Liver Tumors In Children Research Articles

Hepatoblastoma misdiagnosed as infantile hemangioendothelioma in a child – a case report

Infantile hemangioendothelioma (IHH) is the most common benign tumor of the liver in children, which accounts for 12% of all pediatric liver tumors, and hepatoblastoma (HBL) is the most common malignant liver tumor in children. Although they share some clinical manifestations, the treatment strategies and prognoses are quite different. The most important alternative diagnosis to IHH in children is HBL. Histopathologic confirmation of a radiologically suspected hemangioendothelioma is often obtained before medical treatment is initiated. We are presenting here a case of HBL in a 2-year-male child misdiagnosed as having IHH on imaging studies.

Pediatric hepatocellular carcinoma.

Pediatric hepatocellular carcinoma (HCC) is the second common malignant liver tumor in children after hepatoblastoma. It differs from the adult HCC in the etiological predisposition, biological behavior and lower frequency of cirrhosis. Perinatally acquired hepatitis-B virus, hepatorenal tyrosinemia, progressive familial intrahepatic cholestasis, glycogen storage disease, Alagille’s syndrome and congenital portosystemic shunts are important predisposing factors. Majority of children (87%) are older than 5 years of age. Following mass immunization against hepatitis-B, there has been a drastic fall in the incidence of new cases of pediatric HCC in the Asia-Pacific region. Management is targeted on complete surgical removal either by resection or liver transplantation. There is a trend towards improving survival of children transplanted for HCC beyond Milan criteria. Chemotherapeutic regimens do not offer good results but may be helpful for down-staging of advanced HCC. Surveillance of children with chronic liver diseases with ultrasound and alpha-fetoprotein may be helpful in timely detection, intervention and overall improvement in outcome of HCC.

Long-term outcomes of liver transplantation for hepatoblastoma: A single-center 14-year experience.

HB is the most common primary liver tumor in children. Complete tumor excision, either by partial resection or by total hepatectomy and liver transplantation, in combination with chemotherapy provides the best chance for cure. We performed a retrospective analysis of patients who underwent liver transplantation for HB and herein present our 14-year single-institution experience. Twenty-five patients underwent liver transplantation for HB at a median age of 26months (IQR: 15-44). Graft survival was 96%, 87%, and 80% at 1, 3, and 5years, respectively. There were four patient deaths, three of them due to disease recurrence within the first year post-transplant. Ten-year overall survival was 84%. Three recipients initially presented with pulmonary metastases and underwent resection of metastatic disease, of which two are alive at 3.9years. Of three patients who underwent salvage transplants, two are alive at 1.5years after transplant. Non-survivors were associated with lower median alpha fetoprotein value at presentation compared to survivors (21707 vs 343214; P=.04). In conclusion, the overall long-term outcome of primary liver transplantation for HB is excellent. Tumor recurrence was the highest contributor to mortality. Even patients with completely treated pulmonary metastases prior to transplant demonstrated a favorable survival.

MicroRNA‐26‐5p functions as a new inhibitor of hepatoblastoma by repressing lin‐28 homolog B and aurora kinase a expression

Hepatoblastoma (HB) is the most common liver tumor in children. Despite recent improvements in treatment strategies, the survival of children with hepatoblastoma remains poor. In this study, we identified a novel role of microRNA‐26a‐5p (miR‐26a‐5p), lin‐28 homolog B (LIN28B), Ras‐related nuclear protein (RAN), and aurora kinase A (AURKA) in HB. The expression of LIN28B, RAN, and AURKA was significantly up‐regulated in human HB livers and cell lines. Knockdown of LIN28B and RAN by small interfering RNAs inhibited HB tumor cell proliferation and foci formation. We also elucidated miR‐26a‐5p‐mediated translational inhibition of LIN28B and AURKA in HB. Overexpression of miR‐26a‐5p markedly decreased LIN28B and AURKA 3′‐untranslated region activities and protein expression and repressed HB cell proliferation and colony formation. In contrast, re‐expression of LIN28B and AURKA rescued miR‐26a‐5p‐mediated suppression of HB cell growth and clonality. Importantly, a decreased miR‐26a‐5p expression correlated with the poor outcome of patients with HB. Conclusion: miR‐26a‐5p is a newly identified repressor of HB growth through its inhibition of the oncogenic LIN28B–RAN–AURKA pathway. (Hepatology Communications 2018;2:481‐491)

