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Special Issue "Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma)"

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Pediatric Oncology".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 7091

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Special Issue Editors

Dr. Ronald de Krijger

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Guest Editor

Princess Máxima Center for Pediatric Oncology, Laboratory for Childhood Cancer Pathology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands
Interests: solid pediatric tumors; endocrine tumors; molecular genetics

Dr. Carolina Armengol

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Guest Editor

Germans Trias y Pujol Research Institute, Department of Gastroenterology, Childhood Liver Oncology Group, Cami de les Escoles, 08916 Badalona, Spain
Interests: liver pediatric tumors; biomarkers; molecular stratification; biology-driven therapies

Prof. Dr. Sarangarajan Ranganathan

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Guest Editor

Cincinnati Children’s Hospital, Department of Pathology and Laboratory Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229, USA
Interests: solid pediatric tumors; pediatric liver tumors and disease; transplant pathology

Special Issue Information

Dear Colleagues,

Pediatric liver tumors, including hepatoblastomas (HB) and pediatric hepatocellular carcinomas (HCC), are rare but devastating malignancies, the incidence of which has been increasing over the past few decades. The pathogenesis of these tumors is only partially known, with HBs having an extremely low mutational burden, with beta catenin mutations and Wnt pathway dysregulation being the most frequent molecular abnormalities. Pediatric HCC may develop against the background of specific hereditary diseases, including tyrosinemia and progressive familial intrahepatic cholestasis or viral infections, or may not have any predisposing factors. In addition, several rare pediatric tumors exist, including mesenchymal hamartoma, undifferentiated embryonal sarcoma, malignant rhabdoid tumors, and calcifying nested stromal–epithelial tumors of the liver.

The current treatment for HB and HCC is based on an international effort that resulted in the Paediatric Hepatic International Tumour Trial (PHITT), which was launched in 2017. The PHITT is a randomised phase III trial that studies how well different drugs/protocols (i.e., cisplatin, doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan, sorafenib, gemcitabine, and oxaliplatin) work in children and young adults with HB or HCC and is stratified according to the new international clinical staging system that emerged from the Children's Hepatic tumours International Collaboration (CHIC). This stratification relies on clinical prognostic factors such as the PRETreatment EXTent of the disease stage, metastasis, patient age, AFP levels, and annotation factors related to dissemination. Despite significant advances, treatment options remain limited for ~20% of patients with aggressive tumours that are resistant to current pharmacological treatments, and survivors experience long-term effects from treatment toxicity.

Several studies have extensively reviewed the pathology of childhood liver cancer as well as explored the genetic, epigenetic, and transcriptomic profiles of pediatric liver tumors to better understand this rare disease and to identify novel biomarkers, therapeutic targets, and drugs that could improve current clinical management and move forward precision medicine in HB and pediatric HCC.

This current Special Issue of Cancers aims to collect a series of original and review articles on pediatric liver tumors from all angles of clinical and basic research, sharing both increases in the understanding of the pathogenesis of these tumors as well translational and clinical findings that may have direct effects on patient management.

Dr. Ronald de Krijger
Dr. Carolina Armengol
Prof. Dr. Sarangarajan Ranganathan
Guest Editors

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 short 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

hepatoblastoma
hepatocellular carcinoma
pathogenesis
treatment
molecular genetics
animal models

Published Papers (6 papers)

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Research

Open AccessArticle

Retreatment with Cisplatin May Provide a Survival Advantage for Children with Relapsed/Refractory Hepatoblastoma: An Institutional Experience

Katherine M. Somers

Rachel Bernstein Tabbouche

Alexander Bondoc

Alexander J. Towbin

Sarangarajan Ranganathan

Greg Tiao

and

James I. Geller

Cancers 2023, 15(15), 3921; https://doi.org/10.3390/cancers15153921 - 01 Aug 2023

