Distinct Clinicopathologic and Genetic Features of 2 Histologic Subtypes of Intrahepatic Cholangiocarcinoma

Previous studies have identified 2 clinically significant morphologic subtypes of intrahepatic cholangiocarcinoma (ICC) on the basis of anatomic location and/or histologic appearances. Recognizing that these classification schemes are not always applicable practically, this study aimed to establish a novel classification system based on mucin productivity and immunophenotype and to determine the rationale of this classification by examining the clinicopathologic and genetic characteristics of the 2 subtypes defined by this method. We retrospectively investigated 102 consecutive ICC cases and classified them on the basis of mucin productivity and immunophenotype (S100P, N-cadherin, and NCAM). We found that 42 and 56 cases were classified as type 1 and type 2 ICCs, respectively, and only 4 cases were of indeterminate type. Type 1 ICC, generally characterized by mucin production and diffuse immunoreactivity to S100P, arose less frequently in chronic liver diseases and showed higher levels of serum CEA and CA 19-9 than did type 2 ICC, which generally showed little mucin production and exhibited immunoreactivity to N-cadherin and/or NCAM. Type 1 ICC was characterized by several pathologic features, including higher frequencies of perineural invasion and lymph node metastasis. Although the log-rank test demonstrated that type 1 ICC had significantly worse survival, the multivariate Cox regression analysis showed no prognostic significance of this histologic subtype. Genetic analyses revealed that KRAS mutation was significantly more frequent in type 1 ICC, whereas IDH mutation and FGFR2 translocation were restricted to type 2 ICC. In conclusion, the present classification of ICC based on mucin productivity and immunophenotype identified 2 subtypes with clinicopathologic significance.

[1]  O. Matsui,et al.  A subgroup of intrahepatic cholangiocarcinoma with an infiltrating replacement growth pattern and a resemblance to reactive proliferating bile ductules: ‘bile ductular carcinoma’ , 2007, Histopathology.

[2]  Hepatocyte Paraffin 1 Expression in Human Normal and Neoplastic Tissues , 2004 .

[3]  S. Yamasaki.  Intrahepatic cholangiocarcinoma: macroscopic type and stage classification. , 2003, Journal of hepato-biliary-pancreatic surgery.

[4]  H. Thomas,et al.  Guidelines for the diagnosis and treatment of cholangiocarcinoma: an update , 2012, Gut.

[5]  Hiromi Nakamura,et al.  Genomic spectra of biliary tract cancer , 2015, Nature Genetics.

[6]  Yoshihiko Maehara,et al.  Proposal of Progression Model for Intrahepatic Cholangiocarcinoma: Clinicopathologic Differences Between Hilar Type and Peripheral Type , 2007, The American journal of surgical pathology.

[7]  Y. Jeng,et al.  Viral hepatitis is associated with intrahepatic cholangiocarcinoma with cholangiolar differentiation and N-cadherin expression , 2011, Modern Pathology.

[8]  Nansheng Chen,et al.  Mutational landscape of intrahepatic cholangiocarcinoma , 2014, Nature Communications.

[9]  Y. Jeng,et al.  S100P immunostaining identifies a subset of peripheral‐type intrahepatic cholangiocarcinomas with morphological and molecular features similar to those of perihilar and extrahepatic cholangiocarcinomas , 2012, Histopathology.

[10]  E. Schadt,et al.  Massive parallel sequencing uncovers actionable FGFR2–PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma , 2015, Nature Communications.

[11]  T. Roskams,et al.  Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes , 2012, Hepatology.

[12]  Y. Jeng,et al.  Morphological subclassification of intrahepatic cholangiocarcinoma: etiological, clinicopathological, and molecular features , 2014, Modern Pathology.

[13]  Jesse S. Voss,et al.  Isocitrate dehydrogenase 1 and 2 mutations in cholangiocarcinoma. , 2012, Human pathology.

[14]  M. Matsuda,et al.  Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin , 2007, Hepatology.

[15]  J. Kononen,et al.  Tissue microarrays for high-throughput molecular profiling of tumor specimens , 1998, Nature Medicine.

[16]  Yasunori Sato,et al.  Pathology of peripheral intrahepatic cholangiocarcinoma with reference to tumorigenesis , 2008, Hepatology research : the official journal of the Japan Society of Hepatology.

[17]  Y. Totoki,et al.  Fibroblast growth factor receptor 2 tyrosine kinase fusions define a unique molecular subtype of cholangiocarcinoma , 2014, Hepatology.

[18]  G. Gores,et al.  Clinical diagnosis and staging of cholangiocarcinoma , 2011, Nature Reviews Gastroenterology &Hepatology.

[19]  T. Pawlik,et al.  Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas , 2013, Nature Genetics.

[20]  Chung-Liang Ho,et al.  Mutations of BRAF and KRAS Precede the Development of Ovarian Serous Borderline Tumors , 2004, Cancer Research.

[21]  H. Al-Ahmadie,et al.  Arginase-1: A New Immunohistochemical Marker of Hepatocytes and Hepatocellular Neoplasms , 2010, The American journal of surgical pathology.

[22]  G. Sauter,et al.  Hepatocyte paraffin 1 expression in human normal and neoplastic tissues: tissue microarray analysis on 3,940 tissue samples. , 2004, American journal of clinical pathology.

[23]  Y. Kanda,et al.  Investigation of the freely available easy-to-use software ‘EZR' for medical statistics , 2012, Bone Marrow Transplantation.