Combined hepatocellular cholangiocarcinoma: A clinicopathological update

Table 1 Summary of the findings of studies having examined the molecular landscape of combined hepatocellular-cholangiocarcinoma

Ref.	Technology	Molecular features/conclusion
Fujii et al[30]	Loss of heterozygosity, polymerase chain reaction	4q, 17p, 8p, 16q; common clonal evolution
Cazals-Hatem et al[8]	Loss of heterozygosity, Genome wide allelotyping	TP53, chromosome instability
Coulouarn et al[26]	Genome-wide transcriptional analysis	TGFβ and Wnt/β-catenin; Stem/progenitor features
Fujimoto et al[31]	Whole genome sequencing	TERT/IDH1/2, KRAS; Closer to HCC if hepatitis background and to; CCA in absence of hepatitis
Moeini et al[21]	Whole exome sequencing	TP53, TERT, IDH1/2, Chromosomal instability, MYC, IGF2, mTOR, Stem/progenitor features
Chen et al[54]	Whole genome sequencing	IDH1/2; Stem/progenitor features
Sasaki et al[29]	Whole genome sequencing	KRAS, IDH1/2, ARID1A, TERT; Variable association of HCC and/or CCA mutations
Jeon et al[32]	Multiplexed polymerase chain reaction-based sequencing	TP53, PTEN, MET, c-MYC, CDK6, CTNNB1, CCND1; Clonal heterogeneity
Wang et al[11]	Whole exome sequencing	VCAN, ACVR21, FCGBP; Stemness nature, monoclonal origin, intratumoral heterogeneity
Liu et al[10]	Whole exome sequencing, RNAseq	TP53, CTNNB1
Joseph et al[27]	Capture-based next generation sequencing	TERT, TP53, cell cycle genes (CCND1, CCNE1, CDKN2A), receptor tyrosine kinase/Ras/PI3-kinase pathway genes (MET, ERBB2, KRAS, PTEN), chromatin regulators (ARID1A, ARID2) and Wnt pathway genes (CTNNB1, AXIN, APC)
Sasaki et al[33]	Direct sequence	TERT, ARID1A, PBRM1, ARID2, BAP1, p53, KRAS, IDH1/2; Cholangiocellular carcinoma is different from cHCC-CCA
Xue et al[25]	Whole genome sequencing	TP53, TERT, AXIN1, KMT2D; Monoclonal origin in combined and mixed type; Both mono- and multiclonal origins in the separate type

Table 2 Common mutational signatures in hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma and cholangiocarcinoma

Cholangiocarcinoma	Hepatocellular carcinoma	Combined hepatocellular-cholangiocarcinoma
TP53	TERT promoter	TERT promoter
KRAS	TP53	TP53
IDH1	CTNNB1	MET
PTEN		ERBB2
ARID1A		KRAS
EPPK1		PTEN
ECE2
FYN

Table 3 Reported cohorts of combined hepatocellular-cholangiocarcinoma patients treated with immunotherapy

Ref.	Study type	Drug	Number of patients	Outcome
Tahover et al[55]	Case report	Ipilimumab and nivolumab, followed by nivolumab	1	ECOG performance status improved from 3 to 0. Repeated PET-CT showed near complete response, ca125 decreased by 90% and liver function tests normalized
Rizell et al[56]	Case report	Pembrolizumab	1 (Post resection, pulmonary metastasis)	Complete remission of the pulmonary metastases. There was no sign of cancer recurrence neither in the liver nor in the lungs at 33 months after the start of the checkpoint inhibition treatment
Diab et al[57]	Retrospective case series	Of the six patients 4 (66%) received PD-1 inhibitor alone and 2 (34%) received combination therapy with CTLA-4 inhibitor	6	Objective response rate was 83.3%. One patient achieved complete response and had a treatment holiday after receiving treatment for 2 yr, and restarted immunotherapy upon relapse. Four patients had a partial response, of which two passed away after disease progression. One patient had stable disease on 2 different lines of immunotherapy then progressed
Saito et al[58]	Case report	Atezolizumab plus bevacizumab	1 (3 months after resection, multiple lymph node metastases)	7.5-month progression-free survival
Satake et al[52]	Case series	Atezolizumab plus bevacizumab	6	Three partial responses and one stable disease as the best responses
Saint et al[59]	Case report	Pembrolizumab	1	Complete response which was maintained over time along with toxicity-free tumor control after 18 months treatment
Pomej et al[53]	Retrospective, multicenter cohort	Three (43%) patients received atezolizumab plus bevacizumab, two (29%) patients were treated with nivolumab alone, and one (14%) patient each received pembrolizumab alone and nivolumab in combination with TACE, respectively	7	Overall response rate was 29% with a disease control rate of 43%
Zhou et al[60]	Case report	Sintilimab, lenvatinib, and nab-paclitaxel	1

ECOG: Eastern cooperative oncology group; CT: Computed tomography; TACE: Trans arterial chemoembolization.