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

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

Prognostic DNA mutation and mRNA expression analysis of perineural invasion in oral squamous cell carcinoma

“…Our RNAseq results also showed significant differential expression of EFGR ( p = 0.03, |log2FC|= 0.38) and genes related to EGF pathway ( PRKCA, JAK1, PLCG1, p = 0.01, 0.02, 0.02 and |log2FC|= 0.32, 0.20, 0.16, respectively) in PNI patients, although prognosis was not significant. Higher frequency of KRAS mutations were found in intrahepatic cholangiocarcinoma patients and colon cancer with PNI 14 , 15 , coincide with RNAseq results in Fig. 2 b.…”

Perineural invasion confers poorer clinical outcomes in patients with T1/T2 intrahepatic cholangiocarcinoma: a single center, retrospective cohort study

“…While our study focuses on early-stage ICC patients without further postoperative adjuvant therapy, existing literature has reported that PNI-positive ICC patients exhibit insensitivity to postoperative chemotherapy ( 10 ). However, following combined immunotherapy, the prognosis of PNI-positive postoperative patients is superior to that of negative patients ( 18 , 19 ). ICC, characterized by a poor prognosis, despite numerous studies suggesting various approaches to improve outcomes ( 20 - 23 ), still lacks a standardized and effective treatment.…”

“…This study validated previous work that early ICC patients with PNI had higher rates of more severe jaundice, cholangitis, HBV infection, CA199, serum albumin, and platelet count, all of which were believed to be closely connected with ICC patients’ prognosis ( 27 - 32 ). Moreover, PNI is closely associated with the pathological malignancy phenotype of ICC, with patients exhibiting PNI often accompanied by large duct-type and lymph node metastasis ( 19 ). Furthermore, PNI may serve as a substitute for biological markers of invasive disorders that reflect tumor or stage-specific characteristics substantially.…”

ROR1-AS1 might promote in vivo and in vitro proliferation and invasion of cholangiocarcinoma cells

“…PNI is an independent risk factor for CCA and has been considered a worse prognostic factor in CCA [ 14 ]. In addition, a negative PNI has been considered a reference for postoperative chemotherapy in some studies [ 15 ].…”