa Young Lee, Young A Park, Seok Joo Han, Hong Koh
Korean Journal of Pediatric Gastroenterology and Nutrition.2011; 14(1): 74. CrossRef

Ultrastructural Changes of the Bile Canaliculi after Common Bile Duct Ligation.: Kook Seon Yoo, Suk Hee Lee, Hee Kyung Park, Chang Ho Cho, Jong Min Chae; Korean J Pathol. 1996;30(3):175-183.

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Abstract PDF: The purpose of this study was to investigate the morphologic changes of the bile canaliculi and its associated structures of the liver induced by common bile duct ligation(CBDL) in the rat. The canalicular surface and lateral surface of the dry-fractured hepatocytes was studied with scanning electron microscopy at 1~6 weeks post ligation. The first week after CBDL, the bile canaliculi were dilated. The microvilli were increased in number and the lumens contained granular materials After 2 weeks or more, the bile canaliculi were dilated to a variable degree, and with irregularity, measuring from 1.5 to 5 micrometer in diameter, and in the advanced stage, the canaliculi showed blunting and the disappearance of microvilli. Some canaliculi had sprouting side branches. At 4~6 weeks post-ligation, the lateral surface of the hepatocytes also showed some irregularity and a tortuous appearance, and numerous small sized microvillous projections were formed. The tubular structures of the proliferated SER distributed adjacent to the lateral surface of the hepatocytes, and the direct connection of a tubular structure and the cytoplasmic membrane was observed. These results suggest that the deformity and loss of microvilli of bile canaliculi reflect the disturbance of bile secretion from the hepatocytes. And prolonged obstruction of bile flow may result in bile excretion via the lateral surface of hepatocytes.

The Observation of Histologic Changes of Major Intrahepatic Bile Duct Epithelium in the Resected Liver Tissue with Hepatolithiasis.: Woon Sup Han, Sae Kyung Choi, Sun Hee Sung; Korean J Pathol. 2001;35(1):20-25.

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Abstract PDF: BACKGROUND
The relationship between hepatoliths and cholangiocarcinoma is etiologically unclear. However, histogenetic sequencing with hyperplasia, dysplasia and carcinoma can occur in the bile ducts of hepatolithiasis.
METHODS
We studied 55 cases of hepatolithiasis and examined the specimens of resected liver tissue with a microscope. The growth patterns of bile duct epithelium were divided into four types: flat, tufting, micropapillary and papillary. The dysplasia was also divided into low-grade dysplasia (LGD) and high-grade dysplasia (HGD).
RESULTS
Of 55 cases of hepatolithiasis, 30 cases (54.6%) were of the flat pattern, 13 cases (23.6%) the micropapillary pattern, and 11 cases (20%) the tufting pattern. Epithelial hyperplasia was noted in only 36 cases (65.5%) in the large bile ducts, but dysplastic changes were found in 19 cases. Of 19 cases of dysplasia, LGD was present in 14 cases (25.5% of total 55 cases) an HGD in 5 cases (9% of total 55 cases). The epithelial hyperplasia showed histologic growth of the flat pattern in 29 cases out of 36 cases. But LGD (14 cases) had 6 cases of the tufting pattern and 7 cases of the micropapillary pattern. HGD (5 cases) revealed 4 cases of the micropapillary pattern with one case of the tufting pattern.
CONCLUSION
This study suggests that sequences of hyperplasia, low-grade dysplasia and high-grade dysplasia can play a role in the carcinogenesis of bile duct epithelium in hepatolithiasis with the histologic pattern changing from flat to micropapillary growth.

Pathological Analysis of 62 Liver Biopsy Cases with Hepatocellular Cholestasis: Drug and Toxin Induced Liver Injury.: Min Sun Cho, Young Nyun Park, Myeong Jin Kim, Kwang Jo Chae, Chanil Park; Korean J Pathol. 2001;35(2):123-128.