Isoorientin triggers apoptosis of hepatoblastoma by inducing DNA double-strand breaks and suppressing homologous recombination repair

Hepatoblastoma (HB) is the most common malignant liver tumor in children. DNA and DNA-associated processes are one of the most important targets of chemotherapeutic agents. Isoorientin (Iso), a natural flavonoid compound, can be extracted from several plant species. The effects of Iso and its molecular mechanisms on hepatic malignancies remain unclear. Herein, the anti-tumor effects of Iso in HB and its underlying mechanisms were explored. We found that Iso significantly inhibited the proliferation of HB cells both in vitro and in vivo. Mechanistic studies showed that Iso triggered cell apoptosis by inducing DNA double-stranded breaks and blocking the initiation process of homologous recombination repair, which was related to the attenuation of ataxia telangiectasia mutated (ATM) activation and inhibiting the binding of phosphorylated ataxia telangiectasia mutated (pATM) and the MRE11-RAD50-NBS1 (MRN) complex. Furthermore, Iso markedly sensitized HB cells to the anti-proliferative effects of the poly ADP-ribose polymerase (PARP) inhibitor olaparib both in vivo and in vitro. Taken together, our study first showed that Iso was a DNA-damage agent, and the combination of Iso with a PARP inhibitor might be a promising strategy for treating HB patients.

Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma

BackgroundHepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification.ResultsWe examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature.ConclusionThese findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients.

2017 PRETEXT: radiologic staging system for primary hepatic malignancies of childhood revised for the Paediatric Hepatic International Tumour Trial (PHITT).

Imaging is crucial in the assessment of children with a primary hepatic malignancy. Since its inception in 1992, the PRETEXT (PRE-Treatment EXTent of tumor) system has become the primary method of risk stratification for hepatoblastoma and pediatric hepatocellular carcinoma in numerous cooperative group trials across the world. The PRETEXT system is made of two components: the PRETEXT group and the annotation factors. The PRETEXT group describes the extent of tumor within the liver while the annotation factors help to describe associated features such as vascular involvement (either portal vein or hepatic vein/inferior vena cava), extrahepatic disease, multifocality, tumor rupture and metastatic disease (to both the lungs and lymph nodes). This manuscript is written by members of the Children's Oncology Group (COG) in North America, the International Childhood Liver Tumors Strategy Group (SIOPEL) in Europe, and the Japanese Study Group for Pediatric Liver Tumor (JPLT; now part of the Japan Children's Cancer Group) and represents an international consensus update to the 2005 PRETEXT definitions. These definitions will be used in the forthcoming Trial to Pediatric Hepatic International Tumor Trial (PHITT).

MiR-492 regulates metastatic properties of hepatoblastoma via CD44.

MicroRNAs are important genetic regulators of physiological and pathophysiological processes including cancer initiation and progression of hepatoblastoma, the most common liver tumour in childhood. We aimed to identify malignant and metastasis promoting effects of miR-492, a miRNA, previously reported to be overexpressed in metastatic hepatoblastoma. Furthermore, we intended to evaluate its diagnostic and prognostic potential. Stable and transient overexpression of miR-492 in two liver tumour cell lines HepT1 and HUH7 was used to analyse features of metastatic tumour progression such as proliferation, anchorage-independent growth, migration and invasion. Via a mass spectrometry based proteomic screen, we investigated miRNA-492-dependent effects on proteome level and explored the underlying biology. One of the predicted target genes, CD44, was experimentally validated via luciferase assays. Diagnostic and prognostic properties of miR-492 were studied in hepatoblastoma tumour samples. We show that miR-492 significantly enhances cell proliferation, anchorage-independent growth, migration and invasion of hepatoblastoma cells. We also identified and validated CD44, a transmembrane adhesion receptor for hyaluronan, as direct and functional target of miR-492. This miRNA has a strong direct impact on two CD44 isoforms (standard and v10). High miR-492 expression correlates with high-risk or aggressive tumours and further bears potential for predicting reduced event-free survival. We identified miR-492 and its target CD44 as regulators of a number of biological features important for malignancy and metastasis. Furthermore, we demonstrated the diagnostic and prognostic potential of miR-492, a promising novel therapeutic target and biomarker for hepatoblastoma.

