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Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management
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Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (29 February 2024) | Viewed by 16951

Special Issue Editor

Prof. Dr. Marcus Bahra

E-Mail Website
Guest Editor
Surgical Oncology and Robotic, Krankenhaus Waldfriede, 14163 Berlin, Germany
Interests: surgical oncology; hepato-pancreato-biliary surgery; robotic surgery

Special Issue Information

Dear Colleagues,

Combined hepatocellular-cholangiocarcinoma (HCC-CC) is an aggressive hepatobiliary tumor composed of two well-known liver carcinomas: hepatocellular carcinoma and cholangiocarcinoma. Hepatocellular carcinomas are known to originate from hepatocytes, whereas the origin of cholangiocarcinoma is believed to be bile duct epithelial cells. Although the incidence of this uncommon type of carcinoma is low, the clinical significance should not be underestimated.

Hepatitis B virus infection and liver cirrhosis are already known to be risk factors for the development of HCC-CC. However, many fundamental questions remain open:

Is it possible to define demographic characteristics in patients with HCC-CC to get more information about the epidemiology and the risk profile for the development of this aggressive tumor? Does the incidence remain as low as when estimated or is there an increase noticeable over the time? We must discuss tumorigenesis of this entity to learn more about the biological behavior—is it more than just the sum of two different tumors?

Survival analysis has shown that the rate of overall survival for HCC-CC lies between those of HCC and CC. However, a challenge for pathologists is to provide a reproducible tumor classification such that valid information in regard to tumor staging and tumor prognosis is acquired.

In the majority of cases of combined hepatocellular-cholangiocarcinoma, the diagnosis occurs postoperatively. To date, there are numerous open questions regarding pre-therapeutical diagnostic options and pre-operative work-up. What is state of the art?

Surgery is the central and first choice in the treatment of HCC-CC and the only curative path of therapy. However, several key questions remain open: Do we have a consensus regarding surgical standards? Is there a role for minimally invasive liver surgery (MILS) or robotic surgery in patients with HCC-CC? Today, oncological concepts are more complex, including multimodal interdisciplinary therapies. How far should we go from a surgical point of view? How far should we go from the perspective of the oncologist?

Last but not least, there are many open questions in the complex context of oncological treatment. Is adjuvant therapy important? If yes, what proportion of the tumor should define the therapy?

Furthermore, we have to ask if there is any role for radiotherapy or radiochemotherapy. What is the impact of local tumor therapies such as TACE (transcatheter arterial chemoembolization), brachytherapy or yttrium-90 radioembolization on HCC-CC?

With this Special Issue, we hope to improve our understanding of this rare but highly aggressive tumor entity

Prof. Dr. Marcus Bahra
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • combined hepatocellular-cholangiocarcinoma
  • therapy
  • prognosis
  • epidemiology
  • classification
  • diagnosis
  • management

Published Papers (7 papers)

