The clinical implications and molecular features of intrahepatic cholangiocarcinoma with perineural invasion

Author:

Meng Xian-Long,Lu Jia-Cheng,Zeng Hai-Ying,Chen Zhen,Guo Xiao-Jun,Gao Chao,Pei Yan-Zi,Hu Shu-Yang,Ye Mu,Sun Qi-Man,Yang Guo-Huang,Cai Jia-Bin,Huang Pei-Xin,Yv Lei,Zhang Lv,Shi Ying-Hong,Ke Ai-Wu,Zhou Jian,Fan Jia,Chen Yi,Huang Xiao-Yong,Shi Guo-MingORCID

Abstract

Abstract Background Perineural invasion (PNI) is associated with metastasis in malignancies, including intrahepatic cholangiocarcinoma (ICC), and is correlated with poor prognosis. Methods The study included three large cohorts: ZS-ICC and TMA cohorts from our team, MSK cohort from a public database, and a small cohort named cohort 4. Prognostic implications of PNI were investigated in MSK cohort and TMA cohort. PNI-related genomic and transcriptomic profiles were analyzed in MSK and ZS-ICC cohorts. GO, KEGG, and ssGSEA analyses were performed. Immunohistochemistry was used to investigate the relationship between PNI and markers of neurons, hydrolases, and immune cells. The efficacy of adjuvant therapy in ICC patients with PNI was also assessed. Results A total of 30.6% and 20.7% ICC patients had PNI in MSK and TMA cohorts respectively. Patients with PNI presented with malignant phenotypes such as high CA19-9, the large bile duct type, lymph node invasion, and shortened overall survival (OS) and relapse-free survival (RFS). Nerves involved in PNI positively express tyrosine hydroxylase (TH), a marker of sympathetic nerves. Patients with PNI showed high mutation frequency of KRAS and an immune suppressive metastasis prone niche of decreased NK cell, increased neutrophil, and elevated PD-L1, CD80, and CD86 expression. Patients with PNI had an extended OS after adjuvant therapy with TEGIO, GEMOX, or capecitabine. Conclusion Our study deciphered the genomic features and the immune suppressive metastasis-prone niche in ICC with PNI. Patients with PNI showed a poor prognosis after surgery but a good response to adjuvant chemotherapy. Graphical abstract

Funder

the Clinical Research Plan of SHDC

the Key Disease Joint Research Program of Xuhui District

Key Technologies Research and Development Program

Innovative Research Group Project of the National Natural Science Foundation of China

the Shanghai Municipal Natural Science Foundation

Beijing Mutual Care Public Welfare Foundation

Sanming Project of Medicine in Shenzhen

National College Students Innovation and Entrepreneurship Training Program

Publisher

Springer Science and Business Media LLC

Subject

Hepatology

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