Pediatric Hepatocellular Carcinoma Research Articles

Cytomorphology of paediatric hepatocellular carcinoma: A useful diagnostic adjunct.

Hepatocellular carcinoma (HCC) is a common primary malignancy of the liver but is rare in the paediatric age group; thus, it may be misdiagnosed as the more common tumour, hepatoblastoma. Management varies in both these tumours, and pathological diagnosis thus plays an important role for definitive therapy. Only a few case reports available in the literature have described the cytological characteristics of paediatric HCC. The present study was thus planned to evaluate the cytomorphological features of paediatric HCC. Cases diagnosed with HCC on ultrasound-guided fine needle aspiration cytology over a period of 14 years were retrieved. The cases were evaluated for detailed cytological features including cellularity, architecture, sinusoidal wrapping, trabecular thickness, necrosis, anisonucleosis, chromatin, nucleoli, nuclear contours, bi- or multinucleation, intranuclear and intracytoplasmic inclusions, naked nuclei, extra-medullary haematopoiesis, monomorphism, and nuclear overlapping. Twelve cases of HCC were included in the study. The median age at diagnosis was 10 years. Serum alpha-fetoprotein level was raised in most of them. Five of the 12 cases were characterised as moderately differentiated, three as poorly differentiated, two as well differentiated, and two as the fibrolamellar type of HCC. Cytohistological correlation was performed in seven cases. Ultrasound-guided fine needle aspiration serves as a useful tool to diagnose paediatric HCC and differentiate it from other primary hepatic malignancies, especially hepatoblastoma which closely mimics HCC in this age group, as serum alpha protein levels and imaging findings are unable to distinguish these two tumours.

Hepatoblastomas with carcinoma features represent a biological spectrum of aggressive neoplasms in children and young adults.

Background & AimsHepatoblastoma (HB) and hepatocellular carcinoma (HCC) are the predominant liver cancers in children, though their respective treatment options and associated outcomes differ dramatically. Risk stratification using a combination of clinical, histological, and molecular parameters can improve treatment selection, but it is particularly challenging for tumors with mixed histological features, including those in the recently created hepatocellular neoplasm not otherwise specified (HCN NOS) provisional category. We aimed to perform the first molecular characterization of clinically annotated cases of HCN NOS.MethodsWe tested whether these histological features are associated with genetic alterations, cancer gene dysregulation, and outcomes. Namely, we compared the molecular features of HCN NOS, including copy number alterations, mutations, and gene expression profiles, with those in other pediatric hepatocellular neoplasms, including HBs and HCCs, as well as HBs demonstrating focal atypia or pleomorphism (HB FPAs), and HBs diagnosed in older children (>8).ResultsMolecular profiles of HCN NOS and HB FPAs revealed common underlying biological features that were previously observed in HCCs. Consequently, we designated these tumor types collectively as HBs with HCC features (HBCs). These tumors were associated with high mutation rates (∼3 somatic mutations/Mb) and were enriched with mutations and alterations in key cancer genes and pathways. In addition, recurrent large-scale chromosomal gains, including gains of chromosomal arms 2q (80%), 6p (70%), and 20p (70%), were observed. Overall, HBCs were associated with poor clinical outcomes.ConclusionsOur study indicates that histological features seen in HBCs are associated with combined molecular features of HB and HCC, that HBCs are associated with poor outcomes irrespective of patient age, and that transplanted patients are more likely to have good outcomes than those treated with chemotherapy and surgery alone. These findings highlight the importance of molecular testing and early therapeutic intervention for aggressive childhood hepatocellular neoplasms.Lay summaryWe molecularly characterized a class of histologically aggressive childhood liver cancers and showed that these tumors are clinically aggressive and that their observed histological features are associated with underlying recurrent molecular features. We proposed a diagnostic algorithm to identify these cancers using a combination of histological and molecular features, and our analysis suggested that these cancers may benefit from specialized treatment strategies that may differ from treatment guidelines for other childhood liver cancers.

