• combined hepatocellular cholangiocarcinoma (cHCC-ICC)
• intrahepatic cholangiocarcinoma (ICC)
• overall survival
• recurrence-free survival
• surgical resection

• Carcinogenesis
• Combined hepatocellular-cholangiocarcinoma
• Diagnosis
• Liver cancer
• Systemic tumor therapy
• Tumor biology

• atezolizumab
• bevacizumab
• case series
• combined hepatocellular-cholangiocarcinoma
• immunotherapy

• Cholangiocarcinoma
• Combined hepatocellular-cholangiocarcinoma
• Hepatocellular carcinoma
• Liver cancer
• Non-invasive imaging

• 81725008 National Natural Science Foundation of China
• ZD-11-202151 Fundamental Research Funds for the Central Universities
• 19DZ2251100 Science and Technology Commission of Shanghai Municipality
• 2019LJ21 Shanghai Municipal Health Commission
• SHSLCZDZK 03502 Shanghai Municipal Health Commission
• 2022ZSQD07 Scientific Research and Development Fund of Zhongshan Hospital of Fudan University

• artificial intelligence
• biomarker
• cholangiocarcinoma
• combined hepatocellular-cholangiocarcinoma
• diagnostic approach
• future outlook
• hepatocellular carcinoma
• liquid biopsy
• radiomics

• Combined hepatocellular-cholangiocarcinoma
• HBV integration
• Hepatitis B virus
• Intrahepatic cholangiocarcinoma

• anti‐programmed death ligand‐1
• hepatic resection
• immune checkpoint inhibitor
• liver cancer
• vascular endothelial growth factor

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare type of primary liver malignancy. Among the risk factors, hepatitis B and hepatitis C virus infections, cirrhosis, and male gender are widely reported. The clinical appearance of cHCC-CCA is similar to that of HCC and iCCA and it is usually silent until advanced states, causing a delay of diagnosis. Diagnosis is mainly based on histology from biopsies or surgical specimens. Correct pre-surgical diagnosis during imaging studies is very problematic and is due to the heterogeneous characteristics of the lesion in imaging, with overlapping features of HCC and CCA. The predominant histological subtype within the lesion establishes the predominant imaging findings. Therefore, in this scenario, the radiological findings characteristic of HCC show an overlap with those of CCA. Since cHCC-CCAs are prevalent in patients at high risk of HCC and there is a risk that these may mimic HCC, it is currently difficult to see a non-invasive diagnosis of HCC. Surgery is the only curative treatment of HCC-CCA. The role of liver transplantation (LT) in the treatment of cHCC-CCA remains controversial, as is the role of ablative or systemic therapies in the treatment of this tumour. These lesions still remain challenging, both in diagnosis and in the treatment phase. Therefore, a pre-treatment imaging diagnosis is essential, as well as the identification of prognostic factors that could stratify the risk of recurrence and the most adequate therapy according to patient characteristics.

• biliary tract
• cholangiocarcinoma
• combined hepatocellular cholangiocarcinoma

• 5-FU, 5-Fluorouracil
• AFP, alpha-fetoprotein
• APHE, arterial phase hyperenhancement
• CA19-9, carbohydrate antigen 19-9
• CCA, cholangiocarcinoma
• CEUS, contrast-enhanced ultrasound
• CK, cytokeratin
• CLC, cholangiolocellular carcinoma
• EpCAM, epithelial cell adhesion molecule
• FISH, fluorescence in situ hybridisation
• FLC, fibrolamellar carcinoma
• Fibrolamellar carcinoma
• HAS, hepatic angiosarcoma
• HCC, hepatocellular carcinoma
• HEH, hepatic epithelioid haemangioendothelioma
• HepPar1, hepatocyte specific antigen antibody
• Hepatic angiosarcoma
• Hepatic hemangioendothelioma
• Hepatocellular carcinoma
• Hepatocholangiocarcinoma
• IHC, immunohistochemistry
• LI-RADS, liver imaging reporting and data system
• LT, liver transplantation
• Mixed tumor
• RT-PCR, reverse transcription PCR
• SIRT, selective internal radiation therapy
• TACE, transarterial chemoembolisation
• WHO, World Health Organization
• cHCC-CCA, combined hepatocholangiocarcinoma
• iCCA, intrahepatic cholangiocarcinoma

• Classification
• Combined hepatocellular-cholangiocarcinoma
• Diagnostic approach
• Therapeutic management

Combined hepatocellular and cholangiocarcinoma (HCC/CC) is a rare primary hepatic malignancy which carries a poor prognosis due to its aggressive nature. Few centers have enough cases to draw definitive conclusions and there is limited understanding of prognosis. Given the rarity of HCC/CC, an analysis of large national cancer database was needed to obtain larger number of HCC/CC cases.

