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Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma: Real-life Data on Liver Disease, Treatment and Prognosis

  • Xavier Adhoute1,* ,
  • Olivia Pietri1,
  • Guillaume Pénaranda2 ,
  • Thomas Wolf1,
  • Patrick Beaurain3,
  • Olivier Monnet3,
  • Arthur Laquière1 ,
  • Justine Bonomini4 ,
  • Frédéric Neumann5,
  • Olivier Levrel5,
  • Jean-Pascal Buono5 ,
  • Xavier Hanna6 ,
  • Paul Castellani1,
  • Hervé Perrier1,
  • Marc Bourliere1  and
  • Rodolphe Anty7 
 Author information
Journal of Clinical and Translational Hepatology   2023;11(5):1106-1117

doi: 10.14218/JCTH.2022.00141


Background and Aims

Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) have common features and differences. This real-life study investigated their characteristics, treatment modalities, and prognoses.


This retrospective comparative study was performed in 1,075 patients seen at one tertiary center between January 2008 and December 2020. Overall survival (OS) was estimated by the Kaplan-Meier method. Subclassification of iCCAs after histological and radiological review, and molecular profiling was performed.


HCCs patients were more likely to have early-stage disease than iCCA patients. iCCA patients were more likely to be female, especially those patients without cirrhosis (43% vs. 17%). Cirrhosis was prominent among HCC patients (89% vs. 34%), but no difference in underlying liver disease among cirrhotic patients was found. OS of HCC patients was 18.4 (95% CI: 6.4, 48.3) months, that of iCCA patients was 7.0 (95% CI: 3.4, 20.1) months. OS of Barcelona Clinic Liver Cancer C HCC patients was 7.8 (95% CI: 4.3, 14.2) months, that of advanced/metastatic iCCA patients was 8.5 (95% CI: 5.7, 12.3) months. In patients treated with sorafenib, OS was longer in HCC patients who received subsequent tyrosine kinase inhibitor therapies. No significant OS difference was found between iCCA patients with and without cirrhosis or according to histological subtype. A targetable molecular alteration was detected in 50% of the iCCA patients.


In this French series, cirrhosis was common in iCCA, which showed etiological factors comparable to those of HCC, implying a distinct oncogenic pathway. Both entities had a dismal prognosis at advanced stages. However, systemic therapies sequencing in HCC and molecular profiling in iCCA offer new insights.

Graphical Abstract


Intrahepatic cholangiocarcinoma, Hepatocellular carcinoma, Cirrhosis, NASH, Oncogenic alterations


Intrahepatic cholangiocarcinoma (iCCA), or peripheral cholangiocarcinoma, is the second most common primary liver cancer after hepatocellular carcinoma (HCC).1 Based on their geographical distribution, iCCAs can be rare or common malignancies related to specific risk factors.2 The iCCA incidence has increased in recent years in Western countries, and the age-related death rate is higher in France than in other European countries.3 iCCAs are tumors with a poor prognosis and are commonly diagnosed at an advanced stage.4 Histological subclassification as well as molecular profiling of the tumors through genomic and transcriptomic analyses,5 and the latest therapeutic advances will improve their management. Biliary tree cellular diversity as well as various hepatic and biliary risk factors leading to chronic inflammation and specific oncogenic dysregulation are probably responsible for the biliary tumor heterogeneity.5 There are two major subtypes of iCCAs: those that arise from small ducts, which have nodular morphology and are associated with chronic liver disease, and those that arise from large ducts.6 The latter iCCAs are morphologically different, mucinous, and resemble juxta hilar CCAs histologically, and they are associated with cholangitis, flukes, and precursor lesions. Another major distinctive feature is that the two subtypes have unique oncogenic alterations.5 The two most common primary liver cancers (HCC and iCCA) share common risk factors,1 and may have similar radiological patterns.7 Thus, we conducted a retrospective study to (1) investigate iCCA patient characteristics (especially underlying liver diseases) and those of HCC patients seen at the same center for more than a decade; (2) analyze treatment modalities and patient survival in these real-life cohorts; and (3) assess the impact of cirrhosis and histological subtype in the iCCA group as well as the presence of actionable oncogenic alterations.



This was a single-center retrospective study conducted from January 2008 to December 2020. The medical files of all consecutive patients enrolled in this period with a diagnosis of HCC or iCCA (recorded from 2010 onward) were considered for the study. Data were collected prospectively through an internal database and analyzed retrospectively. Our workup included systematic assessment to detect underlying liver disease for HCC or iCCA patients, supported by noninvasive measurement of liver stiffness by transient elastography and controlled attenuation parameters. The diagnosis of HCC was by radiology following international guidelines8 or on histology in the absence of formal radiological criteria and in the absence of cirrhosis. HCC patients were classified according to the Barcelona Clinic Liver Cancer (BCLC) staging system. Those with a single nodule of >50 mm were designated as having BCLC stage AB disease. The treatment strategy was discussed during multidisciplinary concertation sessions, with recommendations based on the National Thesaurus of Digestive Cancerology (TNCD). Early tumors were treated with a curative approach or according to the stage migration concept.8 Advanced HCCs with sectorial portal thrombosis were sometimes treated with an intra-arterial procedure such as transarterial chemoembolization (TACE) based on expert recommendations.9 HCC patients who had transplantation as the first treatment were not included.

