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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 16742

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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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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

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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.

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Keywords

hepatoblastoma
hepatocellular carcinoma
pathogenesis
treatment
molecular genetics
animal models

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Published Papers (8 papers)

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13 pages, 3557 KiB

Open AccessArticle

Histopathological Spectrum and Molecular Characterization of Liver Tumors in the Setting of Fontan-Associated Liver Disease

by Paola Francalanci, Isabella Giovannoni, Chantal Tancredi, Maria Giulia Gagliardi, Rosalinda Palmieri, Gianluca Brancaccio, Marco Spada, Giuseppe Maggiore, Andrea Pietrobattista, Lidia Monti, Aurora Castellano, Maria Cristina Giustiniani, Andrea Onetti Muda and Rita Alaggio

Cancers 2024, 16(2), 307; https://doi.org/10.3390/cancers16020307 - 11 Jan 2024

Cited by 1 | Viewed by 1802

Abstract

Purpose: Univentricular heart is corrected with the Fontan procedure (FP). In the long term, so-called Fontan-associated liver diseases (FALDs) can develop. The aim of this study is to analyze the molecular profile of FALDs. Methods: FALDs between January 1990 and December 2022 were reviewed for histology and immunohistochemistry, laboratory data, and images. Targeted next generation sequencing (NGS), performed on the DNA and RNA of both neoplastic and non-lesional liver tissue, was applied. Results: A total of 31/208 nodules > 1 cm in diameter were identified on imaging, but a liver biopsy was available for five patient demonstrating the following: one hepatocellular adenoma (HA), two hepatocellular carcinomas (HCCs), one fibrolamellar carcinoma (FLC), and one intrahepatic cholangiocarcinoma (ICC). Molecular analysis showed a copy number alteration involving FGFR3 in three cases (two HCCs and one ICC) as well as one HCC with a hotspot mutation on the CTNNB1 and NRAS genes. Tumor mutational burden ranged from low to intermediate. A variant of uncertain significance in GNAS was present in two HCCs and in one ICC. The same molecular profile was observed in a non-lesional liver. A DNAJB1-PRKACA fusion was detected only in one FLC. Conclusions: Neoplastic FALDs show some unusual molecular profiles compared with non-Fontan ones. The presence of the same alterations in non-lesional cardiac cirrhosis could contribute to the development of FALD. Full article

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

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10 pages, 964 KiB

Open AccessArticle

Parenchyma Sparing Anatomic Liver Resections (Bi- and Uni-Segmentectomies) for Liver Tumours in Children—A Single-Centre Experience

by Maciej Murawski, Hanna Garnier, Joanna Stefanowicz, Katarzyna Sinacka, Ewa Izycka-Swieszewska, Malgorzata Sawicka-Zukowska, Pawel Wawrykow, Grazyna Wrobel, Agnieszka Mizia-Malarz, Patrycja Marciniak-Stepak and Piotr Czauderna

Cancers 2024, 16(1), 38; https://doi.org/10.3390/cancers16010038 - 20 Dec 2023

Viewed by 1165

Abstract

Purpose: To present a single-centre experience in bi- and uni-segmentectomies for primary liver tumours in children. Methods: This study included 23 patients that underwent (bi)segmentectomy. There were 15 malignant tumours (hepatoblastoma—13 patients), 7 benign tumours, and 1 calcifying nested stromal epithelial tumour. Results: The median tumour diameter was 52 mm (range 15–170 mm). Bisegmentectomy 2–3 was most frequently performed (seven patients), followed by bisegmentectomy 5–6 (four patients). The median operative time was 225 min (range 95–643 min). Intraoperative complications occurred in two patients—small bowel perforation in one and an injury of the small peripheral bile duct resulting in biloma in the other. The median resection margin in patients with hepatoblastoma was 3 mm (range 1–15 mm). Microscopically negative margin status was achieved in 12 out of 13 patients. There were two recurrences. After a median follow-up time of 38 months (range 12–144 months), all 13 patients with HB were alive with no evidence of disease. Two relapsed patients were alive with no evidence of disease. Conclusions: From the available literature and data presented here, we propose that (bi)segmentectomy can become a viable surgical option in carefully selected paediatric patients and is sufficient to achieve a cure. Further studies evaluating the impact of parenchymal preservation surgery on surgical and oncological outcome should be conducted with a larger dataset. Full article

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

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10 pages, 453 KiB

Open AccessArticle

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

by 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 - 1 Aug 2023

Cited by 2 | Viewed by 1928

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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11 pages, 763 KiB

Open AccessArticle

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

by Thomas N. Nissen, Catherine Rechnitzer, Birgitte K. Albertsen, Lotte Borgwardt, Vibeke B. Christensen, Eva Fallentin, Henrik Hasle, Lars S. Johansen, Lisa L. Maroun, Karin B. Nissen, Allan Rasmussen, Mathias Rathe, Steen Rosthøj, Nicolai A. Schultz, Peder S. Wehner, Marianne H. Jørgensen and Jesper Brok

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

Viewed by 1373

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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11 pages, 1175 KiB

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)

by Angela D. Trobaugh-Lotrario, Rudolf Maibach, Daniel C. Aronson, Arun Rangaswami, Beate Häberle, Allison F. O’Neill, Irene Schmid, Marc Ansari, Tomoro Hishiki, Sarangarajan Ranganathan, Rita Alaggio, Ronald R. de Krijger, Yukichi Tanaka, Soo-Jin Cho, Christian Vokuhl, Rebecca Maxwell, Mark Krailo, Eiso Hiyama, Piotr Czauderna, Milton Finegold, James H. Feusner, Marcio H. Malogolowkin, Rebecka L. Meyers and Dolores Lopez-Terrada Show full author list Hide full author list

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

Cited by 6 | Viewed by 2282

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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17 pages, 4537 KiB

Open AccessArticle

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

by Mieun Lee-Theilen, Delaine D. Fadini, Julia R. Hadhoud, Fleur van Dongen, Gabriela Kroll, Udo Rolle and Henning C. Fiegel

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

Cited by 1 | Viewed by 1930

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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19 pages, 3729 KiB

Open AccessArticle

Targeting the Unwindosome by Mebendazole Is a Vulnerability of Chemoresistant Hepatoblastoma

by 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 4 | Viewed by 3231

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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13 pages, 2694 KiB

Open AccessEditor’s ChoiceReview

Pediatric Hepatocellular Adenomas: What Is Known and What Is New?

by Andres F. Espinoza, Sanjeev A. Vasudevan, Prakash M. Masand, Dolores H. Lòpez-Terrada and Kalyani R. Patel

Cancers 2023, 15(19), 4790; https://doi.org/10.3390/cancers15194790 - 29 Sep 2023

Cited by 2 | Viewed by 1566

Abstract

Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to pediatric tumors have led to several “unclassifiable” lesions. Although typically considered benign, few can show atypical features and those with beta-catenin mutations have a risk for malignant transformation. Small lesions can be monitored while larger (>5.0 cm) lesions are excised due to symptoms or risk of bleeding/rupture, etc. Management depends on gender, age, underlying liver disease, multifocality, size of lesion, histologic subtype and presence of mutation, if any. In this review, we summarize the data on pediatric HCAs and highlight our experience with their diagnosis and management. Full article

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

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