Abstract PO010: Molecular characterization of pediatric hepatocellular carcinoma: genomic, methylomic and transcriptomic analysis

Abstract Background: The main pediatric liver tumors are hepatoblastoma (HB) and, to a lesser extent, pediatric hepatocellular carcinoma (HCC). HB appears at an early age (<3 years) while HCC is diagnosed mainly in older children (>8 years) or adolescents and it is usually associated to underlying metabolic diseases. HEM-NOS (Hepatocellular malignant neoplasm, not otherwise specified) is a recent entity with histopathological features of HB and HCC. Due to the rarity of the disease (<1 case per million children), the biology of HCC and their similarity with HB has been poorly explored. Aims: To molecularly characterize pediatric HCC at the genomic, transcriptomic and epigenomic level and to perform a comparative study with HB and HEM-NOS. Methodology: We performed a genomic (Cytoscan, ThermoFisher), epigenomic (EPIC/850k, Illumina) and transcriptomic (HTA 2.0 array, ThermoFisher) studies on 8 HCC and compared them with already published omics data of 31 HB, 2 HEM-NOS and 19 control non-tumor liver (NT) samples (Carrillo-Reixach et al, J Hepatol, 2020). The results obtained were validated in an independent series of 19 HCC, including 10 fibrolamellar HCC (FL-HCC), 56 HB, 7 HEM-NOS and 5 NTs using QUAlu and Nanostring techniques for assessing DNA methylation and gene expression, respectively. Results: We identified CTNNB1 gene mutations in 73%, 50% and 14% of HB, HEM-NOS and HCC, respectively. Contrarily, TERT mutations were only found in HEM-NOS and HCC tumors. FL-HCC had the DNAJB1:PRKACA fusion transcript and in one case without this fusion, a deletion in the PRKCA gene was identified. The genome of HCC and HEM-NOS had higher number of chromosomal losses than HB. Moreover, HBs and HEM-NOS showed a higher DNA hypomethylation than HCC whereas HCC was characterized by CpG island hypermethylation. Two imprinting regions were differently expressed in 14q32 (DLK1/DIO3) and 15q11.2 (SNORD115/116) in HB and HCC, respectively. Finally, we identified the SPINK1 gene (Serine peptidase inhibitor, kazal type 1) as an overexpressed gene in HCC that was strongly associated with prognosis of patients with liver cancer in both training (Log-Rank=0.008) and validation sets (Log-rank=0.028). Using XENA database, we found also that different SPINK1 expression was also associated with adult HCC prognosis (n=357, Log-rank=0.017). Conclusions: The characterization of HCC and its comparison with HB allowed us to identify potential diagnostic and prognostic markers that could help to improve the clinical management of childhood liver cancer. Citation Format: Juan Carrillo-Reixach, Álvaro del Río-Álvarez, Laura Royo, Montserrat Domingo-Sàbat, Rita Alaggio, Ronald de Krijger, Christian Vokuhl, Marta Garrido, Laura Guerra, Constantino Sábado, Francisco Hernández, Manuel López-Santamaría, Viera Bajčiová, Rudolf Maibach, Margaret Childs, Piotr Czauderna, Keith Wheatley, Roland Kappler, Stefano Cairo, Bruce Morland, Margarita Sala, Maria Rosa Sarrias, Carolina Armengol. Molecular characterization of pediatric hepatocellular carcinoma: genomic, methylomic and transcriptomic analysis [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr PO010.

Integrated analysis using ToppMiR uncovers altered miRNA- mRNA regulatory networks in pediatric hepatocellular carcinoma-A pilot study.