To identify associated factors for 5-year survival of HCC/CC.

We conducted a retrospective study of The Surveillance, Epidemiology, and End Results (SEER) database obtained from SEER*Stat 8.3.6 software. Previously defined histology code 8180 for the International Classification of Disease for Oncology, 3rd edition was used to identify HCC/CC cases from 2004 to 2015. We collected demographics, American Joint Committee on Cancer (AJCC) stage, treatment, tumor size, and survival data. These data were converted to categorical variables. The Shapiro-Wilk normality test was used to assess normal distribution. Mann-Whitney U test was used to compare continuous variables without normal distribution, and t-test was used to compare continuous variables with a normal distribution. The Kaplan-Meier survival curve analyzed 5-year survival. Univariate and multivariate logistic regression model was used to analyze factors associated with 5-year survival. Multivariate Cox proportional hazard regression was done on 5-year survival. We defined P < 0.05 was statistically significant.

We identified 497 patients with the following characteristics: Mean age 62.4 years (SD: 11.3), 149 (30.0%) were female, racial distribution was: 276 (55.5%) white, 53 (10.7%) black, 84 (16.9%) Asian and Pacific Islander (API), 77 (15.5%) Hispanic, and 7 (1.4%) others or unknown. Stage I/II disease occurred in 41.5% and tumor size < 50 mm was seen in 35.6% of patients. Twenty-four (4.8%) received locoregional therapy (LRT), 119 (23.9%) underwent resection, and 50 (10.1%) underwent liver transplantation. The overall median survival was 6 mo [Interquartile range (IQR): 1-22]. After multivariate logistic regression, tumor size < 50 mm [Odds ratios (OR): 2.415, P = 0.05], resection (OR: 12.849, P < 0.01), and transplant (OR: 27.129, P < 0.01) showed significance for 5-year survival. Age > 60, sex, race, AJCC stages, metastasis, and LRT were not significant. However, API vs white showed significant OR of 2.793 (CI: 1.120-6.967). Cox proportional hazard regression showed AJCC stages, tumor size < 50 mm, LRT, resection, and transplant showed significant hazard ratio.

HCC/CC patients with tumor size < 50 mm, resection, and transplant were associated with an increase in 5-year survival. API showed advantageous OR and hazard ratios over white, black.

• Combined hepatocellular and cholangiocarcinoma
• Surveillance, Epidemiology, and End Results database
• Survival
• Race
• Hepatobiliary cancer
• Transplant

• Fibrolamellar carcinoma
• combined hepatocellular-cholangiocarcinoma
• computed tomography
• hepatobiliary contrast agents
• magnetic resonance imaging
• primary hepatic tumors

The aim of the study was to investigate the performance of the Liver Imaging Reporting and Data System (LI-RADS) v2018 for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) identifying the features that allow an accurate characterization.

Sixty-two patients (median age, 63 years; range, 38–80 years), with pre-surgical biopsy diagnosis of hepatocellular carcinoma (HCC) that underwent hepatic resection, comprised our retrospective study. All patients were subject to multidetector computed tomography (MDCT); 23 patients underwent to magnetic resonance (MR) study. The radiologist reported the presence of the HCC by using LIRADS v2018 assessing major and ancillary features.