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Research

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12 pages, 1455 KiB  
Article
Liver Transplantation for Incidental Cholangiocarcinoma or Combined Hepatocellular Carcinoma/Cholangiocarcinoma—Own Experiences and Review of the Literature
by Laura Schwenk, Oliver Rohland, Aladdin Ali-Deeb, Felix Dondorf, Utz Settmacher and Falk Rauchfuß
Cancers 2023, 15(14), 3609; https://doi.org/10.3390/cancers15143609 - 13 Jul 2023
Cited by 1 | Viewed by 1184
Abstract
Background: Data about liver transplantation for mixed tumors from hepatocellular carcinoma to cholangiocarcinoma are limited. Furthermore, the diagnosis of intrahepatic cholangiocarcinoma or combined tumors in a cirrhotic liver is considered a contraindication for transplantation. Our aim was to evaluate the long-term outcomes of [...] Read more.
Background: Data about liver transplantation for mixed tumors from hepatocellular carcinoma to cholangiocarcinoma are limited. Furthermore, the diagnosis of intrahepatic cholangiocarcinoma or combined tumors in a cirrhotic liver is considered a contraindication for transplantation. Our aim was to evaluate the long-term outcomes of patients with incidental cholangiocarcinoma or combined tumors after liver transplantation. Methods: In our descriptive analysis, data were evaluated from all patients since 2010 who received a liver transplant due to an assumed hepatocellular carcinoma at Jena University Hospital. Survival rates were determined using the Kaplan–Meier method. Results: Between January 2010 and December 2022, an incidental intrahepatic cholangiocarcinoma was found in eight patients post-transplant. Four combined hepatocellular and cholangiocarcinoma and four sole intrahepatic cholangiocarcinomas were found. A recurrence through distant metastases from combined hepatocellular- and cholangiocarcinoma was found in one patient at one year after transplantation. Another patient developed a pulmonary primary tumor independently one year post-transplant. The recurrence rate was at 14.3%. While two patients died, the 1- and 5-year overall survival rates post-transplant were 87.5% and 75%, respectively. Conclusion: Patients with intrahepatic cholangiocarcinoma or combined hepatocellular- and cholangiocarcinoma could profit from liver transplantation. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
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15 pages, 6063 KiB  
Article
Mixed Hepatocellular Cholangiocarcinoma: A Comparison of Survival between Mixed Tumors, Intrahepatic Cholangiocarcinoma and Hepatocellular Carcinoma from a Single Center
by Lea Penzkofer, Lisa-Katharina Gröger, Maria Hoppe-Lotichius, Janine Baumgart, Stefan Heinrich, Jens Mittler, Tiemo S. Gerber, Beate K. Straub, Arndt Weinmann, Fabian Bartsch and Hauke Lang
Cancers 2023, 15(3), 639; https://doi.org/10.3390/cancers15030639 - 19 Jan 2023
Cited by 2 | Viewed by 1833
Abstract
Background: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy, followed by intrahepatic cholangiocarcinoma (ICC). In addition, there is a mixed form for which only limited data are available. The aim of this study was to compare recurrence and survival of the [...] Read more.
Background: Hepatocellular carcinoma (HCC) is the most frequent primary liver malignancy, followed by intrahepatic cholangiocarcinoma (ICC). In addition, there is a mixed form for which only limited data are available. The aim of this study was to compare recurrence and survival of the mixed form within the cohorts of patients with HCC and ICC from a single center. Methods: Between January 2008 and December 2020, all patients who underwent surgical exploration for ICC, HCC, or mixed hepatocellular cholangiocarcinoma (mHC-CC) were included in this retrospective analysis. The data were analyzed, focusing on preoperative and operative details, histological outcome, and tumor recurrence, as well as overall and recurrence-free survival. Results: A total of 673 surgical explorations were performed, resulting in 202 resections for ICC, 344 for HCC (225 non-cirrhotic HCC, ncHCC; 119 cirrhotic HCC, cHCC), and 14 for mHC-CC. In addition, six patients underwent orthotopic liver transplant (OLT) in the belief of dealing with HCC. In 107 patients, tumors were irresectable (resection rate of 84%). Except for the cHCC group, major or even extended liver resections were required. Vascular or visceral extensions were performed regularly. Overall survival (OS) was highly variable, with a median OS of 17.6 months for ICC, 26 months for mHC-CC, 31.8 months for cHCC, and 37.2 months for ncHCC. Tumor recurrence was common, with a rate of 45% for mHC-CC, 48.9% for ncHCC, 60.4% for ICC, and 67.2% for cHCC. The median recurrence-free survival was 7.3 months for ICC, 14.4 months for cHCC, 16 months for mHC-CC, and 17 months for ncHCC. The patients who underwent OLT for mHC-CC showed a median OS of 57.5 and RFS of 56.5 months. Conclusions: mHC-CC has a comparable course and outcome to ICC. The cholangiocarcinoma component seems to be the dominant one and, therefore, may be responsible for the prognosis. ‘Accidental’ liver transplant for mHC-CC within the Milan criteria offers a good long-term outcome. This might be an option in countries with no or minor organ shortage. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
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Review