Viewed by 542

Abstract

Background: Hepatoblastoma (HB) is the most common liver malignancy in children. There is no standard of care for management of relapsed/refractory HB (rrHB) and reports in the literature are limited. Objective: To describe presenting features, biology, treatment strategies, and outcomes for pediatric patients with relapsed/refractory hepatoblastoma. Methods: An IRB-approved retrospective institutional review of patients with rrHB who presented for consultation and/or care from 2000–2019. Clinical, radiographic, and histologic data were collected from all patients. Results: Thirty subjects were identified with a median age of 19.5 months (range 3–169 months) at initial diagnosis and 32.5 months (range 12–194 months) at time of first relapse. 63% of subjects were male, 70% Caucasian, and 13% were born premature. Three subjects had a known cancer predisposition syndrome. Eight patients had refractory disease while 22 patients had relapsed disease. Average time from initial diagnosis to relapse or progression was 12.5 months. Average alpha-fetoprotein (AFP) at initial diagnosis was 601,203 ng/mL (range 121–2,287,251 ng/mL). Average AFP at relapse was 12,261 ng/mL (range 2.8–201,000 ng/mL). For patients with tumor sequencing (n = 17), the most common mutations were in CTNNB1 (13) and NRF2 (4). First relapse sites were lungs (n = 12), liver (n = 11) and both (n = 6). More than one relapse/progression occurred in 47% of subjects; 6 had ≥3 relapses. Pathology in patients with multiply relapsed disease was less differentiated including descriptions of small cell undifferentiated (n = 3), pleomorphic (n = 1), transitional liver cell tumor (n = 2) and HB with carcinoma features (n = 1). All subjects underwent surgical resection of site of relapsed disease with 7 subjects requiring liver transplantation. Overall survival was 50%. Survival was associated with use of cisplatin at relapse (78.6% with vs. 25% without, p = 0.012). The most common late effect was ototoxicity with at least mild sensorineural hearing loss found in 80% of subjects; 54% required hearing aids. Conclusions: Retreatment with cisplatin at the time of relapse may provide an advantage for some patients with hepatoblastoma. Multiply relapsed disease was not uncommon and not associated with a worse prognosis. Careful attention should be paid to cumulative therapy-induced toxicity while concurrently aiming to improve cure. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma))

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Open AccessArticle

Epidemiological Study of Malignant Paediatric Liver Tumours in Denmark 1985–2020

Thomas N. Nissen

Catherine Rechnitzer

Birgitte K. Albertsen

Lotte Borgwardt

Vibeke B. Christensen

Marianne H. Jørgensen

and

Jesper Brok

Cancers 2023, 15(13), 3355; https://doi.org/10.3390/cancers15133355 - 26 Jun 2023

Viewed by 535

Abstract

Background: Malignant liver tumours in children are rare and national outcomes for this tumour entity are rarely published. This study mapped paediatric liver tumours in Denmark over 35 years and reported on the incidence, outcomes and long-term adverse events. Methods: We identified all liver tumours from the Danish Childhood Cancer Registry and reviewed the case records for patient and tumour characteristics, treatment and clinical outcome. Results: We included 79 patients in the analyses. Overall crude incidence was ~2.29 per 1 million children (<15 yr) per year, with 61 hepatoblastomas (HB), 9 hepatocellular carcinomas and 9 other hepatic tumours. Overall 5-year survival was 84%, 78% and 44%, respectively. Nine patients had underlying liver disease or predisposition syndrome. Seventeen children underwent liver transplantation, with two late complications, biliary stenosis and liver fibrosis. For HB, age ≥ 8 years and diagnosis prior to 2000 were significant predictors of a poorer outcome. Adverse events included reduced renal function in 10%, reduced cardiac function in 6% and impaired hearing function in 60% (19% needed hearing aids). Behavioural conditions requiring additional support in school were registered in 10 children. Conclusions: In Denmark, incidences of malignant liver tumours during the last four decades have been increasing, as reported in the literature. HB survival has improved since the year 2000 and is comparable with international results. Reduced hearing is the major treatment-related side effect and affects approximately 60% of patients. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma))

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Open AccessArticle

Outcomes of Patients Treated for Hepatoblastoma with Low Alpha-Fetoprotein and/or Small Cell Undifferentiated Histology: A Report from the Children’s Hepatic Tumors International Collaboration (CHIC)

Cancers 2023, 15(2), 467; https://doi.org/10.3390/cancers15020467 - 11 Jan 2023

Cited by 3 | Viewed by 1161

Abstract

Small cell undifferentiated (SCU) histology and alpha-fetoprotein (AFP) levels below 100 ng/mL have been reported as poor prognostic factors in hepatoblastoma (HB); subsequent studies reported SMARCB1 mutations in some SCU HBs confirming the diagnosis of rhabdoid tumor. The Children’s Hepatic tumors International Collaboration (CHIC) database was queried for patients with HB who had AFP levels less than 100 ng/mL at diagnosis or were historically diagnosed as SCU HBs. Seventy-three of 1605 patients in the CHIC database were originally identified as SCU HB, HB with SCU component, or HB with low AFP levels. Upon retrospective review, they were re-classified as rhabdoid tumors (n = 11), HB with SCU component (n = 41), and HB with low AFP (n = 14). Seven were excluded for erroneously low AFP levels. Overall survival was 0% for patients with rhabdoid tumors, 76% for patients with HB with SCU component, and 64% for patients with HB with AFP less than 100 ng/mL. Patients with HB with SCU component or low AFP should be assessed for SMARCB1 mutations and, if confirmed, treated as rhabdoid tumors. When rhabdoid tumors are excluded, the presence of SCU component and low AFP at diagnosis were not associated with poor prognosis in patients diagnosed with HB. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma))

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Open AccessArticle

Teratoid Hepatoblastoma—Our Experience

Lara Berklite

and

Sarangarajan Ranganathan

Cancers 2022, 14(24), 6135; https://doi.org/10.3390/cancers14246135 - 13 Dec 2022