The diagnosis of iCCA was based on histology, and tumors were classified according to the eighth American Joint Committee on Cancer Staging System.10 Patients with a diagnosis of combined hepatocellular-cholangiocarcinoma were excluded. The treatment options, especially iCCA resection, were discussed during multidisciplinary concertation sessions in accordance with the National Thesaurus of Digestive Cancerology recommendations at that time. Advanced iCCA was treated with systemic chemotherapy, a cisplatin/gemcitabine (CisGem) regimen,11 or a combination of oxaliplatin, 5-FU and LV (FOLFOX) according to patient performance status (PS 0/1). If the PS was 2, the patient was treated with gemcitabine alone. Patients with unresectable iCCA without extrahepatic disease were sometimes treated with locoregional therapies [TACE or selective internal radiotherapy (SIRT)] in combination with systemic chemotherapy.

As part of this study, a histological review was performed to classify iCCA cases into the two main histopathological subtypes according to the size of the affected duct: small bile duct (SD), or large bile duct (mucinous) (LD). A radiological review was also performed on all iCCA cases, especially in histologically indeterminate iCCAs, to classify them according to gross appearance into the mass forming (MF) (mostly associated with SD iCCA) or periductal infiltrative (PDI) (+/− MF) subtype; the PDI subtype is exclusively seen with LD type iCCA. In addition to immunohistochemical study of tumor tissue to evaluate the protein expression of human epidermal growth factor receptor 2 (HER2) and to investigate the mismatch repair phenotype, we performed molecular profiling of iCCA patients to detect oncogenic molecular alterations targetable by therapies after gaining access to a molecular genetics platform in 2020. The platform employed tumor DNA and RNA targeted sequencing panels to detect activating mutations and chromosomal rearrangements, respectively. The Oncomine Focus Assay (Thermo Fisher Scientific, Waltham, MA, USA) was used to conduct concurrent DNA and RNA next-generation sequencing analysis from formalin-fixed paraffin-embedded samples, targeting 77 genes (mutations in 45 genes including BRAF, CDKN2A, EGFR, ERBB3, FGFR1, 2, 3, IDH1/2, KRAS, MET, NTRK1, 2, PIK3CA, PTEN, RAF-1, RET, TP53; fusions in 18 genes including EGFR, FGFR1, 2, 3, MET, NTRK1, 2, 3; copy number variations in 14 genes including EGFR, ERBB2 et 3, FGFR1, 2 et 3, KRAS, MET), and 15 genes that have various roles in the homologous DNA damage repair pathway (Oncomine BRCA Expanded panel). The current study was approved by the ethics committees of our institution. It followed the Good Clinical Practice guidelines and was conducted following the ethical principles of the Declaration of Helsinki.

Statistical analysis

Quantitative data were reported using the mean and standard deviation (SD); qualitative data were reported using the frequency and percentage. Quantitative data were compared between groups using Student’s t test for normally distributed data or the nonparametric Wilcoxon test otherwise; the chi-squared test or Fisher’s test was used for comparison of qualitative data. The Mantel-Haenszel chi-squared test was performed to compare ordinal scale data. Risk factors for HCC or iCCA were analyzed by univariate logistic regression analysis prior to multivariate logistic regression analysis. Items that were identified as significant in the univariate analysis were included in the multivariate model analysis. The multivariate results were reported using odds ratios (ORs) and 95% confidence intervals (CIs). Overall survival (OS) was defined as the time interval between the diagnosis of cancer and death or the time of last follow-up for patients who were still alive. Survival was compared between groups using the log-rank test. OS results were reported using median and interquartile range (q1, q3) and hazard ratios (HRs) and 95% CIs. All p-values were considered significant at α-level=0.05. All calculations were performed using SAS V9.4 statistical software (SAS Institute Inc., Cary, NC, USA).


Characteristics of HCC and iCCA patients: descriptive study

Data from 1,075 patients were analyzed; 972 patients with HCC classified as BCLC stage A (45%, including 8% with a single nodule of >50 mm), B (18%), C (26%) or D (11%), and 103 patients with iCCA of the SD MF (62%) or LD PDI (38%) subtypes. HCCs (53%) and iCCAs (9%) were detected following systematic follow-up, based on symptoms (29% and 67% respectively), or incidentally (18% and 24% respectively). PS was better in the HCC group (Table 1). The two cohorts did not differ in mean age at diagnosis (67.7 years and 67.8 years, respectively) or mean body mass index (26.0 kg/m2 and 26.3 kg/m2, respectively), but there were more female iCCA (34%) than HCC (17%) patients, especially in those without cirrhosis (43% vs. 17% among iCCA patients with cirrhosis; Tables 1 and 2). Cirrhosis was more common in the HCC group (89% compared with 34%), but there was no difference in liver disease etiology among cirrhotic patients between the two groups (HCC: viral 38.8%, alcohol 33.1%, nonalcoholic steatohepatitis 16.4% vs. iCCA: 25.7%, 37.1%, 25.7%, respectively; p=0.4763; Table 3). Most patients with cirrhosis had preserved liver function assessed by Child-Pugh score and ALBI grade in each cohort. Esophageal varices were described in 49.6% of patients in the HCC group vs. 20% of iCCA patients with cirrhosis. Regarding tumor characteristics, the iCCA group had larger tumor diameters at diagnosis, more multinodular tumors, greater vascular invasion and more patients with metastases.

