Combined hepatocellular-cholangiocarcinoma (cHCC-iCCA) is a rare type of primary liver cancer displaying characteristics of both hepatocytic and cholangiocytic differentiation.

Because of its aggressive nature, patients with cHCC-iCCA exhibit a poorer prognosis than those with HCC. Surgical resection and liver transplantation may be considered curative treatment approaches; however, only a minority of patients are eligible at the time of diagnosis, and postoperative recurrence rates are high. For cases that are not eligible for surgery, locoregional and systemic therapy are often administered based on treatment protocols applied for HCC or iCCA. Owing to the rarity of this cancer, there are still no established standard treatment protocols; therefore, the choice of therapy is often personalized and guided by the suspected predominant component. Further, the genomic and molecular heterogeneity of cHCC-iCCA can severely compromise the efficacy of the available therapies.

In the present review, we summarize the latest advances in cHCC-iCCA and attempt to clarify its terminology and molecular biology. We provide an overview of the etiology of cHCC-iCCA and present new insights into the molecular pathology of this disease that could contribute to further studies aiming to improve the patient outcomes through new systemic therapies.

Combined hepatocellular and cholangiocarcinoma (cHCC-CCA) is a rare but aggressive primary liver cancer with dismal prognosis. We aim to develop a new scoring method for personalized prognostic prediction in patients with cHCC-CCA undergoing surgical resection.

Between January 1993 and December 2015, a total of 296 Allen type C cHCC-CCA patients who had received surgical resection in Liver Cancer Institute, Zhongshan Hospital were retrospectively enrolled. A novel prognostic scoring method for cHCC-CCA (PSM-CHCC model) was established and validated. The predictive value of the new model was compared with current prognostic staging systems.

The scoring model was developed based on the independent prognostic variables identified by Cox regression model. Based on the PSM-CHCC model, patients were stratified into three prognostic subgroups according to their individual score: A (scoring 0-2), B (scoring 3-5), and C (scoring > 5). The prediction performance of the PSM-CHCC model outperformed the widely accepted TNM staging system and other staging systems in both training and validation cohorts. Subgroup analysis also verified the discrimination efficacy of the PSM-CHCC model.

The newly established PSM-CHCC model may facilitate prognostic stratification and clinical decision-making in patients with cHCC-CCA.

Primary liver cancer (PLC) is a fatal disease that affects millions of lives worldwide. PLC is the leading cause of cancer-related deaths and the incidence rate is predicted to rise in the coming decades. PLC can be categorized into three major histological subtypes: hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined HCC-ICC. These subtypes are distinct with respect to epidemiology, clinicopathological features, genetic alterations, and clinical managements, which are thoroughly summarized in this review. The state of treatment strategies for each subtype, including the currently approved drugs and the potential novel therapies, are also discussed.

Background: The clinical significance of Albumin-to-Alkaline Phosphatase Ratio (AAPR) has been discussed in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). The aim of this study is to clarify the prognostic value of AAPR in patients with combined hepatocellular and cholangiocarcinoma (cHCC-CCA). Methods: A total of 267 patients pathologically diagnosed as Allen type C cHCC-CCA in our institution were retrospectively enrolled and randomly divided into the training (N=187) cohort and validation (N=80) cohort. The prognostic value of AAPR was evaluated and validated. An AAPR-based nomogram was constructed and its prediction performance was assessed. Results: We identified 0.43 as the optimal threshold value of AAPR by the X-tile software. In the training cohort, the median overall survival (OS) of patients with AAPR < 0.43 was significant shorter than that of those with AAPR ≥ 0.43(15.8 months vs 35 months, respectively, P < 0.001). Univariate and multivariate analyses demonstrated that AAPR was a strong indicator of OS. The concordance index (C-index), receiver operating characteristic (ROC) curves, likelihood ratio tests (LAT), Akaike information criteria (AIC) and decision curve analysis (DCA) demonstrated that AAPR outperformed the Child-Pugh (CP) grade and albumin-bilirubin (ALBI) grade in predicting OS. These findings were further verified in the validation cohort. The AAPR-based nomogram achieved C-index values of 0.76 (95%CI: 0.71-0.81) in the training cohort and 0.69 (95%CI: 0.60-0.78) in the validation cohort, which presented significant superiority to TNM stage. Conclusions: Preoperative AAPR is an independent prognostic predictor in cHCC-CCA. The AAPR-based nomogram contributes to personalized prognosis prediction and clinical decision making for cHCC-CCA.