Pediatric hepatocellular carcinoma (HCC) is a group of liver cancers whose mechanisms behind their pathogenesis and progression are poorly understood. We aimed to identify alterations in the expression of miRNAs and their putative target mRNAs in not only tumor tissues of patients with pediatric HCC but also in corresponding non-tumorous background livers by using liver tissues without underlying liver disease as a control. We performed a small-scale miRNA and mRNA profiling of pediatric HCC (consisting of fibrolamellar carcinoma [FLC] and non-FLC HCC) and paired liver tissues to identify miRNAs whose expression levels differed significantly from control livers without underlying liver disease. ToppMiR was used to prioritize both miRNAs and their putative target mRNAs in a gene-annotation network, and the mRNA profile was used to refine the prioritization. Our analysis generated prioritized lists of miRNAs and mRNAs from the following three sets of analyses: (a) pediatric HCC versus control; (b) FLC versus control; and (c) corresponding non-tumorous background liver tissues from the same patients with pediatric HCC versus control. No liver disease liver tissues were used as the control group for all analyses. Many miRNAs whose expressions were deregulated in pediatric HCC were consistent with their roles in adult HCC and/or other non-hepatic cancers. Our gene ontology analysis of target mRNAs revealed enrichment of biological processes related to the sustenance and propagation of cancer and significant downregulation of metabolic processes. Our pilot study indicates that alterations in miRNA-mRNA networks were detected in not only tumor tissues but also corresponding non-tumorous liver tissues from patients with pediatric HCC, suggesting multi-faceted roles of miRNAs in disease progression. Our results may lead to novel hypotheses for future large-scale studies.

Imaging Features of Hepatocellular Carcinoma in Children With and Without Underlying Risk Factors.

BACKGROUND. Pediatric hepatocellular carcinoma (HCC) is an aggressive malignancy for which imaging findings remain poorly described. In comparison with adult HCC, pediatric HCC more commonly occurs without underlying risk factors, and standardized surveillance guidelines for those with predispositions are lacking. OBJECTIVE. The purpose of this article was to evaluate imaging findings of nonfibrolamellar pediatric HCC and to identify associations between these imaging findings and the presence of predisposing factors. METHODS. This retrospective study included children (≤ 18 years) with histologically confirmed nonfibrolamellar HCC who underwent multiphase CT or MRI at one of four academic children's hospitals between July 2009 and April 2019. Surveillance regimens in children with predispositions were at the discretion of treating physicians. Clinical characteristics were recorded. Scan indications were classified as surveillance versus clinical signs and symptoms. Images from all sites were submitted to a cloud-based server. Two radiologists independently assessed imaging features of HCC, including tumor size, tumor in vein, Pre-Treatment Extent of Tumor (PRETEXT) stage, and LI-RADS major features of adult HCC. Imaging findings were compared between patients with and without predispositions. RESULTS. The study included 39 patients: 17 with predispositions (mean age, 10.5 ± 4.5 years; nine boys, eight girls) and 22 without predispositions (mean age, 11.3 ± 5.1 years; 12 boys, 10 girls). Scan indication was surveillance in 14/17 patients with predispositions versus 0/22 patients without predispositions (p < .001). Patients with versus those without predispositions had smaller tumor size (reader 1: 6.0 vs 11.9 cm [p = .003]; reader 2: 6.0 vs 12.9 cm [p < .001]) and less frequent tumor in vein (reader 1: 0% vs 41% [p = .002]; reader 2: 0% vs 36% [p = .006]). PRETEXT stage IV disease was observed in 18% (both readers) of patients with predispositions versus 50-55% of patients without predispositions. No LI-RADS major feature of adult HCC showed a significant difference in frequency between patients with and without predispositions for either reader (all p > .05). CONCLUSION. Among children with HCC, those with predispositions exhibited smaller and lower-stage tumors and less frequent tumor in vein, likely because of surveillance imaging. CLINICAL IMPACT. The study supports the role of routine surveillance imaging in children with HCC predispositions to facilitate earlier detection. Standardization of surveillance guidelines remains needed.