A practical diagnostic approach to hepatic masses.

The differential diagnosis of hepatic mass lesions is broad and arriving at the right diagnosis can be challenging, especially on needle biopsies. The differential diagnosis of liver tumors in children is different from adults and is beyond the scope of this review. In adults, the approach varies depending on the age, gender, and presence of background liver disease. The lesions can be divided broadly into primary and metastatic (secondary), and the primary lesions can be further divided into those of hepatocellular origin and nonhepatocellular origin. The first category consists of benign and malignant lesions arising from hepatocytes, while the second category includes biliary, mesenchymal, hematopoietic, and vascular tumors. Discussion of nonepithelial neoplasms is beyond the scope of this review. The hepatocytic lesions comprise dysplastic nodules, focal nodular hyperplasia, hepatic adenoma, and hepatocellular carcinoma, and the differential diagnosis can be challenging requiring clinicopathological correlation and application of immunohistochemical (IHC) markers. Liver is a common site for metastasis, sometimes presenting with an unknown primary site, and proper workup is the key to arriving at the correct diagnosis. The correct diagnosis in this setting requires a systematic approach with attention to histologic features, imaging findings, clinical presentation, and judicious use of IHC markers. The list of antibodies that can be used for this purpose keeps on growing continually. It is important for pathologists to be up to date with the sensitivity and specificity of these markers and their diagnostic role and clinical implications. The purpose of this review is to outline the differential diagnosis of hepatic masses in adults and discuss an algorithmic approach to make a right diagnosis.

Abstract 4936: Modelling clinical issues by using patient-derived xenografts: Evaluation of partial hepatectomy on hepatoblastoma intrahepatic and distant growth

Abstract Hepatoblastoma (HB) is a rare disease that represents the most frequent liver malignancy during childhood. HB incidence is approximately 1.5 cases per million children less than 15-years old in Western countries. HB is histologically classified as epithelial or mixed depending on the presence of mesenchymal component. The most common epithelial components are the embryonal and fetal phenotype, reminiscent of at early or late stages of liver development. The improvement of the clinical management in the last 30 years has allowed 5-year survival rate to pass from 35 to 80%,due to the introduction of cisplatin-based chemotherapy. More than 50% of tumors are either inoperable or are metastatic at diagnosis. Neoadjuvant chemotherapy allows tumor size reduction and sometimes leads to complete regression of pulmonary metastasis. In Europe, the SIOPEL (International Childhood Liver Tumors Strategy Group) protocols recommend the use of cisplatinum-based neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. All international studies recommend resecting all the metastases remaining after neoadjuvant chemotherapy, however, to date no indication is provided that defines whether metatases removal must take place before or after primary tumor resection by partial or total hepatectomy. As liver regeneration is a complex process that involves the expression and release of numerous factors that induce cell hypertrophy and proliferation, the risk that hepatectomy-induced release of regenerating factors might help the survival and proliferation of microscopic intrahepatic or distant tumor cells leads several clinicians to perform hepatectomy only after the removal of all detectable metastases. To challenge this paradigm, we used a panel of HB patient-derived xenograft and evaluated the impact of partial hepatectomy on intrahepatic and extrahepatic tumor growth. Partial hepatectomy performed either concomitantly with interscapular implantation of HB-217 xenograft, a model established from a patient with intrahepatic recurrence, or at the time of tumor appearance in mice failed to increase tumor growth. When hepatectomy was realized on several HB models concomitantly with either intrahepatic injection of bioluminescent HB cells derived from HB PDXs or by tumor fragments’ direct implantation, one of these models, HB-243, also a model established from a patient with intrahepatic recurrence, showed increased tumor growth in mice concomitantly subjected to partial hepatectomy. These results suggest that increased tumor growth induced by hepatectomy can occur in HB, albeit heterogeneously. We are now evaluating the molecular features of this hepatectomy-sensitive model and the impact of different cytokines on HB-243 PDX-derived tumor cells. The aim of this study will be to identify molecular markers and drivers of tumor sensitivity to hepatectomy. Citation Format: Marianna Cornet, Anais Delaitre Delattre, Laura Brulle Soumare, Victorine Boissay, Thierry Tordjmann, Antoinette Lemoine, Olivier Deas, Jean-Gabriel Judde, Sophie Branchereau, Stefano Cairo. Modelling clinical issues by using patient-derived xenografts: Evaluation of partial hepatectomy on hepatoblastoma intrahepatic and distant growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4936. doi:10.1158/1538-7445.AM2017-4936

Hepatoblastoma: Transplant Versus Resection Experience in a Latin American Transplant Center.