Final histological diagnosis was HCC for 51 patients and cHCC-CCA for 11 patients. The median nodule size was 46.0 mm (range 10–190 mm). For cHCC-CCA the median size was 33.5 mm (range 20–80 mm), for true HCC the median size was 47.5 mm (range 10–190 mm). According to LIRADS categories: 54 (87.1%) nodules as defined as LR-5, 1 (1.6%) as LR-3, and 7 (11.3%) as LR-M. Thirty-nine nodules (63%) showed hyper-enhancement in arterial phase; among them 4 were cHCC-CCA (36.4% of cHCC-CCA) and 35 (68.6%) true HCC. Forty-three nodules (69.3%) showed washout appearance; 6 cHCC-CCAs (54.5% of cHCC-CCA) and 37 true HCC (72.5%) had this feature. Only two cHCC-CCA patients (18.2% of cHCC-CCA) showed capsule appearance. Five cHCC-CCA (71.4% of cHCC-CCA) showed hyperintensity on T2-W sequences while two (28.6%) showed inhomogeneous signal in T2-W. All cHCC-CCA showed restricted diffusion. Seven cHCC-CCA patients showed a progressive contrast enhancement and satellite nodules.

The presence of satellite nodules, hyperintense signal on T2-W, restricted diffusion, the absence of capsule appearance in nodule that shows peripheral and progressive contrast enhancement are suggestive features of cHCC-CCA.

• combined hepatocellular-cholangiocarcinoma
• hepatocellular carcinoma
• magnetic resonance imaging
• multidetector computed tomography

• chinese
• hepatectomy
• liver cancer
• survival rate

• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/surgery
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/surgery
• China
• Cholangiocarcinoma/mortality
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/surgery
• Disease-Free Survival
• Female
• Humans
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/surgery
• Lymphatic Metastasis
• Male
• Middle Aged
• Neoplasms, Multiple Primary/mortality
• Neoplasms, Multiple Primary/surgery

• Thailand
• bile duct dilatation
• cholangiocarcinoma
• periductal fibrosis
• screening
• ultrasonography

• Adult
• Animals
• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/pathology
• Bile Ducts, Intrahepatic/pathology
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/pathology
• Cross-Sectional Studies
• Dilatation
• Female
• Fibrosis
• Humans
• Logistic Models
• Male
• Middle Aged
• Multivariate Analysis
• Opisthorchiasis/diagnosis
• Opisthorchiasis/pathology
• Opisthorchis
• Risk Assessment
• Risk Factors
• Thailand
• Ultrasonography

• National Research Council of Thailand
• Khon Kaen University

To assess the impact of hepatitis B surface (HBsAg) seroclearance on survival outcomes in hepatitis B-related primary liver cancer.

Information from patients with hepatitis B-related liver cancer admitted in our hospital from 2008-2017 was retrieved. Cases diagnosed with HBsAg (-) and HBcAb (+) liver cancer were included in the HBsAg seroclearance (SC) group. HBsAg (+) liver cancer patients strictly matched for liver cancer stage (AJCC staging system, 8^th edition), Child-Pugh score, and first diagnosis/treatment method (surgery, ablation and TACE) were assigned to the HBsAg non-seroclearance (NSC) group. Then, clinical, pathological and survival data in both groups were assessed.

The SC and NSC groups comprised of 72 and 216 patients, respectively. Patient age (P < 0.001) and platelet count (P = 0.001) in the SC group were significantly higher than those of the NSC group. SC group patients who underwent surgery had more intrahepatic cholangiocarcinoma (ICC) and combined HCC-CC (CHC) cases than the NSC group, but no significant differences in tumor cell differentiation and history of liver cirrhosis were found between the two groups. The numbers of interventional treatments were similar in both groups (4.57 vs 5.07, P > 0.05). Overall survival was lower in the SC group than the NSC group (P = 0.019), with 1-, 3-, and 5-year survival rates of 82.1% vs 85.1%, 43.2% vs 56.8%, and 27.0% vs 45.2%, respectively. Survival of patients with AJCC stage I disease in the SC group was lower than that of the NSC group (P = 0.029).

Seroclearance in patients with hepatitis B-related primary liver cancer has protective effects with respect to tumorigenesis, cirrhosis, and portal hypertension but confers worse prognosis, which may be due to the frequent occurrence of highly malignant ICC and CHC.

• Primary liver cancer
• Hepatitis B surface
• Hepatitis B surface seroclearance
• Prognosis
• Chronic hepatitis B

Aims: To compare the long-term prognosis of younger and elderly patients with combined hepatocellular-cholangiocarcinoma (CHC) who underwent curative resection between 1993 and 2014 at our center.

Methods: Two hundred and thirteen patients who underwent liver resection for CHC were enrolled in our study. The overall survival (OS) and disease-free survival (DFS) of elderly patients (age≥60, n=52) and younger patients (age<60, n=161) were compared by multivariate analysis and propensity score matching (PSM) analysis.