Second Generation Small Molecule Inhibitors of Gankyrin for the Treatment of Pediatric Liver Cancer.

Simple SummaryNew therapy options are needed for children with liver cancer. The goal of this study was to evaluate the role of three new compounds in the treatment of liver cancer cells. These compounds all inhibit a protein called Gankyrin, which is known to promote liver cancer by destroying tumor suppressor proteins. We demonstrated that liver cancer cells have significantly reduced proliferation when treated with these compounds by preventing the degradation of tumor suppressor proteins. We also discovered that these compounds enhance the effects of doxorubicin, which is a chemotherapy drug commonly used in liver cancer. These results support continued efforts in Gankyrin-based therapy for the treatment of pediatric liver cancer.Background: Gankyrin, a member of the 26S proteasome, is an overexpressed oncoprotein in hepatoblastoma (HBL) and hepatocellular carcinoma (HCC). Cjoc42 was the first small molecule inhibitor of Gankyrin developed; however, the IC50 values of >50 μM made them unattractive for clinical use. Second-generation inhibitors demonstrate a stronger affinity toward Gankyrin and increased cytotoxicity. The aim of this study was to characterize the in vitro effects of three cjoc42 derivatives. Methods: Experiments were performed on the HepG2 (HBL) and Hep3B (pediatric HCC) cell lines. We evaluated the expression of TSPs, cell cycle markers, and stem cell markers by Western blotting and/or real-time quantitative reverse transcription PCR. We also performed apoptotic, synergy, and methylation assays. Results: The treatment with cjoc42 derivatives led to an increase in TSPs and a dose-dependent decrease in the stem cell phenotype in both cell lines. An increase in apoptosis was only seen with AFM-1 and -2 in Hep3B cells. Drug synergy was seen with doxorubicin, and antagonism was seen with cisplatin. In the presence of cjoc42 derivatives, the 20S subunit of the 26S proteasome was more available to transport doxorubicin to the nucleus, leading to synergy. Conclusion: Small-molecule inhibitors for Gankyrin are a promising therapeutic strategy, especially in combination with doxorubicin.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT)

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n=157) and 62% for HCC (n=18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p=NS). Salvage (n=13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p=NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p=NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p=.02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p<.001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Liver Transplantation for Pediatric Hepatocellular Carcinoma: A Systematic Review.

Simple SummaryHepatocellular carcinoma is a type of primary liver cancer and the second most common type of liver cancer in children. Although partial hepatectomy can be curative, many children present with tumors that are not amenable to resection and thus the only potentially curative option is liver transplantation. In this systematic review, we have pooled the data from the worldwide literature and showed that survival after liver transplantation for pediatric hepatocellular carcinoma is favorable and many children do well even if their tumors exceed certain potentially restrictive criteria originally developed to select adults with hepatocellular carcinoma for liver transplantation.Liver transplantation (LT) is the only potentially curative option for children with unresectable hepatocellular carcinoma (HCC). We performed a systematic review of the MEDLINE, Scopus, Cochrane Library, and Web of Science databases (end-of-search date: 31 July 2020). Our outcomes were overall survival (OS) and disease-free survival (DFS). We evaluated the effect of clinically relevant variables on outcomes using the Kaplan–Meier method and log-rank test. Sixty-seven studies reporting on 245 children undergoing LT for HCC were included. DFS data were available for 150 patients and the 1-, 3-, and 5-year DFS rates were 92.3%, 89.1%, and 84.5%, respectively. Sixty of the two hundred and thirty-eight patients (25.2%) died over a mean follow up of 46.8 ± 47.4 months. OS data were available for 222 patients and the 1-, 3-, and 5-year OS rates were 87.9%, 78.8%, and 74.3%, respectively. Although no difference was observed between children transplanted within vs. beyond Milan criteria (p = 0.15), superior OS was observed in children transplanted within vs. beyond UCSF criteria (p = 0.02). LT can yield favorable outcomes for pediatric HCC beyond Milan but not beyond UCSF criteria. Further research is required to determine appropriate LT selection criteria for pediatric HCC.