Table 1

Baseline characteristics of patients with HCC or iCCA

Patient characteristicsHCC (n=972)iCCA (n=103)
Age, years, mean (SD)67.7 (11.0)67.8 (11.1)
Sex, n (%)
  Male805 (83)68 (66)
  Female167 (17)35 (34)
PS, n (%)
  0543 (56)29 (28)
  1188 (19)49 (48)
  >1241 (25)25 (24)
BMI, mean (SD)26.0 (4.6)26.3 (5.1)
Cirrhosis, n (%)
  Yes/No868 (89)/104 (11)35 (34)/68 (66)
Underlying liver diseases
  Etiology, n (%)
    Viral/Viral+Alcohol358 (36.8)/56 (5.8)14 (13.6)/2 (1.9)
    Alcohol301 (31)20 (19.4)
    NASH178 (18.3)29 (28.2)
    Other62 (6.4)2 (1.9)
    Healthy liver17 (1.8)36 (35)
  Tumor histological confirmation, n (%)361 (37)103 (100)
Laboratory tests
  Albumin (g/L), mean (SD)34.3 (7.1)35.4 (7.2)
  Bilirubin (µmol/L), mean (SD)37.5 (147.8)62.0 (116.7)
  PT (%), mean (SD)75.5 (17.0)83.0 (17.5)
  Platelets (109/L), mean (SD)160 (92)229 (92)
  Alkaline phosphatase (U/L), mean (SD)148.8 (129.2)219.1 (218.1)
  ASAT (U/L), mean (SD)86.2 (110.0)81.2 (96.2)
  ALBI grade, n (%)
    1209 (23.0)28 (32.6)
    2531 (58.4)41 (47.7)
    3170 (18.7)17 (19.8)
  AFP (ng/mL), median (q1, q3)18 (5, 317)3 (2, 14)
Tumor characteristics
  Largest tumor diameter mm, mean (SD)52.4 (42.6)73.9 (38.1)
  Nodules*, n (%)
    <3635 (66.3)52 (50)
    ≥3323 (33.7)51 (50)
  Vascular invasion, n (%)
    No/Yes717 (74)/255 (26)59 (57)/44 (43)
  Metastases, n (%)36 (4)43 (42)
  Staging system for HCC: BCLC, n (%)BCLC 0/A 359 (37); BCLC AB 75 (8); BCLC B 175 (18); BCLC C 254 (26); BCLC D 109 (11)IA/B, n=27 (26); II, n=33 (32); IV, n=43 (42)
  Staging system for iCCA: 8th AJCC, n (%)
  Treatment type, n (%)
    Curative treatment308 (32)20 (20)
    Noncurative treatment480 (49)61 (59)
    SC184 (19)22 (21)
Table 2

iCCA: Characteristics of patients with or without liver cirrhosis

Patient characteristicsCirrhotic patients (n=35)Noncirrhotic patients (n=68)p
Age, years, mean (SD)67.4 (9.0)67.7 (12.0)0.6164
Sex, n (%)0.0149
  Male/Female29 (83)/6 (17)39 (57)/29 (43)
PS 0/1/>1, n (%)8 (23)/15 (43)/12 (34)21 (31)/34 (50)/13 (19)0.1231
BMI, mean (SD)26.8 (5.3)26.0 (5.0)0.5435
Etiology, n (%)<0.0001
  Virus/Virus+Alcohol9 (25.7)/2 (5.7)5 (7.4)/0
  Alcohol13 (37.1)7 (10.2)
  NASH9 (25.7)20 (29.4)
  Other2 (5.7)14 (20.6)
  Healthy liver022 (32.4)
Laboratory tests
  Albumin (g/L), mean (SD)35.7 (6.4)35.2 (7.7)0.7842
  Bilirubin (µmol/L), mean (SD)67.9 (118.4)59.1 (116.7)0.2421
  PT (%), mean (SD)79.1 (16.8)84.9 (17.7)0.0825
  Platelets (109/L), mean (SD)192 (101)246 (83)0.0054
  Alkaline phosphatase (U/L), mean (SD)183 (123)234 (247)0.5021
  ASAT (U/L), mean (SD)104.8 (133.6)71.6 (75.1)0.2232
  ALBI grade, n (%)0.3339
    17 (24)21 (37)
    217 (59)24 (42)
    35 (17)12 (21)
  CA19.9 (U/mL), mean (SD)4,566 (11,015)2,551 (6,491)0.7229
Tumor characteristics
  Largest tumor diameter mm, mean (SD)75.0 (42.6)73.4 (36.0)0.8175
  Nodules, n (%)0.0929
    <314 (38%)38 (56%)
    ≥321 (62%)30 (44%)
  Vascular invasion, n (%)0.0007
    No/Yes12 (34)/23 (66)47 (69)/21 (31)
  Metastases, n (%)14 (40)29 (43)0.7964
  Treatment type, n (%)0.1166
    Curative treatment4 (11)16 (24)
    Noncurative treatment20 (57)41 (60)
    Supportive care11 (31)11 (16)
Table 3