BackgroundHepatoblastoma is the most common primary malignant liver tumor in children and is usually diagnosed during the first 3 years of life. Overall survival has increased 50% due to chemotherapeutic schemes, expertise surgery centers, and liver transplantation.MethodsA retrospective collection of data was performed from pediatric patients with diagnosis of hepatoblastoma. Variables included demographic, diagnostic tools and histological classification; chemotherapy and surgical treatment; and outcomes and patient survival. The PRETEXT classification was applied, which included the risk evaluation, and according to the medical criterion in an individualized way, underwent resection or transplant. The morbidity of patients was evaluated by the Clavien-Dindo classification. Statistical analysis was performed according to the distribution of data and the survival analysis was carried out using the Kaplan-Meier method.ResultsThe patients (n = 16) were divided in a resection group (n = 8) and a transplant group (n = 8). The median age at the time of diagnosis was 13.5 months. The motive for the initial consultation was the discovery of a mass; all patients had high levels of α-fetoprotein and an imaging study. Ten of 16 patients required chemotherapy before the surgical procedure. In the resection group, 5 of 8 patients were classified as Clavien I and 4 of 8 patients of the transplant group were classified as Clavien II. Patient survival at 30 months was 100% in the resection group and 65% in the liver transplantation group.ConclusionsTo our knowledge, this is the first case report of pediatric patients with hepatoblastoma and liver resection or transplant in Colombia and Latin America. Our results are comparable with the series worldwide, showing that resection and transplant increase the survival of the pediatric patients with hepatoblastoma. It is important to advocate for an increase of reporting in the scientific literature in Latin America.

Beyond the Milan criteria for liver transplantation in children with hepatic tumours

The Milan criteria were originally defined in the context of adult liver transplantation for patients with hepatocellular carcinoma and cirrhotic livers. The aim of the criteria was to select patients with small tumours and no disease spread who had a good chance of success, thus avoiding futile transplants. This objective was reached successfully. For the management of selected children with unresectable hepatoblastoma, an almost opposite strategy was proposed and has been implemented in the past two decades, in which transplantation is indicated on the basis of large tumour size and anatomy that precludes the possibility of safe and radical resection. This approach has also had great success. Although both strategies are well established for these two different age groups and diseases, a grey area exists with regard to hepatocellular carcinoma or other tumour types in children. In this Viewpoint, we aim to review the existing literature about the indications, selection process, and results of liver transplantation for liver tumours in children, and discuss evidence that supports the implementation of either of the two strategies in the context of managing selected children with liver tumours using transplantation.

Liver Transplant in Children with Hepatoblastoma.

In this paper, the results of liver transplant due to hepatoblastoma in 10 pediatric patients at Istanbul Şişli Memorial Hospital Transplantation Center are presented. We retrospectively evaluated medical records of pediatric patients diagnosed with hepatoblastoma and who underwent liver transplant at our clinic between January 2009 and March 2014. We examined age, weight, chemotherapy regimen, graft type for liver transplant, duration of hospital stay, complications, follow-up duration, and survival information. The median age of the 10 patients included in our study was 13.5 months (range, 8-120 mo), and the median weight was 10 kg (range, 6.5-30 kg). Two of the patients were twins. Five patients had pretreatment extent of disease III (centrally placed cases), and five had pretreatment extent of disease IV hepatoblastoma. Preoperative chemotherapy was given to 7 patients as cisplatin plus doxorubicin and to 3 patients per the International Childhood Liver Tumors Strategy Group 3 High-Risk Protocol at external centers. These protocols were administered according to treatment center preference. Nine patients received transplants from living donors. Two grafts were right lobes, and 7 were left lateral segments. In the remaining patient, a whole liver was received from a deceased donor. The histopathologic subgroups were epithelial in 5 patients, with others being of mixed type. Postoperative complications occurred in 3 patients as infection, intra-abdominal fluid collection, and acute rejection. The median follow-up was 32 months. One patient died because of lung metastasis within 9 months after transplant. Centers should offer liver transplant to patients with centrally located tumors. For centers that have an insufficient number of deceased donors, living-donor liver transplant with optimal planning and early treatment can be performed.