Demographics and Clinical Outcomes of Pediatric Hepatocellular Carcinoma in the United States: A Population Based Analysis (SEER 1975-2018)

Introduction: Pediatric Hepatocellular Cancer (HCC) makes up less than 1% of all HCC and constitutes only 0.5% of all pediatric malignancies. The goal of this study was to examine the demographic, and clinical outcomes of pediatric HCC using a population-based database.

Cohort study of familial viral hepatitis and risks of paediatric cancers.

Although viral hepatitis causes paediatric hepatocellular carcinoma and hepatic and extrahepatic cancers in adults, there are few epidemiologic studies on paediatric-cancer risks from parental viral hepatitis. In a nationwide study in a viral hepatitis endemic region and with confirmation in another population-based sample, we examined associations between parental hepatitis B (HBV) and C (HCV) infections and risks of cancers in offspring. We included all children born in Taiwan in 2004-2014 (N = 2 079 037) with 2160 cancer cases ascertained from the Cancer Registry. We estimated risks for paediatric cancers using Cox proportional-hazard regressions. We checked these associations in a nationwide case-control study in Denmark (6422 cases, 160 522 controls). In Taiwan, paternal HBV was related to child's hepatoblastoma [hazard ratio (HR) = 1.77, 95% confidence interval (CI) = 1.05, 2.97] when identified at any time in the medical record, and when analyses were limited to hepatitis diagnoses occurring before the child's birth, risks increased (HR = 2.08, 95% CI = 1.13-3.80). Paternal HCV was related to child's non-Hodgkin lymphoma (HR = 2.06, 95% CI = 1.13-3.74). Maternal HCV was weakly related to increased risks of all childhood cancers [all types combined; HR = 1.45, 95% CI = 0.95-2.22]. The population-attributable fraction of hepatoblastoma for maternal, paternal and child HBV was 2.6%, 6.8% and 2.8%, respectively. Parental HBV and HCV may be risk factors for hepatic and non-hepatic cancers in children. If associations are causal, then parental screening and treatment with antivirals may prevent some paediatric cancers.

НАЧАЛЬНЫЙ ОПЫТ ОЦЕНКИ МУТАЦИОННОЙ НАГРУЗКИ ОПУХОЛИ У ДЕТЕЙ С ГЕПАТОЦЕЛЛЮЛЯРНОЙ КАРЦИНОМОЙ

The level of tumor mutation burden (TMB) is a predictive factor of immune checkpoints that determines the potential effectiveness of immune checkpoint inhibitors and indications for their prescription regardless of the type of tumor in adults and children. However, the prevalence of tumors with high TMB in the pediatric population has not been well studied. Objective of the research: to assess the detection frequency of high TMB (&gt;10 mutations per megabase) in pediatric hepatocellular carcinoma (HCC). Materials and methods of research: Next Generation Sequencing, Ion AmpliSeq™ Comprehensive Cancer Panel (409 genes) of tumor DNA samples from 4 children with HCC was performed. The calculation of the mutational load was carried out according to the work of Z.R. Chalmers et al. Results: out of 4 analyzed samples, TMB levels have lower cut-off value than needed for the immunity checkpoint inhibitors for 2 patients to administer: 5,9 mut/MB (primary tumor), 9,2 mut/MB (metastasis), while in 2 other patients the TMB has level above the threshold – 10,9 mut/MB (primary tumor) and 48,5 mut/MB (relapse metastasis), respectively. Conclusion: this paper presents the initial experience of estimation of the TMB level in children with HCC. In our case series report, the level allowing the prescription of immunotherapy (&gt;10 mut/MB) was observed in 2 patients. Further research on a larger cohort of patients is useful to assess the role of mutational burden in disease prediction and effectiveness of immunotherapy.