Combined hepatocellular and cholangiocarcinoma (HCC-CC) is a rare primary liver cancer. It is constituted by neoplastic cells of both hepatocellular and cholangiocellular derivation. Different histology types of HCC-CC have been reported, hinting at heterogeneous carcinogenic pathways leading to the development of this cancer. Due to its rarity and complexity, mixed HCC-CC is a scantly investigated condition with unmet needs and unsatisfactory outcomes. Surgery remains the preferred treatment in resectable patients. The risk of recurrence, however, is high, especially in comparison with other primary liver cancers such as hepatocellular carcinoma. In unresectable or recurring patients, the therapeutic options are challenging due to the dual nature of the neoplastic cells. Consequently, the odds of survival of patients with HCC-CC remains poor. We analysed the literature systematically about the treatment of mixed HCC-CC, reviewing the main therapeutic options and their outcomes and analysing the most interesting developments in this topic with a focus on new potential therapeutic avenues.

To compare outcomes of unresectable hepatocellular-cholangiocarcinoma (HCC-CC) with hepatocellular carcinoma (HCC) after locoregional therapy (LRT).

Consecutive patients with histologically confirmed HCC-CC or HCC treated with LRT between 2007 and 2017 were retrospectively reviewed. Ten patients (8 men; median age, 60 y) with 12 HCC-CCs (mean diameter, 4.2 cm ± 1.9; mean number, 3.7 ± 3.3) treated with chemoembolization (n = 6), yttrium-90 radioembolization (n = 2), RF ablation (n = 1), or chemoembolization/RF ablation (n = 1) were compared with 124 patients (92 men; median age, 59 y) with 134 HCCs (mean diameter, 4.8 cm ± 4.0; mean number, 2.6 ± 2.2) treated with chemoembolization (n = 51), yttrium-90 radioembolization (n = 17), RF ablation (n = 41), or chemoembolization/RF ablation (n = 15). Propensity score-matched analysis with conditional logistic regression adjusted for age, sex, LRT modality, tumor-specific features, and Child-Pugh class. Tumor-volume doubling time (TVDT) before LRT and objective response rates were compared by Kruskal-Wallis and Fisher exact test; progression-free survival (PFS) and transplant-free survival (TFS) were compared by Cox proportional hazards model.

On univariate analysis, HCC-CC was associated with lower median TVDT (2.4 months vs 5.2 months, P = .03), objective response (30% vs 71%, P = .01), and median PFS (2.4 months vs 7.4 months, HR 4.3, 95% CI 2.2-8.4, P < .0001). Propensity score-matched analysis demonstrated greater distant progression (60% vs 30%, P = .003) and significantly shorter median PFS (2.4 months vs 6.0 months, HR 3.3, 95% CI 1.3-8.9, P = .017) for HCC-CC. No significant difference was observed in TFS (7.5 months vs 13.8 months, HR 1.5, 95% CI 0.4-6.1).

HCC-CC was associated with reduced PFS and greater distant progression after LRT compared with HCC, indicating a need for adjunctive treatment strategies to improve outcomes.

Combined hepatocellular-cholangiocarcinoma (CHC) is a primary liver cancer containing both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) elements. Its reported clinicopathological features and prognoses have varied because of its low prevalence. This study aimed to clarify these aspects of CHC.

We enrolled 28 patients with CHC, 1050 with HCC, and 100 with ICC and compared the clinicopathological characteristics and prognosis of CHC with HCC and ICC. We also analyzed prognostic factors, recurrence patterns, and management in CHC patients.

The incidences of hepatitis B virus and high α-fetoprotein and protein induced by vitamin K absence or antagonists-II levels were significantly higher among CHC compared with ICC patients. Multiple tumors were more frequent in CHC compared with the other groups, while vascular invasion and lymph node metastasis were more frequent in the CHC than the HCC group. The 5-year overall survival and disease-free survival rates for CHC were 25.1% and 22.6%, respectively. Overall survival was significantly lower than for HCC (P < 0.001) but not ICC (P = 0.152), while disease-free survival was significantly lower than for HCC and ICC (P = 0.008 and P = 0.005, respectively). Multivariate analysis identified carcinoembryonic antigen levels and tumor size as independent predictors in patients with CHC.