Baseline characteristics of cirrhotic patients with HCC or iCCA

CharacteristicsHCC (n=868)iCCA (n=35)
Age, years, mean (SD)67.3 (10.7)67.4 (9.0)
Sex, n (%)
  Male724 (83)29 (83)
  Female144 (17)6 (17)
PS, n (%)
  0473 (54)8 (23)
  1164 (19)15 (43)
  >1231 (27)12 (34)
BMI, mean (SD)26.0 (4.6)26.8 (5.3)
Cirrhosis etiology, n (%)
  Viral/Virus+Alcohol337 (38.8)/55 (6.3)9 (25.7)/2 (5.7)
  Alcohol287 (33.1)13 (37.1)
  NASH142 (16.4)9 (25.7)
  Other47 (5.4)2 (5.7)
EV¥, n (%)
  No EV341 (50.4)28 (80)
  Grade 1124 (18.3)2 (6)
  Grade 2/3212 (31.3)5 (14)
#Child-Pugh score, n (%)
  A536 (65)20 (69)
  B274 (34)8 (27.5)
  C10 (1)1 (3.5)
Laboratory tests
  Albumin (g/L), mean (SD)34.0 (7.0)35.7 (6.4)
  Bilirubin (µmol/L), mean (SD)40.2 (156.2)67.9 (118.4)
  PT (%), mean (SD)73.9% (16.8)79.1 (16.8)
  Platelets (109/L), mean (SD)150.1 (88.0)192.0 (101.3)
  AP (U/L), mean (SD)151.1 (130.7)183.1 (123.3)
  ASAT (U/L), mean (SD)88.1 (112.3)104.8 (133.6)
  ALBI grade, n (%)
    1167 (20)7 (24)
    2489 (60)17 (59)
    3164 (20)5 (17)
  AFP (ng/mL), mean (SD)5,560 (39,811)3,581 (19,547)
Tumor characteristics
  Largest tumor diameter mm, mean (SD)49.4 (40.9)75.0 (42.6)
  Nodules*, n (%)
    <3548 (64)13 (38)
    ≥3308 (36)21 (62)
  Vascular invasion, n (%)
    No627 (72)12 (34%
    Yes241 (28)23 (66)
  Metastases, n (%)33 (4)14 (40)
  Treatment type, n (%)
    Curative treatment236 (27)4 (11)
    Noncurative treatment458 (53)20 (57)
    SC174 (20)11 (31)

Characteristics of iCCA patients with and without cirrhosis: comparative study

Apart from male sex and underlying viral or alcohol-related liver disease being overrepresented in the cirrhosis group, there was no significant difference in age at diagnosis, tumor diameter, multinodularity, CA19-9 serum level, or liver function between the groups (Table 2). There was more vascular invasion in the cirrhosis group.

Characteristics of iCCA patients with the SD MF or LD PDI subtype: comparative study

The comparative study of SD MF iCCAs and LD PDI iCCAs showed that the SD group had more women, but the LD group had higher rates of cholestasis and aspartate aminotransferase serum levels as well as lower serum albumin and more frequent vascular invasion (Table 4).

Table 4

Characteristics of patients with SD vs. LD iCCA

iCCA patient characteristicsSD MF (n=64)LD PDI (n=39)p
Age, years, mean (SD)67.5 (11.2)67.6 (10.9)0.9149
Sex, n (%)0.0319
  Male/Female37 (58)/27 (42)31 (79)/8 (21)
PS 0/1/>1, n (%)19 (30)/33 (51)/12 (19)10 (26)/16 (41)/13 (33)0.2047
BMI, mean (SD)26.2 (5.2)26.5 (4.9)0.7705
Etiology, n (%)0.2169
  Virus/Virus+Alcohol11 (17.2)/1 (1.6)3 (7.7)/1 (2.6)
  Alcohol8 (12.5)12 (30.8)
  NASH18 (28.1)11 (28.2)
  Other10 (15.6)5 (15.4)
  Healthy liver16 (25.0)6 (15.4)
Cirrhosis, n (%)0.2386
  No/Yes45 (70)/19 (30)23 (59)/16 (41)
OV, n (%)0.4081
  No/Yes19 (86)/3 (14)11 (73)/4 (27)
Laboratory tests
  Albumin (g/L), mean (SD)37.1 (7.4)32.9 (6.4)0.0077
  Bilirubin (µmol/L), mean (SD)16.3 (12.9)132.5 (162.9)<0.0001
  PT (%), mean (SD)84.9 (15.0)80.0 (20.8)0.6162
  Platelets (109/L), mean (SD)237 (81)216 (108)0.3417
  Alkaline phosphatase (U/L), mean (SD)164.1 (91.5)307.7 (315.8)0.0140
  ASAT (U/L), mean (SD)63.2 (86.8)110.2 (104.5)0.0094
  ALBI grade, n (%)0.0004
    123 (45.1)5 (14.3)
    223 (45.1)18 (51.4)
    35 (9.81)12 (34.3)
  CA19.9 (U/mL), mean (SD)1,858 (6,475)5,899 (10,646)0.1984
Tumor characteristics
  Largest tumor diameter mm, mean (SD)79.0 (39.4)65.5 (34.6)0.0926
  Nodules, n (%)0.2192
    <329 (45.3)22 (56.5)
    ≥335 (54.7)17 (43.5)
  Vascular invasion, n (%)0.0283
    No/Yes42 (66)/22 (34)17 (44)/22 (56)
  Metastases27 (42)16 (39)0.9077
  Treatment type, n (%)0.0120
    Curative treatment12 (19)8 (21)
    Noncurative treatment44 (69)17 (44)
    Supportive care8 (12)14 (36)