C/EBPβ enhances efficacy of sorafenib in hepatoblastoma.

Hepatoblastoma (HB) is the predominant hepatic neoplasm in infants and young children. Sorafenib has been used to treat adult and pediatric hepatocellular carcinoma. However, efficacy of monotherapy of sorafenib in HB is not sustained. In this study, we tested a possible combinatory therapy of sorafenib with the CCAAT/enhancer-binding proteins (C/EBP) overexpression in HB cell line. Firstly, we evaluated the expression level of C/EBPβ in the patients with HB by analyzing The Cancer Genome Atlas data. Lower level of C/EBPβ was observed in tumor tissues in comparison with matched normal tissues. Next, we observed that combination of sorafenib and C/EBPβ overexpression led to dramatic growth and migration inhibition of live tumor cells which implied promising probability for clinical trial. Mechanistically, C/EBPβ which can be downregulated by Ras v12, augmented messenger RNA and protein levels of p53. These data suggested that a combination of sorafenib and C/EBPβ overexpression inhibited tumor growth synergistically and provided a promising approach to treat HB.

Clinical, Pathological and Genetic Characteristics of Pediatric Hepatocellular Carcinoma Associated with Hepatitis B Virus Infection.

IntroductionHepatocellular carcinoma (HCC) remains the major challenge in the management of patients with hepatitis B virus (HBV) infection. To date, limited studies have been done on pediatric HBV-associated HCC specifically.MethodsPediatric patients younger than 16 years with HBV-associated HCC were included in the study. HBV integration detection was performed using a high-throughput viral integration detection (HIVID) method.ResultsAmong the 13 included pediatric patients, boys predominated (10, 76.9%). The median age at diagnosis of HCC was 13 years and the youngest age was 6 years. Nine patients had initially seronegative hepatitis B e antigen (HBeAg) and 4 had seropositive HBeAg. All patients had cirrhosis and elevated alpha-fetoprotein. Splenomegaly was present in all patients. Intrahepatic HBsAg was not detected in any tumor tissues from 5 patients who underwent biopsy or excision, while it was positive in all matched non-tumor tissues. In the tumor and matched non-tumor tissues from 3 individuals, HBV integration was identified except in the neoplastic specimen from 1 patient. Integration into the reported genes associated with hepatocarcinogenesis was not found in the tumor tissues from the 3 patients.DiscussionHypervigilance for HCC development is required in HBeAg-negative cirrhotic children. The findings based on the immunohistochemical and genetic results expand the knowledge of pediatric HCC development.

Imaging and clinical features of pediatric hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is rare in children and there is limited data on its imaging features. To describe imaging features of pediatric HCC and correlate them with clinical and laboratory findings. We retrospectively reviewed imaging in all pediatric HCC cases seen between January 2000 and January 2019. Imaging features defined in LI-RADS (Liver Imaging Reporting and Data System) and tumor extent by PRETEXT (pretreatment extent of disease) criteria were noted by two radiologists. Patient charts were reviewed to collect clinical features, alpha-fetoprotein (AFP) level and pathology findings. Of the 15 children (7 boys, 8 girls; mean age: 11.8years, age range: 6-17years) included in the study, 12/15 had computed tomography, 9/15 had magnetic resonance imaging and 9/15 had ultrasound exams available for review. Pathological types of HCC included classic (11/15, 73%), fibrolamellar (3/15, 20%) and mixed cholangiocarcinoma-HCC (1/15, 7%). Eighty percent occurred de novo in normal liver and 67% showed elevated AFP levels. Arterial phase hyperenhancement was seen in 83% of cases, washout in 86%, capsule in 50% and tumor-in-vein in 33%. The mean tumor size was 9.8cm and 40% were multifocal on imaging. Staging revealed PRETEXT II tumors in 47%, III in 20% and IV in 33%. There were no PRETEXT I tumors. The two most common PRETEXT annotation factors were portal vein and caudate lobe involvement in 71% and 43% of cases, respectively. Fibrolamellar HCC demonstrated central scar, normal AFP levels and normal background liver. Pediatric HCC are large heterogeneous tumors, as reflected by high PRETEXT staging, and commonly include portal vein and caudate involvement. This affects resectability of these tumors at presentation. Central scar, normal AFP level and normal liver background may help differentiate fibrolamellar HCC from other types of HCC.

