The concept and definition of combined hepatocellular-cholangiocarcinoma (cHCC-CCA), an extremely rare condition accounting for only 1% of all primary liver cancers, has shifted in recent years. The latest World Health Organization Classification (fifth edition) includes two types of cHCC-CCAs, (i) the classical type described in the previous edition, which contains a mixture of distinctly differentiated components of both hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) and (ii) intermediate cell carcinoma wherein all cells comprising the tumor express both hepatocellular and cholangiocellular features. However, the pathogenesis of cHCC-CCA, including its origins, remains controversial even among experts. Treatment strategies for cHCC-CCA in clinical practice have been determined based on imaging findings, tumor markers, and pathologically predominant tumor components for either HCC or ICC, suggesting that cHCC-CCA has yet to be been established as an independent disease entity. As with HCC and ICC, the treatment strategy for HCC-CCA involves initially considering resectability. Although systemic therapy has been considered for patients unsuitable for local treatment, no prospective clinical trials have evaluated the efficacy and safety of systemic therapy for cHCC-CCA, which could explain the lack of a standard of care. In recent years, however, studies have demonstrated the efficacy of immune checkpoint inhibitors for HCC and ICC, with therapeutic results having been reported for cHCC-CCA. Hence, further accumulation of cases is expected to facilitate the establishment of a consensus on treatment strategies in the near future.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer, with intermediate biological characteristics between hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA). Given its rarity and the lack of robust data from randomized clinical trials, treatment is not standardized, and the choice on how to best manage the disease is left to the expertise of each institution. In the metastatic setting, given the more aggressive behavior of the CCA component, the usual approach is to start treatment with chemotherapy instead of tyrosine-kinase inhibitors (TKIs). We present a case report on a Caucasian male with a poor response to first-line treatment with chemotherapy directed against CCA, but with an excellent and long overall survival (OS) of 71 months, thanks to HCC-directed treatment with TKI. Here, we highlight the difficulty in selecting an appropriate treatment upfront for this rare cancer and we also discuss future perspectives regarding predictive tools, especially considering the recent genomic analysis of cHCC-CCA, and regarding the potential use of immunotherapy and target therapy.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) represents an uncommon variant of primary liver cancer. In recent years, its incidence rate has increased. Thus, it is essential to perform comprehensive investigations into cHCC-CCA to develop suitable treatment strategies. So far, only two cell lines (CLs) of this cancer type have been reported. More cHCC-CCA CLs need to be established for research purposes. In this investigation, we developed a stable cHCC-CCA CL, named CHC-X1. STR analysis confirmed that CHC-X1 is a new human cHCC-CCA CL. CHC-X1 is a complex karyotype. Its population doubling time is 50.72 h. Under suspended conditions, CHC-X1 can form tumor spheres and organoids in Matrigel. These cells exhibit sensitivity to paclitaxel while demonstrating resistance against oxaliplatin, gemcitabine, and 5-FU. After inoculation into NXG mice, CHC-X1 can quickly form subcutaneous transplant tumors, exhibiting a tumor establishment rate of 67%. Immunohistochemical staining showed that CHC-X1 is a tumor CL with both liver cell differentiation and bile duct cell differentiation characteristics. It may function as a useful model for identifying the origins of cHCC-CCA and the advancement of potential treatments.

Combined hepatocellular cholangiocarcinoma is a rare and challenging primary liver malignancy that lacks any established standard treatments for unresectable cases. We herein present the first known case of a 49-year-old woman diagnosed with unresectable combined hepatocellular-cholangiocarcinoma, who underwent novel chemotherapy involving durvalumab plus tremelimumab combination therapy. The treatment was temporarily discontinued owing to immune-related adverse events, such as rash, and the patient was subsequently managed with systemic steroid therapy; however, the disease progressed after two courses of this treatment. Further studies are needed to validate the efficacy and safety of immune checkpoint inhibitors such as durvalumab and tremelimumab for the treatment of unresectable combined hepatocellular cholangiocarcinoma.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer associated with an appalling prognosis. The diagnosis and management of this entity have been challenging to physicians, radiologists, surgeons, pathologists, and oncologists alike. The diagnostic and prognostic value of biomarkers such as the immunohistochemical expression of nestin, a progenitor cell marker, have been explored recently. With a better understanding of biology and the clinical course of cHCC-CCA, newer treatment modalities like immune checkpoint inhibitors are being tried to improve the survival of patients with this rare disease. In this review, we give an account of the recent developments in the pathology, diagnostic approach, and management of cHCC-CCA.

