• combined hepatocellular-cholangiocarcinoma
• immunotherapy
• systemic therapy

• Biomarker
• Cholangiocarcinoma
• Combined hepatocellular-cholangiocarcinoma
• Genomic landscape
• Hepatocellular carcinoma
• Immune checkpoint inhibitors
• Immunotherapy
• Liver cancer
• Nestin
• Pathology

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a form of rare primary liver cancer that combines intrahepatic cholangiocarcinoma (ICC) and hepatocellular carcinoma.

To investigate overall survival (OS) and recurrence-free survival (RFS) after radical resection in patients with cHCC-CCA, and the clinicopathological factors affecting prognosis in two center hospitals of China.

We reviewed consecutive patients with cHCC-CCA who received radical resection between January 2005 and September 2021 at Peking Union Medical College and the 5th Medical Center of the PLA General Hospital retrospectively. Regular follow-up and clinicopathological characteristics were systematic collected for baseline and prognostic analysis.

Our study included 95 patients who received radical resection. The majority of these patients were male and 82.7% of these patients were infected with HBV. The mean tumor size was 4.5 cm, and approximately 40% of patients had more than one lesion. The median OS was 26.8 (95%CI: 18.5-43.0) mo, and the median RFS was 7.27 (95%CI: 5.83-10.3) mo. Independent predictors of OS were CA19-9 ≥ 37 U/mL (HR = 8.68, P = 0.002), Child-Pugh score > 5 (HR = 5.52, P = 0.027), tumor number > 1 (HR = 30.85, P = 0.002), tumor size and transarterial chemoembolization (TACE) after surgery (HR = 0.2, P = 0.005).

The overall postoperative survival of cHCC-CCA patients is poor, and most patients experience relapse within a short period of time after surgery. Preoperative tumor biomarker (CA19-9, alpha-fetoprotein) levels, tumor size, and Child-Pugh score can significantly affect OS. Adjuvant TACE after surgery prolongs RFS, suggesting that TACE is a possible option for postoperative adjuvant therapy in patients with cHCC-CCA.

• Combined hepatocellular-cholangiocarcinoma
• Radical resection
• Clinicopathological factor
• Integrated nomogram
• Multicenter cohort

• Humans
• Male
• Female
• Carcinoma, Hepatocellular/pathology
• Prognosis
• Bile Duct Neoplasms/pathology
• Liver Neoplasms/pathology
• Chemoembolization, Therapeutic/adverse effects
• CA-19-9 Antigen
• Retrospective Studies
• Cohort Studies
• Neoplasm Recurrence, Local/pathology
• Cholangiocarcinoma/pathology
• Bile Ducts, Intrahepatic/pathology
• Multicenter Studies as Topic

Cholangiocarcinoma (CC) is a rare tumor that arises from the epithelium of the bile ducts. It is classified according to anatomic location as intrahepatic, perihilar, and distal. Intrahepatic CC (ICC) is rare in patients with cirrhosis due to causes other than primary sclerosing cholangitis. Mixed hepatocellular carcinoma-CC (HCC-CC) is a rare neoplasm that shows histologic findings of both HCC and ICC within the same tumor mass. Due to the difficulties in arriving at the correct diagnosis, patients eventually undergo liver transplantation (LT) with a presumptive diagnosis of HCC on imaging when, in fact, they have ICC or HCC-CC.

To evaluate the outcomes of patients with intrahepatic cholangiocarcinoma or mixed hepatocellular-cholangiocarcinoma on pathological examination after liver transplant.

Propensity score matching was used to analyze tumor recurrence (TR), overall mortality (OM), and recurrence-free survival (RFS) in LT recipients with pathologically confirmed ICC or HCC-CC matched 1:8 to those with HCC. Progression-free survival and overall mortality rates were computed with the Kaplan-Meier method using Cox regression for comparison.

Of 475 HCC LT recipients, 1.7% had the diagnosis of ICC and 1.5% of HCC-CC on pathological examination of the explant. LT recipients with ICC had higher TR (46% vs 11%; P = 0.006), higher OM (63% vs 23%; P = 0.002), and lower RFS (38% vs 89%; P = 0.002) than those with HCC when matched for pretransplant tumor characteristics, as well as higher TR (46% vs 23%; P = 0.083), higher OM (63% vs 35%; P = 0.026), and lower RFS (38% vs 59%; P = 0.037) when matched for posttransplant tumor characteristics. Two pairings were performed to compare the outcomes of LT recipients with HCC-CC vs HCC. There was no significant difference between the outcomes in either pairing.