Diagnostic Performance of LI-RADS Version 2018 for Evaluation of Pediatric Hepatocellular Carcinoma.

Background The Liver Imaging Reporting and Data System (LI-RADS) has standardized the evaluation of adult but not pediatric hepatocellular carcinoma (HCC). Purpose To evaluate the performance of LI-RADS version 2018 for diagnosis of pediatric HCC. Materials and Methods This multi-institution retrospective study evaluated all available dynamic CT and/or MRI scans of pediatric (≤18 years) HCC from five institutions between July 2009 and April 2019. The control group included an equal number of other enhancing hepatic lesions. Blinded to final diagnosis, three radiologists independently applied LI-RADS version 2018 criteria. The reference standard was pathologic examination or more than 1 year follow-up. Sensitivity and specificity of LI-RADS were computed using a dichotomous classification of LR-1, LR-2, or LR-3 versus LR-4, LR-5, LR-TIV (tumor in vein), or LR-M (probably or definitely malignant but not HCC-specific) for predicting hepatic malignancy in the entire cohort and in patients at risk for HCC. Results The cohort consisted of 116 children: 58 with HCC (mean age, 12 years ± 5; 31 girls) and 58 with other enhancing hepatic masses (mean age, 12 years ± 5; 42 girls). Frequencies of major criteria in classic HCC for the three readers were as follows: nonrim arterial phase hyperenhancement, 49%-62% (19-24 of 39 patients); nonperipheral "washout," 36%-59% (14-23 of 39 patients); and enhancing "capsule," 28%-38% (11-15 of 39 patients). For the full cohort, the sensitivity of LR-4, LR-5, LR-TIV, or LR-M for malignancy among the three readers ranged from 85% (95% CI: 76, 94) to 88% (95% CI: 80, 96); specificity of LR-1, LR-2, or LR-3 for benignity ranged from 54% (95% CI: 40, 68) to 70% (95% CI: 57, 83). In the at-risk subgroup, sensitivity ranged from 58% (95% CI: 36, 80) to 68% (95% CI: 48, 89); specificity ranged from 56% (95% CI: 37, 74) to 63% (95% CI: 45, 81). All lesions categorized as LR-TIV (n = 10-13) were HCCs. Conclusion Liver Imaging Reporting and Data System version 2018 had moderate sensitivity but low specificity for the diagnosis of pediatric hepatocellular carcinoma (HCC), which had low frequencies of the major criteria used for adult HCC diagnosis. © RSNA, 2021 See also the editorial by Paltiel in this issue.

Peri-operative outcomes of liver resection for hepatocellular carcinoma in 1,936 pediatric patients: a retrospective population based study (NIS 1998-2014)