Treatment modalities and survival of HCC and iCCA patients

HCC patients

The first-line treatment modalities used are shown in Figure 1. Most patients with early HCC (60% (BCLC stage 0/A+AB), n=260) received curative treatment. TACE was the primary treatment modality for BCLC stage B HCC (64%, n=112). Patients with advanced HCC were primarily treated with sorafenib (44%, n=113) or with intra-arterial procedures, most commonly TACE (30%, n=77). Treatment allocation was driven by baseline liver function.12 Most HCC patients with Child-Pugh B liver function were only suitable for noncurative or supportive care (Supplementary Table 1). The mean follow-up of HCC patients was 27.2±30.1 months. The OS of BCLC stage A patients (47 months) was significantly better than that of BCLC stage B, C and D patients (p<0.0001; Fig. 2). The OS of HCC patients treated with surgical resection was significantly better than that of HCC patients treated with other modalities for early (including single tumors >50 mm) or intermediate-stage disease, especially compared with that of HCC patients treated with TACE (Table 5). Regarding advanced HCC, there was no significant difference in OS between patients treated with intra-arterial procedures and those treated with sorafenib as the primary treatment modality (Table 5). However, the analysis of a larger cohort of patients treated with sorafenib, including those who received subsequent tyrosine kinase inhibitor (TKI) therapies (regorafenib or cabozantinib, n=253; Supplementary Fig. 1), had a significantly better OS, sorafenib 6.7 (95% CI: 3.9, 11.9) months vs. TKIs 15.2 (95% CI: 6.2, 32.8) months, p=0.0009.

First-line treatment modalities in patients with HCC or iCCA.
Fig. 1  First-line treatment modalities in patients with HCC or iCCA.

*Including seven treated by TARE. Plus radiation therapy n=2. HCC with noncirrhotic liver includes 17 patients with healthy liver and 87 patients with underlying liver fibrosis. HCC, hepatocellular carcinoma; iCCA, intrahepatic cholangiocarcinoma; BCLC, Barcelona Clinic Liver Cancer; SC, supportive care; TACE, transarterial chemoembolization; TKI, tyrosine kinase inhibitor; TARE, transarterial radioembolization.

Kaplan-Meier survival curves of patients with HCC classified according to the BCLC staging system.
Fig. 2  Kaplan-Meier survival curves of patients with HCC classified according to the BCLC staging system.

BCLC, Barcelona Clinic Liver Cancer; Mo, months. Data on 895 HCC. The survival time could not be calculated for 77 patients because of missing date of last follow-up.

Table 5

Survival of HCC patients according to BCLC stage and treatment modality

BCLC stageOS (95% CI) - monthsp-value (log-rank)HR (95% CI)p-value
BCLC 0/A<0.0001
  TACE (n=133)33.9 (19.2, 52.4)Ref
  Resection (n=74)109.3 (47.9, n.e.)0.27 (0.17, 0.42)<0.0001
  Ablation+TACE (n=63)74.6 (32.4, 147.0)0.36 (0.24, 0.53)<0.0001
  Ablation (n=71)47.0 (26.6, 83.7)0.62 (0.43, 0.90)0.0104
BCLC A/B0.0001
  TACE (n=21)26.0 (17.3, 37.3)Ref
  Resection (n=39)72.9 (48.6, 96.6)0.33 (0.17, 0.64)0.0010
  Resection+1st TACE (n=9)56.4 (28.9, n.e.)0.45 (0.18, 1.14)0.0918
BCLC B0.0109
  TACE (n=112)18.0 (11.2, 31.9)Ref
  Resection±1st TACE (n=21)26.9 (17.8, 55.6)0.54 (0.36, 0.82)0.0037
BCLC C0.1111
  TACE (n=77)8.1 (5.0, 15.0)Ref
  Sorafenib (n=113)6.7 (3.9, 11.9)1.35 (1.01, 1.82)0.0465

iCCA patients

Regarding the iCCA group, less than a quarter of patients underwent curative surgical resection (Fig. 1). Nearly half of the patients received systemic chemotherapy (46%, n=47), mostly the CisGem regimen (n=31), the FOLFOX regimen (n=8), or gemcitabine alone (n=8). Ten percent of patients were treated with a locoregional intra-arterial procedure. There was no significant difference in the therapeutic strategy for iCCA patients with and without cirrhosis (Table 2). More than one-third of the patients with LD PDI iCCA were ineligible for specific treatment (Table 4).

The mean follow-up of iCCA patients was 12.1±12.7 months. The OS of iCCA patients who underwent surgical procedures (n=20) was 21.8 (±12.4, 34.2) months, while that of iCCA patients who were treated with noncurative procedures (n=61) was 8.5 (5.7, 12.3) months (p=0.0270). The OS of iCCA patients treated with systemic chemotherapy was 7.8 (95% CI: 5.9, 12.0) months. The OS of iCCA patients with or without cirrhosis across all treatments was not significantly different: 9.0 (95% CI: 5.0, 12.3) vs. 11.0 (95% CI: 5.9, 25.0) months, p=0.1633. The OS of iCCA patients with SD MF vs. LD PDI iCCA across all treatments was not significantly different: 10.1 (95% CI: 5.8, 21.0) months vs. 9.0 (95% CI: 5.6, 32.4) months, p=0.7570.

HCC and iCCA patients - survival analysis

The OS of HCC patients (n=972) was 18.4 (95% CI: 6.4, 48.3) months and that of iCCA patients (n=103) was 7.0 (95% CI: 3.4, 20.1) months. The OS of BCLC stage C HCC patients (n=208) was 7.8 (95% CI: 4.3, 14.2) months and that of locally advanced/metastatic iCCA patients (n=61) was 8.5 (95% CI: 5.7, 12.3) months. Both groups had a similar proportion of patients who were exclusively eligible for supportive care (HCC 19% vs. iCCA 21%; Fig. 1).

iCCA patient genomic profile

Molecular cholangiocarcinoma profiling could be performed in 18 patients: patients experiencing recurrence after surgery (n=7) and patients with unresectable iCCA treated by first-line locoregional (2) or systemic (n=9) therapies. Large-scale genomic and transcriptomic analysis found an actionable molecular alteration targetable by therapy in 50% of 18 iCCA patients (Table 6). iCCA patients harbored alterations in the isocitrate dehydrogenase 1 (IDH1) and fibroblast growth factor receptor 3 (FGFR3) genes, genes in the Ras/phosphatidylinositol 3-kinase (PI3-kinase) pathway (v-raf murine sarcoma viral oncogene homolog B1 (BRAF), mesenchymal epithelial transition factor receptor (MET), and HER2), chromatin regulator genes [BReast CAncer gene 1 (BRCA1)], and genes involved in the DNA mismatch repair system. Other oncogenic alterations in cell cycle genes and DNA repair or chromatin regulators without targeted treatment options were also identified.