Cited by 1 | Viewed by 991

Abstract

Hepatoblastomas (HB) are the most common pediatric liver tumor with several subgroups described, of which teratoid HB is the rarest. The aim of this study is to characterize the histologic and phenotypic spectrum of teratoid HB in order to better understand the biology and behavior of these tumors. A retrospective analysis of all teratoid HB diagnosed at a major pediatric hospital as well as the consultation files of one of the authors (SR) was performed with the available clinical data and surgical pathology material reviewed. A detailed immunohistochemical workup was also performed. A total of 28 cases were included from patients ranging from 5 to 84 months of age and a M:F ratio of 1.07:1. Four patients had syndromic associations. In 14/28 cases, the tumors contained primitive glandular elements with histologic and immunophenotypic overlap with the yolk sac tumor which in two cases became predominant in metastatic sites. One case had extensive primitive neural epithelium mimicking a primitive neuroectodermal tumor (PNET). Other unique elements included melanin, mature neuroglial tissue, rhabdomyoblastic differentiation, and neuroendocrine carcinoma-like areas (n = 2). In conclusion, this study provides the largest series of teratoid HB to date with clinical and outcome data, highlights previously undescribed or under-recognized histologic patterns in these tumors, and describes the immunohistochemical profile of these tumors to aid in diagnosis. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma))

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Open AccessArticle

Hepatoblastoma Cancer Stem Cells Express PD-L1, Reveal Plasticity and Can Emerge upon Chemotherapy

and

Cancers 2022, 14(23), 5825; https://doi.org/10.3390/cancers14235825 - 25 Nov 2022

Cited by 1 | Viewed by 1060

Abstract

The biology of cancer stem cells (CSCs) of pediatric cancers, such as hepatoblastoma, is sparsely explored. This is mainly due to the very immature nature of these tumors, which complicates the distinction of CSCs from the other tumor cells. Previously, we identified a CSC population in hepatoblastoma cell lines expressing the CSC markers CD34 and CD90, cell surface Vimentin (csVimentin) and binding of OV-6. In this study, we detected the co-expression of the immune escape factor PD-L1 in the CSC population, whereas the other tumor cells remained negative. FACS data revealed that non-CSCs give rise to CSCs, reflecting plasticity of CSCs and non-CSCs in hepatoblastoma as seen in other tumors. When we treated cells with cisplatin and decitabine, a new CD34^+/lowOV-6^lowCD90⁺ population emerged that lacked csVimentin and PD-L1 expression. Expression analyses showed that this new CSC subset shared similar pluripotency and EMT features with the already-known CSCs. FACS results further revealed that this subset is also generated from non-CSCs. In conclusion, we showed that hepatoblastoma CSCs express PD-L1 and that the biology of hepatoblastoma CSCs is of a plastic nature. Chemotherapeutic treatment leads to another CSC subset, which is highly chemoresistant and could be responsible for a poor prognosis after postoperative chemotherapy. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma))

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Open AccessArticle

Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma

Qian Li

Salih Demir

Álvaro Del Río-Álvarez

Rebecca Maxwell

Alexandra Wagner

Juan Carrillo-Reixach

Carolina Armengol

Christian Vokuhl

Beate Häberle

Dietrich von Schweinitz

Irene Schmid

Stefano Cairo

and

Roland Kappler

Cancers 2022, 14(17), 4196; https://doi.org/10.3390/cancers14174196 - 30 Aug 2022

Cited by 1 | Viewed by 1796

Abstract

Resistance to conventional chemotherapy remains a huge challenge in the clinical management of hepatoblastoma, the most common liver tumor in childhood. By integrating the gene expression data of hepatoblastoma patients into the perturbation prediction tool Connectivity Map, we identified the clinical widely used anthelmintic mebendazole as a drug to circumvent chemoresistance in permanent and patient-derived xenograft cell lines that are resistant to cisplatin, the therapeutic backbone of hepatoblastoma treatment. Viability assays clearly indicated a potent reduction of tumor cell growth upon mebendazole treatment in a dose-dependent manner. The combination of mebendazole and cisplatin revealed a strong synergistic effect, which was comparable to the one seen with cisplatin and doxorubicin, the current treatment for high-risk hepatoblastoma patients. Moreover, mebendazole treatment resulted in reduced colony and tumor spheroid formation capabilities, cell cycle arrest, and induction of apoptosis of hepatoblastoma cells. Mechanistically, mebendazole causes blockage of microtubule formation and transcriptional downregulation of genes encoding the unwindosome, which are highly expressed in chemoresistant tumors. Most importantly, mebendazole significantly reduced tumor growth in a subcutaneous xenograft transplantation mouse model without side effects. In conclusion, our results strongly support the clinical use of mebendazole in the treatment of chemoresistant hepatoblastoma and highlight the potential theranostic value of unwindosome-associated genes. Full article

(This article belongs to the Special Issue Pediatric Liver Tumors (Hepatoblastoma and Hepatocellular Carcinoma))

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