The clinical features of CHC, including sex, hepatitis B virus infection, α-fetoprotein, and protein induced by vitamin K absence or antagonists-II levels, were similar to HCC, while its prognosis and pathological features, including vascular invasion and lymph node metastasis, were similar to ICC. Carcinoembryonic antigen levels and tumor size were independent prognostic factors in patients with CHC.

Sorafenib, a multiple kinase inhibitor, has been established as first-line standard systemic chemotherapy for patients with advanced hepatocellular carcinoma (HCC). We encountered a patient with combined hepatocellular and cholangiocarcinoma (CHC) who achieved complete remission in response to sorafenib treatment. A 58-year old man with hepatitis C virus (HCV)-induced liver cirrhosis was diagnosed with CHC in segments 6th and 7th of the liver and underwent partial surgical resection. Three months later, CHC recurred as metastases at multiple intrahepatic sites, lymph nodes, and bones, making surgery impossible. Treatment with sorafenib was initiated at 400 mg b.i.d., later reduced to 400 mg/day. After 6 months of sorafenib administration, he no longer showed abnormal uptake on fluorodeoxyglucose positron emission tomography. He was continued on sorafenib for 2.5 years, but later discontinued due to adverse events. He has shown no evidence of tumor recurrence more than 1 year after sorafenib discontinuation. His HCV was eradicated by direct-acting antivirals, and he remains in good health.

Combined hepatocellular cholangiocarcinoma (CC) is a rare and aggressive primary hepatic malignancy with significant histological and biological heterogeneity. It presents with more aggressive behavior and worse survival outcomes than either hepatocellular carcinoma or CC and remains a diagnostic challenge. An accurate diagnosis is crucial for its optimal management. Major hepatectomy with hilar node resection remains the mainstay of treatment in operable cases. Advances in the genetic and molecular characterization of this tumor will contribute to the better understanding of its pathogenesis and shape its future management.

We conducted a multicenter retrospective analysis to evaluate the efficacy of systemic chemotherapy for unresectable combined hepatocellular and cholangiocarcinoma. We enrolled 36 patients with pathologically proven, unresectable combined hepatocellular and cholangiocarcinoma treated with systemic chemotherapy. The log-rank test determined the significance of each prognostic factor. Elevated alpha-fetoprotein, carcinoembryonic antigen and carbohydrate antigen 19-9 levels were observed in 58.3%, 16.7% and 38.9% of patients, respectively. First-line chemotherapy included platinum-containing regimens consisting of gemcitabine/cisplatin (n = 12) and fluorouracil/cisplatin (n = 11), sorafenib (n = 5) and others (n = 8). The median overall and progression-free survival times were 8.9 and 2.8 months, respectively, with an overall response rate of 5.6%. Prognostic factors associated with negative outcomes included poor performance status, no prior primary tumor resection, a Child-Pugh class of B, and elevated carcinoembryonic antigen levels with a hazard ratio of 2.25, 2.48, 3.25 and 2.84 by univariate analysis, respectively. The median overall survival times of the gemcitabine/cisplatin, fluorouracil/cisplatin, sorafenib and other groups were 11.9, 10.2, 3.5 and 8.1 months, respectively. Multivariate analysis revealed that the overall survival of patients within the sorafenib monotherapy group was poor compared with platinum-containing regimens (HR: 15.83 [95% CI: 2.25-111.43], P = .006). All 7 patients in the sorafenib group had progressive disease, including 2 patients with second-line therapy. In conclusion, the platinum-containing regimens such as gemcitabine/cisplatin were associated with more favorable outcomes than sorafenib monotherapy for unresectable combined hepatocellular and cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (HCC-CC) has a reported incidence of less than 5% of primary hepatic malignancies. The treatment approach to this malignancy is undefined. Our objective of this case series is to provide some insight into chemotherapy and/or targeted therapy in this setting.

Pathologic and radiographic review confirmed seven combined HCC-CC patients during a 5-year time frame [2009-2014]. Data points were demographics, chemotherapy and/or targeted therapy given in the first and second-line setting, localized treatment if given, first radiographic result, progression-free survival (PFS), and overall survival (OS).