Table 6

Results of large-scale genomic and transcriptomic analysis of 18 patients with iCCA

Potentially actionable oncogenic alterationsESCAT scorePatients eligible for potential targeted therapyMatched targeted treatment administered
IDH1 mutationsIAPt n°1; Pt n°2None
MSIICPt n°3None
BRAF mutationsIIBPt n°4*None
ERBB2 (HER2) amplifications, mutationsIIIIAPt n°5*, Pt n°6*None
PIK3CA mutationsIIIAPt n°7None
BRCA 1 mutationsIIIAPt n°8None
MET mutationsIIIAPt n°5None
FGFR3 mutationsIIIAPt n°9None
Other oncogenic alterations
  CDKN2A/B lossPt n°3; Pt n° 4*
  TP53 mutationsPt n°9; Pt n°3; Pt n°10
  NF1 mutationsPt n° 4*
  ARID1A mutationsPt n° 4*; Pt n° 7
  KRAS G12D mutationPt n° 11
No oncogenic alterationsPt n°12*; Pt n°13*; Pt n°14; Pt n° 15; Pt n°16; Pt n°17*; Pt n°18*


In this retrospective study from a liver unit, a comparative analysis found differences and similarities among HCC and iCCA patients. We found a higher proportion of HCC patients in this French cohort of patients with primary hepatobiliary tumors. Most patients with HCC were detected as opposed to iCCA patients. However, this trend may change over time, as the main risk factor for iCCA in this series was chronic liver disease with cirrhosis, which was found in more than one-third of the study participants.

iCCAs represent approximately 15% of primary liver cancers.1 The results of this study were in line with that finding, and other features associated with iCCA, such as female sex, multinodularity, and the presence of metastases, were identified, as in other series.4,13 The overrepresentation of women in the iCCA group compared to the HCC group in our series was found in iCCA patients without cirrhosis. Female sex was independently associated with iCCA diagnosis in a study by Lee et al.4 We also found an overrepresentation of females in iCCA in phase 2 and 3 trials evaluating targeted therapies for iCCA patients with specific genomic alterations (ClarIDHy14 (ivosidenib): 65%, FIGHT-20215 (pemigatinib): 58%, NCT0215096716 (infigratinib): 57%) and in the phase 3 TOPAZ-1 study17 (50%), in which 55% of the patients had iCCA. However, we found a similar sex distribution among cirrhotic patients in the HCC and iCCA groups, and there was a male predominance. The result is not surprising, as the risk factors associated with cirrhosis (notably alcohol) affect more men. Multinodularity and extrahepatic spread are classically associated with iCCA.4 Indeed, iCCA is characterized by lack of a capsule and a significant fibrous stroma,18 with effector cells such as tumor-associated macrophages,19 and activated myofibroblasts20 that are driven by cytokines and growth factors such as transforming growth factor-beta (TGF-β) secreted by tumor cells.

In our European series, we found that a large majority of HCC patients had cirrhosis. More than 30% of patients in the iCCA group had cirrhosis, which is a well-documented risk factor in that pathology.1,2 The finding is consistent with other studies.4,21 In an Italian multicenter series from expert centers, nearly half of the patients with iCCA (46%) had cirrhosis, and most of them were detected.22 Thus, there may have been an underestimation.21 Conversely, in phase 2/3 trials evaluating targeted therapies or the combination of chemotherapy plus immunotherapy as treatment for advanced iCCA, there have been few14 or no cirrhotic patients, or data on cirrhosis have not been available.15-17 The association of iCCA with cirrhosis raises several questions. Cirrhotic patients can develop either cancer, which highlights the absolute necessity of histological assessment if the radiological criteria for HCC are not fulfilled.23 Histological confirmation is even more important given the potential identification of therapeutic targets in cholangiocarcinoma (Table 6). Cirrhosis was the main risk factor for iCCA in our series, and as previously reported,24 cirrhosis, chronic hepatitis, alcohol use, and NASH were not associated with the iCCA subtype. The association of iCCA development with cirrhosis may allow earlier detection of this poor prognosis cancer13 and identification of a target population that can benefit from curative therapeutic options.25 Moreover, in previous studies, cirrhosis did not affect the prognosis of patients with iCCA.21,22 These results are not surprising, as liver function and tumor features (tumor size and metastatic spread) were comparable between our two iCCA subgroups with or without cirrhosis. Of course, these results should be interpreted with caution given the small sample size.