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17 pages, 2695 KiB  
Review
Interventional Treatment Strategies in Intrahepatic Cholangiocarcinoma and Perspectives for Combined Hepatocellular-Cholangiocarcinoma
by Timo Alexander Auer, Federico Collettini, Laura Segger, Uwe Pelzer, Raphael Mohr, Felix Krenzien, Bernhard Gebauer, Dominik Geisel, Clarissa Hosse, Wenzel Schöning and Uli Fehrenbach
Cancers 2023, 15(9), 2655; https://doi.org/10.3390/cancers15092655 - 8 May 2023
Cited by 4 | Viewed by 2477
Abstract
cHCC-CCA is an uncommon type of liver cancer that exhibits clinical and pathological characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), which are the two main forms of primary liver cancer. The similarity to HCC and CCA makes therapeutical strategies challenging. The [...] Read more.
cHCC-CCA is an uncommon type of liver cancer that exhibits clinical and pathological characteristics of both hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), which are the two main forms of primary liver cancer. The similarity to HCC and CCA makes therapeutical strategies challenging. The poor prognosis of CCA in general, as well as for cHCC-CCA, is mainly attributable to the fact that diagnosis is often at an advanced stage of disease. During the last decade, locoregional therapies usually performed by interventional radiologists and its established role in HCC treatment have gained an increasing role in CCA treatment as well. These comprise a wide range of options from tumor ablation procedures such as radiofrequency ablation (RFA), microwave ablation (MWA), computed tomography high-dose rate brachytherapy (CT-HDRBT), and cryoablation to transarterial chemoembolization (TACE), including the option of intra-arterial administration of radioactive spheres (transarterial radioembolization—TARE), and much attention has focused on the potential of individual concepts in recent years. The purpose of this review is to provide an overview of current radiologic interventions for CCA (excluding options for eCCA), to review and appraise the existing literature on the topic, and to provide an outlook on whether such interventions may have a role as treatment for cHCC-CCA in the future. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
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15 pages, 292 KiB  
Review
Management of Locally Advanced or Metastatic Combined Hepatocellular Cholangiocarcinoma
by Jemmy Zhao, Susann Stephan-Falkenau, Markus Schuler and Börge Arndt
Cancers 2023, 15(3), 988; https://doi.org/10.3390/cancers15030988 - 3 Feb 2023
Cited by 2 | Viewed by 2373
Abstract
Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the [...] Read more.
Combined hepatocellular cholangiocarcinoma (cHCC-CC) is a rare primary liver malignancy that comprises features of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC). Due to the rarity of this tumor, the treatment of choice has not yet been defined. For resectable disease, liver resection is the mainstay treatment. However, most patients relapse or display advanced disease and were not surgical candidates. Although the majority of patients are either primarily or secondarily treated in palliative intent, no guideline recommendations or prospective trial reports exist to allow reliable evaluation of debated treatment options. We review different locoregional or medical treatment options for advanced combined hepatocellular cholangiocarcinoma (cHCC-CC) in the neoadjuvant, adjuvant, or palliative setting and discuss the possibility of predictive biomarker-guided therapeutic options. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
12 pages, 281 KiB  
Review
Surgical Strategies for Combined Hepatocellular-Cholangiocarcinoma (cHCC-CC)
by Marcus Bahra and Ali Yahyazadeh
Cancers 2023, 15(3), 774; https://doi.org/10.3390/cancers15030774 - 26 Jan 2023
Cited by 5 | Viewed by 1869
Abstract
Combined hepatocellular–cholangiocarcinoma (cHCC-CC) is a tumor entity presenting features of hepatocellular and cholangiocellular epithelial differentiation. Due to the likeness between cHCC-CC, HCC and CC, accurate pretherapeutical diagnosis is challenging and advanced stages are prevalent. Radical oncological surgery is the only curative therapeutical option [...] Read more.
