Distinct clinical and prognostic implication of IDH1/2 mutation and other most frequent mutations in large duct and small duct subtypes of intrahepatic cholangiocarcinoma

Bingqi Ma,Huijuan Meng,Qiang Li,Tianqiang Song,Ye Tian,Yingying Wang,Qiang Wu,Ti Zhang,Wei Zhang,Yunlong Cui,Huikai Li

doi:10.1186/s12885-020-06804-6

Abstract

BackgroundIsocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study.MethodsWe collected clinical data of 130 ICC patients from January 2012 to December 2017. The IDH1/2 mutation and loss of BAP1, ARID1A and PBRM1 expressions were detected by DNA sequencing or immunohistochemical methods, and histological subtype of ICCs was determined by hematoxylin-eosin, Alcian blue and S100P staining.ResultsIDH1/2 mutation was related to decreased preoperative serum total bilirubin (P = 0.039), ferritin (P = 0.000) and higher histological differentiation (P = 0.024), and was associated with prolonged disease-free survival (P = 0.009) and a trend toward increased overall survival (P = 0.126) in small duct type of ICCs. Immunohistochemical staining results of MsMab-1 were generally consistent with DNA sequencing for IDH1/2 mutant in ICCs (κ = 0.691). Only BAP1 expression loss was correlated to prolonged disease-free survival (P = 0.031) and overall survival (P = 0.041) in large duct type of ICCs.ConclusionsIDH1/2 mutation is a favorable predictor and may be related to iron metabolism in small duct type of ICCs. Furthermore, we suggest that the detection of IDH1/2 mutation is indispensable to determine targeted therapy in small duct type ICCs, while it is not necessary in large duct of ICCs. MsMab-1 is a relatively effective multi-specific antibody against IDH1/2 mutant in ICCs. BAP1 expression loss was correlated with improved prognosis only in large duct type ICCs.

Highlights

Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study
Large duct and small duct type of ICCs Subclassification of ICCs We classified 130 cases with ICC into 3 subtypes on the basis of histological features, S100P expression and Alcian blue staining in the first round. 12 cases (9.2%) were recognize as typical large duct type, which met three standards: HE, type1; S100P, score 3–4; and Alcian blue, score 1–2
Since IDH1/2 mutations were typically detected in small duct type of ICCs, we considered these factors (CA19–9, lymph node metastasis and size of tumor) might be associated with small duct type, rather than IDH1/2 mutation

Summary

Introduction

Isocitrate dehydrogenase 1/2 (IDH1/2), BAP1, ARID1A and PBRM1 have been reported as the most frequent mutant genes in intrahepatic cholangiocarcinoma (ICC), and their relationships with clinicopathological features and prognosis were researched in this study. Tumors originated from the bile ducts can be subdivided anatomically into three subgroups: distal, perihilar, and intrahepatic cholangiocarcinoma (ICC). The incidence of ICC is increasing in recent years [3]. With the application of next-generation sequencing technology, many frequent genetic mutations have been discovered in ICCs, such as isocitrate dehydrogenase 1/2 (IDH1/2), KRAS, BAP1, ARID1A, PBRM1 and FGFR2-fusion [4, 5]. Almost all literatures reported that the incidences of their mutations are more than 10% in cases with ICCs [4,5,6,7,8,9]

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