Our comparative analysis of HCC and iCCA found similar underlying liver diseases among cirrhotic patients. While cirrhotic patients are at risk of developing these two cancers, this result highlights the close link between these two entities and the importance of chronic inflammation related to hepatitis.1 Common nucleotide substitutions in HCC and iCCA related to chronic hepatitis have been described.26 The same study showed a similar gene expression profile (RNA-seq analysis) of biliary cancers and poorly differentiated HCC. The result suggests that the diseases involve activation of different oncogenic pathways but may have common cells of origin, although the last point remains controversial.5 Indeed, biliary tree cells harbor different cell types, including hepatocytes, liver progenitor cells (which have a biphenotypic orientation), and biliary epithelial cells (mature nonmucin-producing interlobular cholangiocytes, and cylindrical mucin-producing cholangiocytes located in LDs). In addition to this cellular diversity, mature hepatocytes maintain phenotypic plasticity and thus an ability to differentiate into cholangiocytes. Activation of the Notch pathway or Ras/MAPK cascade and Tp53 mutations has been implicated in the conversion of normal hepatocytes into malignant cholangiocytes.27,28 Thus, the similarities and heterogeneity of hepatobiliary tumors are substantial challenges that need to be considered.5 In addition to iCCA and HCC, there are other rare liver cancers with biliary phenotypes.29

Nearly 20% of the HCC patients in our series had nonalcoholic fatty liver disease (NAFLD), and nearly one-third in the iCCA group had NAFLD. The results are not unexpected since these diseases have been recognized as major causes of chronic liver disease, the incidence of which is increasing.30 Steatosis may be complicated by necrotic-inflammatory processes, which characterizes patients with NASH. Previous studies have shown a change in HCC tumor phenotype after TACE with the development of hepatobiliary cancers, suggesting the importance of necrosis in this process.31 Necroptosis, which is programmed cell necrosis resulting in plasma membrane disruption following osmotic shock, appears to be particularly important in NAFLD and NASH.32 Cells undergoing necroptosis release damage-associated molecular patterns that may shape the microenvironment through specific cytokine delivery by immune cells. A recent study underlines the influence of the microenvironment and necroptosis in biliary or hepatic cancers related to singular epigenetic regulators.33 Thus, specific oncogenes and the tumor microenvironment drive the liver cancer phenotype.

In line with other studies,4 our study found that therapeutic strategies differ between iCCA and HCC. A curative approach is more frequently used for HCC patients because one majority is detected. Some experts consider surgery the most effective treatment modality to achieve the best survival rate in HCC cases up to intermediate stage.34 Moreover, the latest version of the BCLC staging system no longer recommends TACE as the main modality for intermediate-stage disease treatment.35 In our series, stratification according to the BCLC system found tumors with different prognoses. However, BCLC stage AB HCC had a comparable prognosis with BCLC stage 0/A HCC, in contrast with the findings of other studies,36 probably owing to the different treatment modalities within each group. The poor OS seen with sorafenib treatment is comparable to that seen in other real-life cohorts,37 as the populations of patients have differed in trials.38 Moreover, there was no survival benefit following the use of any endovascular procedure, mainly TACE, as an alternative therapeutic option for advanced HCC. These results should be interpreted with caution in the absence of comparison using propensity score matching. Conversely, survival was longer in the sorafenib group treated with second-line TKI therapy, and survival with sorafenib would likely be better over time.38 Once again, the results should be interpreted with caution in the absence of comparison using propensity score matching; however, sequencing of systemic therapies can provide a survival benefit for HCC patients,39 although this strategy can be used in relatively few patients in the TKI era.40

Regarding the iCCA population, our series did not find a significant difference in prognosis between patients with SD iCCA and those with LD iCCA across all treatments despite there being more impaired liver function in the LD group. However, more than one-third of patients with LD iCCA were ineligible for specific treatment. Studies have shown that these two entities differ radiologically and histologically6 and regarding molecular alterations5 and treatment response.41 The LD iCCA subtype is characterized by higher rates of desmoplastic stroma and higher frequencies of TGF-β1 pathway gene alterations and Tp53 and KRAS mutations.41 LD iCCAs appear to have lower sensitivity to chemotherapy than SD iCCAs and they also reportedly show resistance to anti-PD1/PD-L1 immunotherapy41 related to the suppressive immune microenvironment in KRAS-altered tumors. Given the results of the TOPAZ-1 trial,17 which supports the combination of chemotherapy (CisGem regimen) plus anti-programmed death ligand 1 (PDL1) therapy (durvalumab), the management strategy for advanced iCCAs is about to change. This new combination may overcome such resistance. Furthermore, classification according to iCCA subtype is necessary to improve outcomes.

The difference in survival between HCC and iCCA patients is not unexpected and probably reflects the absence of screening in the iCCA group, which had a higher tumor burden than the HCC group (as has been previously reported), along with the difference in follow-up time. The difference was also likely related to the difference in curative approach rate in our series, as more patients in the HCC group were treated with curative strategies (32% vs. 20%). Moreover, the overall prognosis of advanced stage iCCA and HCC remains poor, together with comparable proportions of patients eligible for only palliative care. The situation is even more serious, as pointed out in a recent study conducted in all French hospitals, since most iCCA patients diagnosed during the period 2014–2015 only received supportive care.13