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Abstract PDF: BACKGROUND
Hepatocellular cholestasis denotes the alteration of bile secretion by hepatocytes. The causes, degree of hepatocyte injury and concomitant bile duct loss are considered to influence the clinical course.
METHODS
The causes and pathological features of hepatocellular cholestasis were analyzed in 62 cases of liver biopsies; and the causes of primary biliary cirrhosis, primary sclerosing cholangitis, and biliary obstruction were not included.
RESULTS
The mean age of the patients was 42.2 years, and the ratio of male to female was 1.8:1. Fifty-eight cases (94%) showed cholestatic hepatitis, and 4 cases (6%) showed pure cholestasis without hepatitis activity. The majority of the cases (52 cases, 84%), including 19 cases of herbal medicine, was related to drugs. Loss of bile duct was found in 12 cases (19%), which were all cases of chronic cholestasis. All of them had drug histories, including 9 cases of herbal medicine. Clinical follow-up was performed in 9 out of the 12 cases with bile duct loss, and all of them showed elevated total bilirubin and/or alkaline phosphatase levels for more than 6 months.
CONCLUSION
Drugs are the major cause of hepatocellular cholestatic hepatitis/cholestasis; and information about drugs, including herbal medicines, should be considered for proper evaluation of liver biopsy with hepatocellular cholestasis. Bile duct loss should be evaluated in the cases of chronic hepatocellular cholestasis, especially in drug induced cases.

Expression of Proliferating Cell Nuclear Antigen (PCNA) of Major Intrahepatic Bile Duct Epithelium in Resected Liver Tissue with Hepatolithiasis and Hepatolithiasis Associated with Cholangiocarcinoma.: Shi Nae Lee, Sun Hee Sung, Woon Sup Han; Korean J Pathol. 2002;36(4):232-237.

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Abstract PDF: BACKGROUND
Histologic progressive changes of bile duct epithelium with hyperplasia, dysplasia and cholangiocarcinoma could be caused by hepatolithiasis. To be clarified as a neoplastic process, this histologic process should be evaluated with various aspects of cell biology.
METHODS
Immunohistochemical study of proliferating cell nuclear antigen (PCNA) was performed on 45 cases (10; normal, 15; hyperplasia, 14; low-grade dysplasia:LGD, 6; high-grade dysplasia: HGD) of hepatolithiasis and 10 cases (all HGD) of hepatolithiasis with cholangiocarcinoma.
RESULTS
In the hepatolithiasis, mean PCNA labelling indices (LI) of normal, hyperplasia, LGD and HGD of major intrahepatic bile duct epithelium were 24.5+/-4.3, 51.5+/-0.1, 62.0+/-.4 and 84.7+/-.3, respectively and gradually increased. Mean LI of PCNA in HGD of major intrahepatic bile duct epithelium of hepatolithiasis with cholangiocarcinoma was 68.7+/-.7, which was similar to that of LGD in hepatolithiasis without cholangiocarcinoma.
CONCLUSIONS
Histologic transformation through hyperplasia, dysplasia and carcinoma in major intrahepatic bile duct epithelium of hepatolithiasis may be a neoplastic process if these histologic changes are evaluated in the cellular proliferation aspect.

Utility of Bile Duct Brush Cytology in Pancreaticobiliary Diseases: Prospective Comparative Study of Conventional Smear and MonoPrep2(TM) Liquid Based Cytology.: So Young Jin, Dong Wha Lee, Mee Sun Kim, Young Deok Cho, Young Koog Cheon, Min Sung Choi, Dong Won Kim; Korean J Cytopathol. 2006;17(1):38-45.

