Elsevier

Human Pathology

Volume 43, Issue 12, December 2012, Pages 2177-2186
Human Pathology

Original contribution
Immunohistochemical characteristics and malignant progression of hepatic cystic neoplasms in comparison with pancreatic counterparts

https://doi.org/10.1016/j.humpath.2012.03.007Get rights and content

Summary

The recent World Health Organization classification for tumors of the digestive system defined grossly and histologically hepatic mucinous cystic neoplasms and intraductal papillary neoplasms of the bile duct separately. In this study, the immunohistochemical features of intraductal papillary neoplasm of the bile duct (19 cases) and hepatic mucinous cystic neoplasm (5 cases) were characterized and compared with those of similar pancreatic lesions, intraductal papillary mucinous neoplasm of the pancreas (12 cases), and pancreatic mucinous cystic neoplasm (6 cases) and with those of other biliary cystic lesions, peribiliary cysts (10 cases). Intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas frequently expressed cytokeratin 7; mucin core proteins 1, 2, 5AC, and 6; trypsin; and amylase. Hepatic and pancreatic mucinous cystic neoplasms frequently expressed cytokeratin 7, mucin core proteins 1 and 5AC, estrogen receptor, progesterone receptor, trypsin, and amylase. Estrogen and progesterone receptors were expressed in the subepithelial stromal cells. The groups with intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas were different from the groups with hepatic and pancreatic mucinous cystic neoplasm with respect to several phenotypes reflecting gastric and intestinal metaplasia and also the lack of expression of estrogen and progesterone receptors. The Ki-67 and p53 labeling indexes increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. The p16 labeling index decreased and EZH2 labeling index increased significantly with the malignant progression of intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas. In conclusion, intraductal papillary neoplasm of the bile duct and hepatic mucinous cystic neoplasm might be regarded as biliary counterparts of intraductal papillary mucinous neoplasm of the pancreas and pancreatic mucinous cystic neoplasm, respectively, and the mucinous cystic neoplasm and intraductal papillary neoplasm groups differed from each other. Labeling indexes of Ki-67, p53, p16, and EZH2 were comparable in intraductal papillary neoplasm of the bile duct and intraductal papillary mucinous neoplasm of the pancreas along with their malignant progression, suggesting a common carcinogenic process of the tumors.

Introduction

The recent World Health Organization classification defined hepatic mucinous cystic neoplasms (MCN-Hs) as cyst-forming epithelial neoplasms, usually showing no communication with bile ducts, composed of cuboidal to columnar, mucin-producing epithelium [1]. An association with an ovarian-type subepithelial stroma characterizes MCN-H. A unique biliary tumor named intraductal papillary neoplasm of the bile duct (IPNB) has been proposed as another biliary cystic neoplasm [2], [3], [4], [5], [6]. IPNB is considered a biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas (IPMN) on the basis of predominant papillary intraductal growth, ductal dilatation, and not-infrequent overproduction of mucin, as well as, frequently, communication with the neighboring bile duct lumen [2], [3], [4], [5], [6]. These 2 types of cystic neoplasm need to be distinguished from other cystic liver lesions including simple cysts and peribiliary cysts (PB cysts) [1], [7].

Polycomb group proteins are epigenetic chromatin modifiers involved in cancer development. Polycomb group proteins exist in at least 2 separate complexes, polycomb repressive complex (PRC)2 and PRC1 [8], [9], [10]. Bmi1 and EZH2 are representative of PRC1 and PRC2, respectively. Recent studies showed that EZH2 is a chromatin-modifying enzyme and interacts with key elements that control cell growth and proliferation such as the genes Rb and p16INK4a [9], [10]. p16 and EZH2 are reportedly involved in the progression from biliary intraepithelial neoplasia (BilIN), a premalignant or early neoplastic biliary lesion, to invasive cholangiocarcinoma [8]. Cell proliferative activity and the aberrant expression of p53 are known to increase with the progression of BilIN and also IPNB [9], [10]. IPNB and MCN-H are also known as preneoplastic and early neoplastic lesions followed by invasive cholangiocarcinoma (tubular adenocarcinoma and mucinous carcinoma) [1], [2], [11]. However, the exact molecular and genetic mechanisms associated with the malignant progression of IPNB and MCN-H with respect to pancreatic counterparts remain unexplored.

Recent pathologic studies suggested that IPNB and MCN-H correspond to IPMN and MCN of the pancreas (MCN-P), respectively [5]. IPMN and MCN-P are known to progress to invasive carcinoma of the pancreas. However, an exact comparison of these pancreatic and biliary neoplasms with respect to immunophenotypes and malignant progression has yet to be undertaken.

In this study, the immunohistochemical characteristics of IPNB and MCN-H were compared with those of pancreatic counterparts and PB cysts. The mechanisms behind the progression of IPNB and MCN-H with respect to cell kinetics, p53, EZH2, and p16 were also compared with those for pancreatic counterparts, IPMN and MCN-P, by using surgically resected specimens.

Section snippets

Case selection

A total of 19 cases of IPNB, 5 cases of MCN-H, 10 cases of PB cysts, 12 cases of IPMN, and 6 cases of MCN-P were collected from the Department of Human Pathology, Kanazawa University Graduate School of Medicine; the Pathologic Diagnostic Service, Kanazawa University Hospital; and affiliated hospitals (1993-2011). All except 3 autopsy specimens of PB cysts were surgically resected. The pathologic diagnosis of these diseases and also the histologic grading of IPNB, MCN-H, PB cysts, IPMN, and

Immunophenotypes

Typical immunohistochemical expression patterns of CKs, MUCs, ER, PgR, amylase, and trypsin are shown in Fig. 1. CK7 (Fig. 1A) and CK20 (Fig. 1B) were expressed in the cytoplasm of neoplastic epithelial cells in cases of IPNB. MUC1 (Fig. 1C), MUC2 (Fig. 1D), MUC5AC (Fig. 1E), and MUC6 (Fig. 1F) were expressed in the cytoplasm and also on the luminal surface of neoplastic epithelial cells in cases of IPNB. Amylase (Fig. 1G) and trypsin (Fig. 1H) were expressed in the cytoplasm of neoplastic

Discussion

There have been several reports on radiologic and histologic studies concerning similarities between IPNB and IPMN and also between MCN-H and MCN-P [2], [6], [7]. This study additionally revealed that there were immunophenotypic similarities between IPNB and IPMN and between MCN-H and MCN-P, and also some differences between the MCN group (MCN-H and MCN-P) and IPN group (IPNB and IPMN). The MCN group differed from the IPN group with respect to the expression of ER and PgR, owing to the presence

Acknowledgments

The authors thank Dr Shin Ishiyama and Dr Akio Uchiyama (Department of Human Pathology, Toyama Prefectural Central Hospital, Toyama, Japan) and Dr Tetsuo Ohta and Dr Hirohisa Kitagawa (Department of Gastroenterological Surgery, Kanazawa University Graduate School of Medicine, Kanazawa, Japan) for providing tissue samples.

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