The efficacy of atezolizumab/bevacizumab has never been reported in patients with metastatic/unresectable combined hepatocellular-cholangiocarcinoma (cHCC-CCA).

We retrospectively included patients with a histological diagnosis of unresectable/metastatic cHCC-CCA and treated with atezolizumab/bevacizumab (2020-2022) in 7 centers. Clinical and radiological features were collected at the beginning of atezolizumab/bevacizumab. We reported the radiological response using RECIST criteria, overall survival (OS) and progression-free survival (PFS).

Sixteen patients with cHCC-CCA were included and were predominantly male (75%) with advanced fibrosis/cirrhosis (69%). Nine patients received atezolizumab/bevacizumab as a first-line systemic treatment, 5 as a second line, 1 as a third line and 1 as a fifth line. Severe digestive bleeding occurred in 2 patients. Among the 9 patients treated in the first line, 4 experienced radiological progression, 3 partial response and 1 had stable disease. Patients treated with atezolizumab/bevacizumab in the first line had a median OS of 13 months and a median PFS of 3 months. Among the 7 patients receiving atezolizumab/bevacizumab as a second line or more, 4 patients harbored a stable disease, 2 a partial response, and 1 a progressive disease.

The combination of atezolizumab and bevacizumab showed signs of anti-tumor efficacy in patients with unresectable/metastatic cHCC-CCA.

Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a unique type of liver tumor that contains both hepatocellular carcinoma and cholangiocarcinoma components within a single tumor. The fifth edition of the World Health Organization classification provides a definition and diagnostic criteria for cHCC-CCA. However, the heterogeneous histomorphology and presentation resulting from variation of the proportion of each component poses challenges for clinical diagnosis and treatment. A diagnosis of cHCC-CCA may be suggested by the synchronous elevation of serum tumor markers for hepatocellular carcinoma and cholangiocarcinoma, a mixed enhancement pattern on imaging, and a discrepancy between the elevation of tumor marker and the imaging enhancement pattern. Histopathological examination using hematoxylin and eosin staining is considered the gold standard for diagnosing cHCC-CCA, and comprehensive examination of resection or biopsy specimens is crucial for an accurate diagnosis. Currently, there is no standard treatment for cHCC-CCA, and surgery is the mainstay. Anatomic hepatectomy with lymphadenectomy is among the recommended surgical procedures. The role of liver transplantation in the management of cHCC-CCA is still uncertain. Transarterial chemoembolization may be effective for unresectable cHCC-CCA, particularly for hypervascular tumors. However, the available evidence does not support systemic therapy for advanced cHCC-CCA. The prognosis of cHCC-CCA is generally poor, and there is no established staging system. Further research is needed to better understand the histogenesis and clinical management of cHCC-CCA. This review provides an overview of the current literature on cHCC-CCA with a focus on its clinical characteristics, pathological diagnosis, and management.

Combined hepatocellular-cholangiocarcinoma (cHCC-CC) is an aggressive hepatic cancer that has characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). For resectable disease, liver resection is the preferred first treatment option. As for the advanced or metastatic setting, and due to its rarity, there is still no consensus on which is the optimal systemic treatment. As such, regimens used in both HCC and CC have often been used as first-line treatment options. We report a case of a male patient in his 50s, diagnosed with a cHCC-CC with lymph node and adrenal metastasis, with an extensive portal vein tumour thrombosis, that started treatment with a multikinase inhibitor - lenvatinib.

Systemic therapy for advanced hepatocellular carcinoma has expanded at an unprecedented pace over the past 5 years. After tyrosine kinase inhibitors dominated the field for more than a decade, immune checkpoint inhibitor (ICI)-based therapies have become the main component in systemic first-line treatment of this cancer. Delivery of immunotherapy in routine clinical practice recognises several challenges. In this Viewpoint, we discuss the major gaps in knowledge around the role of ICI-based therapies in patients with Child-Pugh class B. We discuss the challenges in individuals with rare histological subtypes of primary liver cancer, including combined hepatocellular-cholangiocarcinoma, fibrolamellar hepatocellular carcinoma, and sarcomatoid hepatocellular carcinoma. We also review data on ICI rechallenge in patients previously treated with ICIs, and discuss atypical patterns of progression related to immunotherapy (ie, hyperprogressive disease and pseudoprogression).