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Abstract PDF: Bile duct brush cytology has been employed as a diagnostic tool for the evaluation of pancreatic and biliary tract strictures. The specificity of this method is high however, its sensitivity is quite low. A recent study employing liquid based cytology (LBC) reported results comparable to those achieved via conventional cytology. Therefore, we have attempted to prospectively evaluate the diagnostic utility of bile duct brush cytology in pancreaticobiliary diseases. A total of 46 cases with bile duct stricture were enrolled including 11 cases of benign stricture, 29 cases of bile duct carcinoma, 3 cases of gallbladder cancer, and 3 cases of pancreatic cancer. Both conventional smear and LBC using MonoPrep2(TM) system were conducted in each case. The cytological diagnosis of each case was classed into the following categories; benign, suspicious for malignancy, and malignancy. The diagnostic accuracy of both cytologic methods was investigated. LBC evidenced a high rate of material insufficiency (13/46), which was attributed to low cellularity. The kappa index of both cytological methods was 0.508. Cytological and tissue diagnoses were correlated in 25 cases conducted from biopsy or operation. The sensitivity, specificity, positive predictive value, and negative predictive value were 41.2% (7/17), 100% (8/8), 100% (7/7), and 44.4% (10/18) in conventional smear; 58.8% (10/17), 87.5% (7/8), 90.9% (10/11), and 50.0% (7/14) in LBC; and 94.1% (16/17), 87.5% (7/8), 94.1% (16/17), and 87.5% (7/8) in any one of both cytological methods, respectively. Based on these results, the sensitivity of LBC was found to be superior to that of conventional smear and we were able to obtain higher positive predictive value upto 94.1% by simultaneously conducting both cytologic methods.

Case Report

Undifferentiated Carcinoma Arising in a Choledochal Cyst: A Case Report.: Hee Eun Lee, Chang Lim Hyun, You Jeong Lee, Hye Sil Seol, Ja June Jang; Korean J Pathol. 2006;40(6):461-465.

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Abstract PDF: An association between choledochal cyst and carcinoma is well established. Here, we report an extremely rare case of undifferentiated carcinoma exhibiting extensive sarcomatous features arising in a choledochal cyst. The patient in our case had a radiologically confirmed choledochal cyst and anomalous pancreaticobiliary ductal union, and mild wall thickening in the cyst was observed on endoscopic retrograde cholangiopancreatography. The patient underwent common bile duct excision and cholecystectomy. In the choledochal cyst, a nodule measuring 1.5x1 cm was detected. The lesion was composed of atypical, spindle-shaped and large, round pleomorphic tumor cells simulating sarcoma. Neither glandular nor squamous differentiation was observed. These cells were immunoreactive for both vimentin and cytokeratin by immunohistochemistry. These histologic and immunohistochemical findings were consistent with undifferentiated carcinoma, spindle and giant cell type, according to the WHO classification.

Original Article

Expression of the 14-3-3 sigma Protein and Methylation Status of the 14-3-3 sigma gene in Biliary Neoplasms.: Dong Eun Song, Se Jin Jang, Jung Sun Kim, Sang Soo Lee, Myung Hwan Kim, Seung Gyu Lee, Young Joo Lee, Hae Joung Park, Yhong Hee Shim, Eunsil Yu; Korean J Pathol. 2006;40(1):9-16.

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Abstract PDF: BACKGROUND
The 14-3-3 sigma (sigma) protein has a negative regulatory role in the cell cycle progression of the. Down-regulation or overexpression of the 14-3-3 sigma protein has been reported in various human cancers.
METHODS
Immunohistochemistry for the 14-3-3 sigma protein was performed in non-neoplastic bile duct cells, intraductal papillary neoplasms of the liver (IPNL), mass-forming intrahepatic cholangiocarcinomas (ICC) and non-papillary extrahepatic cholangiocarcinomas (ECC). We investigated the methylation status of the 14-3-3 sigma gene in 45 cases of these 3 tumor groups.
RESULTS
The non-neoplastic bile duct cells demonstrated negative or weakly positive cytoplasmic immunoreactivity for the 14-3-3 sigma protein and no methylation of the 14-3-3 sigma gene. Overexpression as well as negative immunoreactivity associated with hypermethylation of the 14-3-3 sigma protein was observed in 16 (69.6%) of 23 cases of IPNL, in 21 (63.6%) of 33 cases of mass-forming ICC and in 27 (71.1%) of 38 cases of non-papillary ECC. Negative immunoreactivity was increased in the invasive IPNL (4/6, 66.7%), as well as in the poorly differentiated cases of mass-forming ICC (8/12, 66.7%) and the non-papillary ECC (5/8, 62.5%).
CONCLUSIONS
The similar rates for the abnormal expression of the 14-3-3 sigma protein among the three groups of biliary neoplasms indicate its general association with biliary carcinogenesis. Furthermore, the loss of the 14-3-3 sigma protein may be involved in the tumor progression and differentiation in the biliary carcinogenesis.

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