Results: Among the 213 CHC patients, the elderly patients had a higher rate of worse Child-Pugh grade (P=0.027), abnormal serum albumin (P<0.001) and lymphoid metastases (P=0.024). The proportion of HBV-positive CHC patients (74.6%, 159/213) was much higher than that observed in healthy cohorts. Younger patients had a higher rate of hepatitis B virus (HBV) infection compared to older patients (83.9% vs 46.2%, P<0.001). OS and DFS of the elderly and younger patients before and after propensity score matching were comparable.

Conclusion: Elderly and younger patients who underwent liver resection for CHC have comparable long-term OS and DFS.

• Combined Hepatocellular-Cholangiocarcinoma
• Hepatic resection
• Propensity score matching
• age

Combined hepatocellular-cholangiocarcinoma (CHC) is a rare tumor with poor prognosis, with incidence ranging from 1.0%-4.7% of all primary hepatic tumors. This entity will be soon renamed as hepato-cholangiocarcinoma. The known risk factors for hepatocellular carcinoma (HCC) have been implicated for CHC including viral hepatitis and cirrhosis. It is difficult to diagnose this tumor pre-operatively. The predominant histologic component within the tumor largely determines the predominant radiographic features making it a difficult distinction. Heterogeneous and overlapping imaging features of HCC and cholangiocarcinoma should raise the suspicion for CHC and multiple core biopsies (from different areas of tumor) are recommended before administering treatment. Serum tumor markers CA19-9 and alpha-fetoprotein can aid in the diagnosis, but it remains a challenging diagnosis prior to resection. There is sufficient data to support bipotent hepatic progenitor cells as the cell of origin for CHC. The current World Health Organization classification categorizes two main types of CHC based on histo-morphological features: Classical type and CHC with stem cell features. Liver transplant is one of the available treatment modalities with other management options including transarterial chemoembolization, radiofrequency ablation, and percutaneous ethanol injection. We present a review paper on CHC highlighting the risk factors, origin, histological classification and therapeutic modalities.

• Combined hepatocellular-cholangiocellular carcinoma
• Hepatocellular carcinoma
• Cholangiocellular carcinoma
• Hepatic progenitor cell(s)
• Histogenesis
• Classification

Little is known about the prognostic impact of cirrhosis on long-term survival of patients with combined hepatocellular-cholangiocarcinoma (cHCC-CC) after hepatic resection. The aim of this study was to elucidate the long-term outcome of hepatectomy in cHCC-CC patients with cirrhosis.

A total of 144 patients who underwent curative hepatectomy for cHCC-CC were divided into two groups: cirrhotic group (n = 91) and noncirrhotic group (n = 53). Long-term postoperative outcomes were compared between the two groups.

Patients with cirrhosis had worse preoperative liver function, higher frequency of HBV infection, and smaller tumor size in comparison to those without cirrhosis. The 5-year overall survival rate in cirrhotic group was significantly lower than that in non-cirrhotic group (34.5% versus 54.1%, P = 0.032). The cancer recurrence-related death rate was similar between the two groups (46.2% versus 39.6%, P = 0.446), while the hepatic insufficiency-related death rate was higher in cirrhotic group (12.1% versus 1.9%, P = 0.033). Multivariate analysis indicated that cirrhosis was an independent prognostic factor of poor overall survival (hazard ratio 2.072, 95% confidence interval 1.041–4.123; P = 0.038).

The presence of cirrhosis is significantly associated with poor prognosis in cHCC-CC patietns after surgical resection, possibly due to decreased liver function.

