Abstract
Neuroendocrine neoplasms in hepatobiliary organs are very rare, but several cases of mixed adenoneuroendocrine carcinoma (MANEC) have been reported. In this study, we characterized the neuroendocrine component of biliary MANEC. A total of 274 cases of biliary cancer including 17 intrahepatic cholangiocarcinomas (CCs), 15 hepatic hilar CCs without preceding hepatobiliary disease, 55 hepatic hilar CCs with hepatolithiasis, 49 gallbladder cancers, 53 extrahepatic CCs, and 85 hepatocellular carcinomas were examined for a neuroendocrine component using immunohistochemistry with neuroendocrine markers (chromogranin A and synaptophysin). In the MANEC cases, in addition to a close histological examination, the proliferative activity and the expression of somatostatin receptor 2A were also evaluated. In addition to an ordinary adenocarcinoma, a neuroendocrine component occupying more than 30% of the entire tumor was also found in 4% (2/55 cases) of hepatic hilar cholangiocarcinomas with hepatolithiasis, 10% (5/49 cases) of gallbladder cancers, and 4% (2/53 cases) of extrahepatic cholangiocarcinomas, but not in the intrahepatic cholangiocarcinomas, hilar cholangiocarcinomas without preceding hepatobiliary disease, and hepatocellular carcinomas. Two cases were positive for somatostatin receptor 2A. The adenocarcinoma components were predominately located at the surface of the tumors, and the majority of stromal and vascular invasion and lymph node metastasis involved neuroendocrine components, showing the features of neuroendocrine tumor G2 or neuroendocrine carcinomas (NECs). NEC components showed higher proliferative activity on Ki67 immunostaining, compared to the adenocarcinoma components. Biliary MANECs are found in hepatic hilar cholangiocarcinomas with hepatolithiasis, gallbladder cancers, and extrahepatic cholangiocarcinomas and show a characteristic histology. Since the neuroendocrine component in biliary MANEC defines the prognosis, it is important to identify it and consider the indications for adjunctive therapy with somatostatin analogues.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Capella C, Solcia E, Sobin L, Arnold R (2000) Endocrine tumors of the gallbladder and extrahepatic bile ducts. In: Hamilton S, Aaltonen L (eds) WHO classification of tumors of the digestive system; World Health Organization of Tumors. IARC, Lyon, pp 214–216
Kloppel G, Perren A, Heitz PU (2004) The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 1014:13–27
Kloppel G (2007) Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 21:15–31
Rindi G, Kloppel G, Alhman H et al (2006) TNM staging of foregut (neuro) endocrine tumors: a consensus proposal including a grading system. Virchows Arch 449:395–401
Rindi G, Klimstra DS, Arnold R et al (2010) Nomenclature and classification of neuroendocrine neoplasms of the digestive system. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumors of the digestive system; World Health Organization of Tumors, 4th edn. IARC, Lyon, pp 13–14
Komminoth P, Arnold R, Capella C et al (2010) Neuroendocrine neoplasms of the gallbladder and extrahepatic bile ducts. In: Bosman FT, Carneiro F, Hruban RH, Theise ND (eds) WHO classification of tumors of the digestive system; World Health Organization of Tumors, 4th edn. IARC, Lyon, pp 274–276
Volante M, Brizzi MP, Faggiano A et al (2007) Somatostatin receptor type 2A immunohistochemistry in neuroendocrine tumors: a proposal of scoring system correlated with somatostatin receptor scintigraphy. Mod Pathol 20:1172–1182
Oberg KE, Reubi JC, Kwekkeboom DJ, Krenning EP (2010) Role of somatostatins in gastroenteropancreatic neuroendocrine tumor development and therapy. Gastroenterology 139:742–753
Kurumaya H, Ohta G, Nakanuma Y (1989) Endocrine cells in the intrahepatic biliary tree in normal livers and hepatolithiasis. Arch Pathol Lab Med 113:143–147
Tsuchiya A, Endo Y, Yazawa T et al (2006) Adenoendocrine cell carcinoma of the gallbladder: report of a case. Surg Today 36:849–852
Nesi G, Lombardi A, Batignani G et al (2006) Well-differentiated endocrine tumor of the distal common bile duct: a case study and literature review. Virchows Arch 449:104–111
Squillaci S, Marchione R, Piccolomini M et al (2010) Well-differentiated neuroendocrine carcinoma (malignant carcinoid) of the extrahepatic biliary tract: report of two cases and literature review. Apmis 118:543–556
Shimizu T, Tajiri T, Akimaru K et al (2006) Combined neuroendocrine cell carcinoma and adenocarcinoma of the gallbladder: report of a case. J Nippon Med Sch 73:101–105
Kuraoka K, Taniyama K, Fujitaka T et al (2003) Small cell carcinoma of the extrahepatic bile duct: case report and immunohistochemical analysis. Pathol Int 53:887–891
Kozaka K, Fujii T, Harada K et al (2007) A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: ‘bile ductular carcinoma’. Histopathology 51:390–400
Conflict of interest statement
The authors have no conflicts of interest to declare.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Harada, K., Sato, Y., Ikeda, H. et al. Clinicopathologic study of mixed adenoneuroendocrine carcinomas of hepatobiliary organs. Virchows Arch 460, 281–289 (2012). https://doi.org/10.1007/s00428-012-1212-4
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-012-1212-4