Patients with ICC had worse outcomes than patients undergoing LT for HCC. The outcomes of patients with HCC-CC did not differ significantly from those of patients with HCC.

• Cholangiocarcinoma
• Hepatocellular carcinoma
• Liver
• Prognosis
• Recurrence
• Survival analysis
• Transplantation

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

Intrahepatic sarcomatoid chonalgiocarcinoma (s-CCC) is an extremely rare disease, accounting for less than 1% of hepatobiliary system malignancies, and its pathophysiology is not well known. On the hypothesis that its clinical, serologic, or radiologic diagnosis are not fully understood and its prognosis is poor, we investigated the distinguishing features of s-CCC compared with those of intrahepatic bile duct adenocarcinoma [cholangiocellular carcinoma (CCC)] in patients from a single center.

To analyze the clinical, serologic, imaging, and histopathologic characteristics of intrahepatic s-CCC patients diagnosed in a single center.

The clinical, serologic, imaging, and histopathologic features of 227 patients diagnosed with intrahepatic cholangiocarcinoma (IHCC) in a single medical center during the last 17 years were analyzed. The characteristics of 11 patients with s-CCC were compared with those of 216 patients with CCC.

The number of patients with s-CCC who presented fever and abdominal pain and past history of chronic viral hepatitis or liver cirrhosis (LC) was higher than that of patients with CCC. In imaging studies, patients with s-CCC showed relatively aggressive features. However, no clear distinction was observed between s-CCC and CCC based on other clinical, serologic or radiologic examination results. An accurate diagnosis could be made only via a histopathologic examination through immunohistochemical staining. The clinical course of s-CCC was generally aggressive, and patients had a relatively poor prognosis.

In patients with s-CCC, early diagnosis through biopsy and aggressive treatment, including surgical resection, are important.

• Intrahepatic sarcomatoid cholangiocarcinoma
• Immunohistochemical staining
• Survival
• Prognosis
• Surgical resection

• Aged
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/mortality
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/therapy
• Bile Ducts, Intrahepatic/diagnostic imaging
• Bile Ducts, Intrahepatic/pathology
• Bile Ducts, Intrahepatic/surgery
• Biomarkers, Tumor/blood
• Biopsy
• Chemotherapy, Adjuvant/methods
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/mortality
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/therapy
• Female
• Follow-Up Studies
• Hepatectomy
• Humans
• Kaplan-Meier Estimate
• Liver Function Tests
• Magnetic Resonance Imaging
• Male
• Middle Aged
• Prognosis
• Rare Diseases/diagnosis
• Rare Diseases/mortality
• Rare Diseases/pathology
• Rare Diseases/therapy
• Republic of Korea/epidemiology
• Retrospective Studies
• Sarcoma/diagnosis
• Sarcoma/mortality
• Sarcoma/pathology
• Sarcoma/therapy
• Tomography, X-Ray Computed
• Treatment Outcome
• Ultrasonography

Hepatocellular carcinoma (HCC) is one of the most common and fatal cancer in the world. HCC frequently presents with advanced disease, has a high recurrence rate and limited treatment options, which leads to very poor prognosis. This warrants urgent improvement in the diagnosis and treatment. Liver biopsy plays very important role in the diagnosis and prognosis of HCC, but with technical advancements and progression in the field of imaging, clinical guidelines have restricted the role of biopsy to very limited situations. Biopsy also has its own problems of needle tract seeding of tumor, small risk of complications, technical and sampling errors along with interpretative errors. Despite this, tissue analysis is often required because imaging is not always specific, limited expertise and lack of advanced imaging in many centers and limitations of imaging in the diagnosis of small, mixed and other variant forms of HCC. In addition, biopsy confirmation is often required for clinical trials of new drugs and targeted therapies. Tissue biomarkers along with certain morphological features, phenotypes and immune-phenotypes that serve as important prognostic and outcome predictors and as decisive factors for therapy decisions, add to the continuing role of histopathology. Advancements in cancer biology and development of molecular classification of HCC with clinic pathological correlation, lead to discovery of HCC phenotypic surrogates of prognostic and therapeutically significant molecular signatures. Thus tissue characteristics and morphology based correlates of molecular subtypes provide invaluable information for management and prognosis. This review thus focuses on the importance of histopathology and resurgence of role of biopsy in the diagnosis, management and prognostication of HCC.