Seven patients were identified. Front-line treatment showed a median PFS of 3.4 months. Total median OS was 8.3 months. Regimens given included gemcitabine alone +/- bevacizumab, gemcitabine + platinum (GP) +/- bevacizumab, and sorafenib. Front-line treatment with these regimens showed progressive disease in 71% (5 patients) on first radiographic scan with all patients who received sorafenib front-line progressing at that restaging. Disease-control (complete response + partial response + stable disease) was seen in 29% of patients (2 patients) with 1 patient receiving GP and 1 patient receiving gemcitabine + bevacizumab. Of note, 2 patients that received GP +/- bevacizumab in the second-line setting had disease control on first radiographic scan.

Our retrospective review speaks to the rarity of this malignancy and challenges that are associated with its diagnosis and treatment. GP +/- bevacizumab showed disease control in first or second-line treatment in 3 patients. Treatment with this regimen in this rare malignancy subgroup warrants further investigation.

Primary liver carcinomas with hepatocellular and cholangiocellular differentiation (b[HB]-PLC) are rare. Surgery offers the best prognosis, but there is a paucity of literature to guide therapy for patients with advanced or unresectable disease. This study aimed to evaluate outcomes of hepatic-directed therapy compared with those of systemic chemotherapy and surgery.

A retrospective evaluation of patients with b(HB)-PLC from 1 January 2008 to 1 September 2014 was conducted. The patients were divided into the following four groups: transplantation (TX) group, surgical resection (SX) group, hepatic directed (HD) group, and systemic chemotherapy alone (SC) group. Overall and progression-free survival, treatment response, and clinicopathologic data were analyzed.

The study included 79 patients (37 females) with an average age of 62 years. The number of patients in each group were as follows: TX group (n = 6), SX group (n = 27), HD group (n = 18), and SC group (n = 28). The mean follow-up periods were 33 months for the TX group, 17 months for the SX group, 14 months for the HD group, and 7 months for the SX group. Overall, 28 % of the patients had cirrhosis and 35 % had viral hepatitis. The candidates for surgery comprised 42 % of the patients. The HD group (n = 18) had a significantly greater objective response than the SC group (n = 28) (47 vs. 6 %; p = 0.02). Two patients who underwent hepatic arterial infusion pump treatment were downstaged to resection. A trend toward improved OS/PFS was observed in the HD group versus the SC group, although statistically significant. The SX group had significantly improved survival (p < 0.001) as did the transplanted patients.

Although surgery offers the best survival for b(HB)-PLC patients, only a minority are candidates for surgery. Because HD therapy showed a superior objective response over SC therapy, it may offer a survival advantage and may downstage patients for surgical resection or transplantation.

Although transplantation has demonstrated survival benefit for patients with hepatocellular carcinoma (HCC), there is limited data to support or refute transplantation for combined hepatocellular-cholangiocarcinoma (cHCC-CC). We hypothesized that cHCC-CC patients had poorer overall survival (OS) than HCC patients after liver transplantation.

Patients with localized HCC and cHCC-CC treated with surgical resection or transplant were identified using the Surveillance, Epidemiology, and End Results (SEER) Database (1973-2007). Cox proportional hazards models were used to examine survival.

We identified 3,378 (1,447 [43%] transplant, 1,931 [57%] resection) patients with HCC, and 54 (19 [35%] transplant, 35 [65%] resection) patients with cHCC-CC. Patients undergoing resection of HCC and cHCC-CC had similar 3-year OS (55% vs. 46%, P = 0.4). Three-year OS of patients undergoing transplant was significantly greater for HCC (78%) than for cHCC-CC (48%, P = 0.01). In adjusted models, patients transplanted for cHCC-CC had higher hazard of death compared to HCC patients (HR 2.5, 95% CI: 1.2-5.1, P = 0.01).

Transplantation for localized cHCC-CC confers a survival benefit similar to liver resection for cHCC-CC, but inferior to transplantation for HCC. With survival data that mimics historic reports of transplant for intrahepatic cholangiocarcinoma, this study questions the benefit of transplantation for patients with cHCC-CC.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is a rare type of primary liver cancer comprising histopathological features of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Because of its rarity and controversial diagnostic criteria, it continues to be poorly understood with a lack of well-delineated treatment options for recurrent or metastatic disease. We report a case of cHCC-CC in a 31-year-old woman with no risk factors for HCC or CC with recurrent pulmonary metastasis treated with systemic chemotherapy.