TY - JOUR
T1 - Comprehensive genetic analysis of cholangiolocellular carcinoma with a coexistent hepatocellular carcinoma-like area and metachronous hepatocellular carcinoma
AU - Kawai-Kitahata, Fukiko
AU - Asahina, Yasuhiro
AU - Kaneko, Shun
AU - Tsuchiya, Jun
AU - Sato, Ayako
AU - Miyoshi, Masato
AU - Tsunoda, Tomoyuki
AU - Inoue-Shinomiya, Emi
AU - Murakawa, Miyako
AU - Nitta, Sayuri
AU - Itsui, Yasuhiro
AU - Nakagawa, Mina
AU - Azuma, Seishin
AU - Kakinuma, Sei
AU - Tanabe, Minoru
AU - Sugawara, Emiko
AU - Takemoto, Akira
AU - Ojima, Hidenori
AU - Sakamoto, Michiie
AU - Muraoka, Masaru
AU - Takano, Shinichi
AU - Maekawa, Shinya
AU - Enomoto, Nobuyuki
AU - Watanabe, Mamoru
N1 - Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers 19H03635, 19?K17392, 19?K17453, 17 K09406, 17?K19647, 18H02790, and AMED under Grant Numbers 19fk0210060, 19fk0210047, 19fk0310103. CLC is a rare primary tumor of the liver, with a reported incidence among resected primary liver cancers of 0.56%. The clinicopathological features of CLC have not been characterized because of its low prevalence. Most CLC cases have hyperenhancement in the early phase of contrast-enhanced CT or MRI and hypervascularity in angiography. Persistent enhancement in the late phase of contrast-enhanced CT or MRI was also found in some cases, reflecting slow diffusion of the contrast agent into the fibrotic component of the tumor, as seen similarly in cases of CCA. Early tumor staining and peritumoral enhancement due to early drainage from the tumor and prolonged enhancement are characteristic findings in CLC. In the present case, the first tumor had the typical characteristics of CLC. Immunohistochemistry also showed that the tumor cells were positive for markers of cholangiocytes (CK7 and CK19), negative for markers of hepatocytes (Hep-Parl and glypican-3), and positive for an intraluminal staining pattern of EMA. A membranous pattern (positive staining in the luminal membrane) of EMA has been considered a specific feature of CLC. In the WHO classification 2010, CK7, CK19, EpCAM, NCAM, and KIT are listed as stem cell features, and were positive in this case, except for KIT. Because pathological and immunohistochemical findings were typical for CLC, diagnosis of the initial tumor was confirmed as CLC according to the Japanese General Rules for the Clinical and Pathological Study of Primary Liver Cancer 6th edition. Furthermore, the present findings are also compatible with diagnosis of the cholangiolocellular type of combined hepatocellular cholangiocarcinoma with stem cell features according to the WHO classification 2010.
Funding Information:
This work was supported by JSPS KAKENHI Grant Numbers 19H03635, 19 K17392, 19 K17453, 17 K09406, 17 K19647, 18H02790, and AMED under Grant Numbers 19fk0210060, 19fk0210047, 19fk0310103.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Aim: The genetic profile of cholangiolocellular carcinoma (CLC) and its origin in relation to hepatocellular carcinoma (HCC) remain unclear. To elucidate the genetic profile of CLC, a comprehensive analysis of genetic mutations was carried out in a case of CLC with an HCC-like focal area and metachronous HCC. Method: Liver tissue was obtained from CLC, a co-existent HCC-like area, and metachronously developed HCC by laser capture microdissection of formalin-fixed paraffin-embedded specimens obtained by hepatectomy. Gene mutational profiles were analyzed comprehensively by next-generation sequencing and digital PCR. Relationships among gene profiles, immunohistochemistry, and clinicopathological findings were investigated. Results: Mutations in EGFR, PTEN, RB1, TP53, and ERBB2 were found in CLC, whereas mutations in KIT, BRAF, PTEN, TP53, and SMAD4 were found in the coexistent HCC-like area. Only the mutation in PTEN has a common Catalogue of Somatic Mutations in Cancer ID in the CLC and coexistent HCC-like area, and is related to the kinase-RAS module. In contrast, no cancer-related mutations were found in the metachronous HCC. No TERT mutations were found in any of the regions by digital PCR. Immunohistochemical staining for p53 was negative in CLC, although ≤10% positive in the coexistent HCC-like area. Immunostaining of C-kit, HER2, PTEN, and SMAD4 were negative. Conclusion: The genomic features of CLC and the focal area of an HCC-like region differ, but are related to the kinase-RAS module. The development of carcinogenesis in the CLC and HCC-like areas in this case might differ, following a common PTEN mutation, although alteration of the kinase-RAS module is the most common molecular event in CLC.
AB - Aim: The genetic profile of cholangiolocellular carcinoma (CLC) and its origin in relation to hepatocellular carcinoma (HCC) remain unclear. To elucidate the genetic profile of CLC, a comprehensive analysis of genetic mutations was carried out in a case of CLC with an HCC-like focal area and metachronous HCC. Method: Liver tissue was obtained from CLC, a co-existent HCC-like area, and metachronously developed HCC by laser capture microdissection of formalin-fixed paraffin-embedded specimens obtained by hepatectomy. Gene mutational profiles were analyzed comprehensively by next-generation sequencing and digital PCR. Relationships among gene profiles, immunohistochemistry, and clinicopathological findings were investigated. Results: Mutations in EGFR, PTEN, RB1, TP53, and ERBB2 were found in CLC, whereas mutations in KIT, BRAF, PTEN, TP53, and SMAD4 were found in the coexistent HCC-like area. Only the mutation in PTEN has a common Catalogue of Somatic Mutations in Cancer ID in the CLC and coexistent HCC-like area, and is related to the kinase-RAS module. In contrast, no cancer-related mutations were found in the metachronous HCC. No TERT mutations were found in any of the regions by digital PCR. Immunohistochemical staining for p53 was negative in CLC, although ≤10% positive in the coexistent HCC-like area. Immunostaining of C-kit, HER2, PTEN, and SMAD4 were negative. Conclusion: The genomic features of CLC and the focal area of an HCC-like region differ, but are related to the kinase-RAS module. The development of carcinogenesis in the CLC and HCC-like areas in this case might differ, following a common PTEN mutation, although alteration of the kinase-RAS module is the most common molecular event in CLC.
KW - cholangiolocellular carcinoma
KW - digital polymerase chain reaction
KW - gene mutation
KW - hepatocellular carcinoma
KW - laser capture microdissection
KW - next-generation sequencing
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U2 - 10.1111/hepr.13403
DO - 10.1111/hepr.13403
M3 - Article
AN - SCOPUS:85070313548
VL - 49
SP - 1466
EP - 1474
JO - Hepatology Research
JF - Hepatology Research
SN - 1386-6346
IS - 12
ER -