• Hepatocellular carcinoma
• Biomarker
• Biopsy
• Histopathology
• Immunohistochemistry
• Targeted therapy
• Molecular
• Diagnosis
• Prognosis

• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Biomarkers, Tumor/analysis
• Biopsy/methods
• Biopsy/trends
• Carcinoma, Hepatocellular/diagnosis
• Carcinoma, Hepatocellular/mortality
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/therapy
• Disease Progression
• Hepatectomy
• Humans
• Immunohistochemistry
• Liver/diagnostic imaging
• Liver/pathology
• Liver/surgery
• Liver Neoplasms/diagnosis
• Liver Neoplasms/mortality
• Liver Neoplasms/pathology
• Liver Neoplasms/therapy
• Prognosis
• Survival Analysis
• Treatment Outcome

To evaluate the significance of resection margin width in the management of hepatocholangiocarcinoma (HCC-CC).

Data of consecutive patients who underwent hepatectomy for hepatic malignancies in the period from 1995 to 2014 were reviewed. Patients with pathologically confirmed HCC-CC were included for analysis. Demographic, biochemical, operative and pathological data were analyzed against survival outcomes.

Forty-two patients were included for analysis. The median age was 53.5 years. There were 29 males. Hepatitis B virus was identified in 73.8% of the patients. Most patients had preserved liver function. The median preoperative indocyanine green retention rate at 15 min was 10.2%. The median tumor size was 6.5 cm. Major hepatectomy was required in over 70% of the patients. Hepaticojejunostomy was performed in 6 patients. No hospital death occurred. The median hospital stay was 13 d. The median follow-up period was 32 mo. The 5-year disease-free survival and overall survival were 23.6% and 35.4% respectively. Multifocality was the only independent factor associated with disease-free survival [P < 0.001, odds ratio 4, 95% confidence interval (CI): 1.9-8.0]. In patients with multifocal tumor (n = 20), resection margin of ≥ 1 cm was associated with improved 1-year disease-free survival (40% vs 0%; log-rank, P = 0.012).

HCC-CC is a rare disease with poor prognosis. Resection margin of 1 cm or above was associated with improved survival outcome in patients with multifocal HCC-CC.

• Hepatocholangiocarcinoma
• Hepatocellular cholangiocarcinoma
• Survival
• Hepatectomy
• Resection margin

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

In recent years, the results of several studies suggest that human liver tumors can be derived from hepatic progenitor cells rather than from mature cell types. The available data indeed strongly suggest that most combined hepatocellular-cholangiocarcinomas arise from hepatic progenitor cells that retained their potential to differentiate into the hepatocytic and biliary lineages. Hepatic progenitor cells could also be the basis for some hepatocellular carcinomas and hepatocellular adenomas, although it is very difficult to determine the origin of an individual hepatocellular carcinoma. There is currently not enough data to make statements regarding a hepatic progenitor cell origin of cholangiocarcinoma. The presence of hepatic progenitor cell markers and the presence and extent of the cholangiocellular component are factors that are related to the prognosis of hepatocellular carcinomas and combined hepatocellular-cholangiocarcinomas, respectively.

• Hepatic progenitor cell
• Hepatocellular carcinoma
• Liver tumor

• Adenoma, Liver Cell/pathology
• Biomarkers, Tumor
• Carcinoma, Hepatocellular/pathology
• Cell Transformation, Neoplastic/pathology
• Cholangiocarcinoma/pathology
• Hepatocytes/pathology
• Humans
• Liver Neoplasms/pathology
• Stem Cells/pathology

• carcinoma, hepatocellular
• cholangiocarcinoma
• stomach neoplasm
• double cancer
• triple cancer

• Adenocarcinoma/diagnosis
• Aged
• Bile Duct Neoplasms/diagnosis
• Bile Ducts, Intrahepatic/pathology
• Carcinoma, Hepatocellular/diagnosis
• Cholangiocarcinoma/diagnosis
• Humans
• Liver Neoplasms/diagnosis
• Male
• Neoplasms, Multiple Primary/diagnosis
• Stomach Neoplasms/diagnosis