Presenter: Sushruta S Nagarkatti MD | Ascension Providence Hospital Background: Hepatocellular carcinoma (HCC) accounts for less than 0.5% of all pediatric malignancies. The etiology and biology of pediatric HCC differs from that seen in adults. However, as in the adult population, surgical resection offers the highest chance of survival. The available literature on the outcomes of hepatic resection in this age group is scarce and is limited by small sample sizes. This is the first population based study analyzing demographic and clinical characteristics as well as peri-operative outcomes of liver resection in pediatric HCC patients Methods: The National Inpatient Database (NIS 1998-2014) was used to identify pediatric patients (age ≤19 years) diagnosed with hepatocellular carcinoma (ICD-9 code 155.0), who had either partial hepatectomy (ICD 9 code 50.22) or liver lobectomy (ICD 9 code 50.3). Discharge weights were applied to obtain national estimates. Demographic, clinical and outcomes data was compared using standard statistical methodology. Results: A total of 1,936 pediatric patients who underwent surgical resection for HCC were identified. The mean age was 4.9 years, with a male to female ratio 1.18:1. Formal anatomic lobectomy was performed in 56.4% with 43.6% of patients undergoing a non-anatomic partial hepatectomy. The all-cause mortality rate was 1.8%, with an overall complication rate of 15.2%. Post-operative hemorrhage occurred in 4.6% patients, with the most common complications being respiratory (7.7%) and GI (7.6%). Overall, the post-operative infection rate was low at 2.4% with < 1.0% of patients developing sepsis. Most patients were discharged home (83.1%) with a mean LOS 11.6 (±12.9) days. Home health services were required for 10.2% of patients with 4.6% requiring subacute rehab services or a skilled nursing facility ( <1.0%). Conclusion: The majority of pediatric HCC patients received a formal anatomic liver lobectomy with reported morbidity and mortality far lower than the published literature on similar procedures in adult HCC patients. Further studies are needed to validate the findings of this study and establish long term survival outcomes in this patient population.

The future of pediatric hepatocellular carcinoma: a combination of surgical, locoregional, and targeted therapy

Hepatoma Research is an open access journal and focuses on all topics related to hepatoma. The following articles are especially welcome: pathogenesis, clinical examination and early diagnosis of hepatoma, complications of hepatoma, and their preventions and treatments, etc.

Pediatric hepatocellular carcinoma - the main differences from adult patients

Aim: to compare features of hepatocellular carcinoma (HCC) in children and adult patients and to assess the possibility of translating the experience of adult patients treating in pediatric oncology. Мethods: the literature dedicated to pediatric and adult HCC investigation and treatment has been analyzed. Pathomorphology, molecular-genetic features of disease, the drug and surgical treatment approaches, in particular immunotherapy and liver transplantation were carefully compared in both groups. Results: for pediatric HCC the analysis revealed that: fibrolamellar subtype as well as large size of primary tumor are more common; typical molecular-genetic markers are presented. It is advisable to use the adopted adults treatment methods such as targeted and immunotherapy in children. In particular, the HCC surgery, and the indications for liver transplantation in children should be different from adults. Conclusion: further translation of th e adult patients treating experience will help to improve outcome in children with HCC. In order to optimize the treatment of pediatric HCC it is necessary to continue the investigations in international research groups.

Pediatric Hepatocellular Carcinoma.

Pediatric hepatocellular carcinoma is rarely seen in childhood. It constitutes approximately 1% of childhood solid organ malignancies. Pediatric hepatocellular carcinoma is the second most common malignant liver tumor after hepatoblastoma in children. In this review, we aimed to review the diagnosis and treatment of pediatric hepatocellular carcinoma in the light of the latest literature. We reviewed the literature in terms of the diagnosis and treatment of pediatric hepatocellular carcinoma. Hepatocellular carcinoma (HCC) and hepatoblastoma constitute 0.5-1.5% of all childhood malignant tumors. HCC is responsible for 27% of all liver tumors and 4% of all pediatric liver transplantations. While 99.6% of HCC is seen in adults, only 0.4% of it is seen in pediatric patients. Etiological predisposition and biological behavior are different from adults. In a child with cirrhosis or liver disease, HCC should be suspected in the presence of a high level of AFP and an abnormal nodule on ultrasonography. Hepatoblastoma should be considered first in the differential diagnosis. Treatment of pediatric HCC is challenging. Complete surgical resection is essential for the cure. To this end, different neoadjuvant chemotherapy protocols have been designed to convert non-resectable tumors into resectable tumors. For tumors that cannot be resected, liver transplantation for each patient with childhood HCC should be decided individually.