• Cirrhosis
• Combined hepatocellular-cholangiocarcinoma
• Long-term survival
• Surgical resection

Background. The inconsistent finding was between hepatitis B virus (HBV) infections and cholangiocarcinoma (CCA). This meta-analysis is to explore this relationship in Asia. Methods. A literature search was performed using PubMed, Web of Science, and Cochrane Library to October 30, 2015. Pooled incidence rate and OR with 95% CI were calculated using STATA 11.0. Results. Thirty-nine studies were included. The pooled incidence rate of CCA patients with HBV infection was 31% (95% CI 22%–39%). The pooled OR showed increased risk of CCA incidence with HBV infection (OR = 2.72, 95% CI 1.90–3.88), especially in ICC (OR = 3.184, 95% CI 2.356–4.302), while it showed no risk in ECC (OR = 1.407, 95% CI 0.925–2.141). Also, the pooled OR showed increased risk of ICC and ECC incidence (OR = 6.857, 95% CI 4.421–10.633 and OR = 1.740, 95% CI 1.260–2.404) in patients with HBsAg+/HBcAb+. The pooled OR showed increased risk of ICC incidence (OR = 1.410, 95% CI 1.095–1.816) in patients with HBsAg−/HBcAb+. Conclusion. It is suggested that HBV infection is associated with an increased risk of CCA in Asia. Two HBV infection models (HBsAg+/HBcAb+ and HBsAg−/HBcAb+) increase the risk of CCA, and patients with HBsAg−/HBcAb+ also had a risk of ICC. This trial is registered with PROSPERO CRD42015029264.

• Carcinogenesis
• Fatty liver
• Hepatoma
• Metabolic liver disease
• Primary liver tumor

• Animals
• Carcinogenesis/metabolism
• Carcinogenesis/pathology
• Carcinoma, Hepatocellular/epidemiology
• Carcinoma, Hepatocellular/etiology
• Carcinoma, Hepatocellular/metabolism
• Carcinoma, Hepatocellular/pathology
• Disease Progression
• Humans
• Incidence
• Liver Neoplasms/epidemiology
• Liver Neoplasms/etiology
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Non-alcoholic Fatty Liver Disease/complications
• Non-alcoholic Fatty Liver Disease/metabolism
• Non-alcoholic Fatty Liver Disease/pathology
• Prevalence
• Risk Factors
• Signal Transduction/physiology

Combined hepatocellular cholangiocarcinoma (CHC) accounts for 0.4%-14.2% of primary liver cancer cases and possesses pathological features of both hepatocellular carcinoma and cholangiocarcinoma. Since this disease was first described and classified in 1949, the classification of CHC has continuously evolved. The latest definition and classification of CHC by the World Health Organization is based on the speculation that CHC arises from hepatic progenitor cells. However, there is no evidence demonstrating the common origin of different components of CHC. Furthermore, the definition of CHC subtypes is still ambiguous and the identification of CHC subtype when a single tumor contains many components has remained unresolved. In addition, there is no summary on the newly recognized histopathology features or the contribution of CHC components to prognosis and outcome of this disease. Here we provide a review of the current literature to address these questions.

• Progenitor cell origin
• Pathology classification
• Combined hepatocellular cholangiocarcinoma

• Bile Duct Neoplasms/classification
• Bile Duct Neoplasms/genetics
• Bile Duct Neoplasms/pathology
• Bile Ducts, Intrahepatic/pathology
• Carcinoma, Hepatocellular/classification
• Carcinoma, Hepatocellular/genetics
• Carcinoma, Hepatocellular/pathology
• Cell Differentiation
• Cell Lineage
• Cholangiocarcinoma/classification
• Cholangiocarcinoma/genetics
• Cholangiocarcinoma/pathology
• Genetic Predisposition to Disease
• Humans
• Liver Neoplasms/classification
• Liver Neoplasms/genetics
• Liver Neoplasms/pathology
• Neoplasms, Complex and Mixed
• Phenotype
• Prognosis

• Cholangiocarcinoma
• Colangiocarcinoma
• Hepatocarcinoma
• Hepatocholangiocarcinoma
• Hepatocolangiocarcinoma
• Liver tumour
• Tumoración hepática

Bi-phenotypic neoplasm refers to tumors derived from a common cancer stem cell with unique capability to differentiate histologically into two distinct tumor types. Bi-phenotypic hepatocellular carcinoma-cholangiocarcinoma (HCC-CC), although a rare tumor, is important for clinicians to recognize, since treatment options targeting both elements of the tumor are crucial. Imaging findings of bi-phenotypic HCC-CC are not specific and include features of both HCC and CC. A combination of imaging and immuno-histochemical analysis is usually needed to make the diagnosis.

• Bi-phenotypic tumors
• Cholangiocarcinoma
• Computed tomography, Magnetic resonance imaging
• Hepatoceullular carcinoma