Combined hepatocellular–cholangiocarcinoma (cHCC-CC) is a tumor entity presenting features of hepatocellular and cholangiocellular epithelial differentiation. Due to the likeness between cHCC-CC, HCC and CC, accurate pretherapeutical diagnosis is challenging and advanced stages are prevalent. Radical oncological surgery is the only curative therapeutical option in patients with cHCC-CC. To reach this goal a profound understanding of this rare liver tumor is crucial. Factors such as clinicopathological characteristics, growth patterns and biological behavior are of central importance. To explore onco-surgical strategies and aspects for complete resection of cHCC-CC and to answer important key questions, an extensive review of the literature was conducted to answer the following questions: What are the best surgical options? Is there a significance for nonanatomical resections? Is there a prognostic value of concomitant lymphadenectomy? What about multimodal concepts in local advanced cHCC-CC? The role of minimally invasive liver surgery (MILS) including the role of robotic liver surgery for cHCC-CC will be discussed. While liver transplantation (LT) is standard for patients with unresectable HCC, the role of LT in cHCC-CC patients is still controversial. How can patients with high risk for early tumor recurrence be identified to avoid aggressive surgical treatment without clinical benefit? The comprehensive understanding of this challenging liver tumor will help to improve future treatment options for these patients. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
28 pages, 5218 KiB  
Review
Pathology of Combined Hepatocellular Carcinoma-Cholangiocarcinoma: An Update
by Florian Roßner, Bruno Valentin Sinn and David Horst
Cancers 2023, 15(2), 494; https://doi.org/10.3390/cancers15020494 - 13 Jan 2023
Cited by 6 | Viewed by 3608
Abstract
Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that is composed of both hepatocellular and cholangiocellular differentiated cells. It is slightly more common in men and among Asian and Pacific islanders. Overall, risk factors are similar to classic risk factors of [...] Read more.
Combined hepatocellular carcinoma-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer that is composed of both hepatocellular and cholangiocellular differentiated cells. It is slightly more common in men and among Asian and Pacific islanders. Overall, risk factors are similar to classic risk factors of hepatocellular carcinoma (HCC). The classification has significantly evolved over time. The last WHO classification (2019) mainly emphasized diagnosis on morphological basis with routine stainings, discarded previously recognized classifications with carcinomas with stem cell features, introduced intermediate cell carcinoma as a specific subtype and considered cholangiolocarcinoma as a subtype of cholangiocellular carcinoma. Immunohistochemical markers may be applied for further specification but have limited value for diagnosis. Recent discoveries in molecular pathway regulation may pioneer new therapeutic approaches for this poor prognostic and challenging diagnosis. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
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13 pages, 1974 KiB  
Review
The Diagnostic Approach towards Combined Hepatocellular-Cholangiocarcinoma—State of the Art and Future Perspectives
by Johannes Eschrich, Zuzanna Kobus, Dominik Geisel, Sebastian Halskov, Florian Roßner, Christoph Roderburg, Raphael Mohr and Frank Tacke
Cancers 2023, 15(1), 301; https://doi.org/10.3390/cancers15010301 - 1 Jan 2023
Cited by 9 | Viewed by 2877
Abstract
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer which displays clinicopathologic features of both hepatocellular (HCC) and cholangiocellular carcinoma (CCA). The similarity to HCC and CCA makes the diagnostic workup particularly challenging. Alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA 19-9) are blood [...] Read more.
Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a rare primary liver cancer which displays clinicopathologic features of both hepatocellular (HCC) and cholangiocellular carcinoma (CCA). The similarity to HCC and CCA makes the diagnostic workup particularly challenging. Alpha-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA 19-9) are blood tumour markers related with HCC and CCA, respectively. They can be used as diagnostic markers in cHCC-CCA as well, albeit with low sensitivity. The imaging features of cHCC-CCA overlap with those of HCC and CCA, dependent on the predominant histopathological component. Using the Liver Imaging and Reporting Data System (LI-RADS), as many as half of cHCC-CCAs may be falsely categorised as HCC. This is especially relevant since the diagnosis of HCC may be made without histopathological confirmation in certain cases. Thus, in instances of diagnostic uncertainty (e.g., simultaneous radiological HCC and CCA features, elevation of CA 19-9 and AFP, HCC imaging features and elevated CA 19-9, and vice versa) multiple image-guided core needle biopsies should be performed and analysed by an experienced pathologist. Recent advances in the molecular characterisation of cHCC-CCA, innovative diagnostic approaches (e.g., liquid biopsies) and methods to analyse multiple data points (e.g., clinical, radiological, laboratory, molecular, histopathological features) in an all-encompassing way (e.g., by using artificial intelligence) might help to address some of the existing diagnostic challenges. Full article
(This article belongs to the Special Issue Combined Hepatocellular-Cholangiocarcinoma: An Update on Epidemiology, Classification, Diagnosis and Management)
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