Chemotherapy with the CisGem regimen has been the only therapeutic approach for advanced biliary tract cancer (BTC) for many years and has produced modest results,11 as reflected by our series. Intensification of chemotherapy has not shown any benefit,42 and the use of new cytotoxics is under investigation. There is significant improvement with the combination of chemotherapy and immunotherapy.17 Moreover, the prognosis of BTC, especially iCCA, is likely to change thanks to personalized therapeutic approaches. In our study, 50% of the patients in whom genomic and transcriptomic studies were performed had a targetable molecular alteration (Table 6). Large-scale sequencing technologies have highlighted BTC heterogeneity along with various oncogenic alterations that may be targeted by therapies. These molecular alterations (mutations, rearrangements, and amplifications) are diverse and affect many cellular processes.5 The most commonly affected genes are those encoding the isocitrate dehydrogenase 1 (IDH1) and IDH2 enzymes (the mutations of which are mutually exclusive) involved in DNA repair mechanisms and epigenetic regulation and those encoding fibroblast growth factors, which are associated with the SD iCCA subtype (mutations seen in approximately <5–20% of patients). These aberrations also less commonly affect pathway kinase genes (BRAF, MET, and ERBB2), chromatin remodeling genes (ARID1A) and mismatch repair genes (MLH1 and MSH2, or the germline mutations of BRCA1 and BRCA2 that we identified in our patients). Several targeted therapies are now approved by the Food and Drug Administration and European Medicines Agency for patients with cholangiocarcinoma who harbor specific genomic alterations. The prescription of these agents is now facilitated and prioritized by the European Medical Oncology Society (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) system.43 Thus, tumor genetic testing should be performed as soon as the first systemic treatment is given and in the case of failure or progression.

This study suffers from limitations related to several factors: (1) It was a retrospective study, and we tried to reduce the relevant limitations by prospectively accessing data from our regular multidisciplinary collegial sessions. (2) We used histological review to classify the iCCA subtypes, as most of the biopsies were tumor biopsies and not surgical specimens. (3) There was a lack of data regarding the combination of anti-PD-L1 therapy (atezolizumab) plus anti-VEGF therapy (bevacizumab), which is the new standard of care for advanced HCC.44 The combination of atezolizumab and bevacizumab was not available in France until 2020. 4) Finally, there was a lack of propensity score matching for some comparisons among HCC patients.


In this French series, cirrhosis was prominent in HCC and was also common in iCCA. The two diseases had similar etiological factors, suggesting a close relationship between the two entities. Thus, iCCA detection should be performed in patients with hepatobiliary tumors and cirrhosis through diagnostic biopsy. Cirrhosis did not affect iCCA prognosis in our series. Histological subclassification of iCCA resulted in distinct patient profiles and should be applied in daily practice. Both primary liver cancers had a comparable prognosis at an advanced stage. However, systemic therapies sequencing in HCC and molecular profiling of iCCAs with its potential therapeutic targets may reveal new therapeutic strategies.

Supporting information

Supplementary Table 1

Hepatocellular carcinoma treatment allocation based on Child-Pugh score.


Supplementary Fig. 1

Sorafenib cohort (n=268) including patients treated with sorafenib as first-line therapy, those treated with sorafenib upon recurrence after resection, ablation or chemoembolization, and those who received subsequent TKI therapies (regorafenib or cabozantinib) (survival data on 253 patients).

BCLC, Barcelona Clinic Liver Cancer; HCC, hepatocellular carcinoma; TACE, transarterial chemoembolization.




Barcelona Clinic Liver Cancer


v-raf murine sarcoma viral oncogene homolog B1


Breast cancer gene


biliary tract cancer


confidence interval




5-FU and LV plus Oxaliplatin


fibroblast growth factor receptor


human epidermal growth factor receptor 2


Hepatocellular carcinoma


Intrahepatic cholangiocarcinoma


isocitrate dehydrogenase




mesenchymal epithelial transition factor receptor


Mass forming


nonalcoholic fatty liver disease


Odds ratio


Overall survival


Periductal infiltrative




Transarterial chemoembolization


tyrosine kinase inhibitor


Ethical statement

This study did not involve humans, and only analyzed already recorded data. This study falls within the scope of the French Reference Methodology MR-004 (according to the 2016-41 law dated 26 January 2016 on the modernization of the French health system). As requested by the French regulations for such noninterventional studies, all patients were informed about the use of their data for research studies. The study was conducted in accordance with the ethical guidelines of the 1975 Declaration of Helsinki. In addition, the study was approved by the internal ethical review boards of the Saint Joseph Hospital of Marseille on March 7, 2022.

Data sharing statement

No additional data are available.


None to decalre.

Conflict of interest

XA: Board member, Consultancy (Bayer, Ipsen, Eisai, Servier); PC: Consultancy (Gilead, Abbvie); MB: Board member, Consultancy (Merck-Schering Plow, Gilead, Janssen, Vertex, Boehringer-Ingelheim, BMS, Roche, Abbvie, GSK); HP: Consultancy (Sanofi); RA: Board member, Consultancy (Gilead, Bayer, Eisai, Intercept, Abbvie, MSD, Ipsen); OP: Abbvie, Gilead; AL: Boston Scientific. GP, JB, TW, PB, OM, FN, OL, JPB and XH have no conflict of interests related to this publication.

Authors’ contributions

Study concept and design (XA, OP, RA, GP), investigation (XA, PO, TW, AL, PC, HP, XH, MB, OM, PB, FN, OL, JPB), acquisition of data (XA, OP, TW), analysis and interpretation of data (GP), drafting of the manuscript (XA, JB, RA), critical revision of the manuscript for important intellectual content (XA, JB, RA), and study supervision (XA). All authors have made a significant contribution to this study and have approved the final manuscript.


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Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma: Real-life Data on Liver Disease, Treatment and Prognosis

Xavier Adhoute, Olivia Pietri, Guillaume Pénaranda, Thomas Wolf, Patrick Beaurain, Olivier Monnet, Arthur Laquière, Justine Bonomini, Frédéric Neumann, Olivier Levrel, Jean-Pascal Buono, Xavier Hanna, Paul Castellani, Hervé Perrier, Marc Bourliere, Rodolphe Anty
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