Pattern and Outcome of primary Liver Tumors in Children: A 10 years report from single oncology center in Upper Egypt

Primary malignant liver tumors are uncommon in children with hepatoblastoma (HB) andhepatocellular carcinoma (HCC) are the most common.

Cure of Hepatoblastoma Through Transcatheter Arterial Chemoembolization.

Hepatoblastoma is the most common malignant liver tumor in children. Contrary to its adult counterparts (hepatocellular carcinoma [HCC]), hepatoblastoma is relatively rare, with a current rate of 1.2 to 1.5 cases/million population/year.1 Surgery and chemotherapy remain the mainstay of treatment for hepatoblastoma. The main controversy between various study groups has been the issue of primary hepatic resection, with Childhood Liver Tumors Strategy Group (SIOPEL) recommending preoperative chemotherapy, whereas other study groups have traditionally held that some early PRETEXT stage groups are amenable to upfront resection. Transcatheter arterial chemoembolization (TACE) is a practical and effective alternative for hepatic malignancies and is performed worldwide for adult patients with inoperable HCC.2 However, in childhood hepatoblastoma, TACE is less frequently performed and is mainly used to shrink advanced-stage hepatoblastoma after initial systemic chemotherapy, thus allowing complete surgical resection.3,4 To our knowledge, the cure of hepatoblastoma by TACE alone has not been reported. Here, we report a case of hepatoblastoma cured by multiple TACE procedures.

Pattern and Outcome of primary Liver Tumors in Children: A 10 years report from single oncology center in Upper Egypt

Pattern and Outcome of primary Liver Tumors in Children: A 10 years report from single oncology center in Upper Egypt

A Clinicopathological Study of Paediatric Liver Tumours in a Tertiary Care Hospital.

Paediatric primary liver tumours are the third largest group of solid abdominal neoplasms in children next to neuroblastoma and Wilms tumour, accounting for about 0.5% to 2% of all paediatric neoplasms, in which hepatoblastoma is the most common. The present study was done to estimate the incidence of paediatric liver tumours over a period of five years and also, to study the clinical behaviour, alpha-fetoprotein correlation and histopathological features of paediatric liver tumours. The details of patients treated for paediatric liver tumours for a period of five years were retrospectively retrieved from the tumour board and medical records. The gross features and all the slides were reviewed and the pathologic diagnosis was confirmed and clinicopathological correlation was then done. A total of 39 paediatric liver tumours were detected during five years, of which 32 (82%) were malignant and seven (18%) were benign with a male to female ratio of 1:1.1. Hepatoblastoma was the most common liver tumour accounting for 28 cases (71.8%), of which 25 cases (89.4%) were of pure epithelial type. The second most common primary tumour was epithelioid haemangioendothelioma with six cases (15.4%) with female preponderance, followed by two cases each of hepatocellular carcinoma and undifferentiated embryonal sarcoma and one case of hepatocellular adenoma. Serum AFP level was increased in hepatoblastoma and in hepatocellular carcinoma, normal in hepatocellular adenoma and embryonal sarcoma. Serum AFP level was increased in few cases of epithelioid haemangioendothelioma. The spectrum of liver tumours in children is different from that in the adults. Hepatoblastoma is the most common paediatric liver tumour, followed by epithelioid haemangioendothelioma. Through better understanding of pathological diagnosis, refined surgical staging, newer and more effective radiological techniques and standardized multimodal therapies, a substantial number of children diagnosed with this highly malignant tumour can expect to survive the disease.

Imaging diagnosis of liver tumors in children

Imaging diagnosis of liver tumors in children

Space Occupying Lesions in the Liver.

Space occupying liver lesions usually present with abdominal pain or abnormal physical findings, such as a palpable abdominal mass or distention. Liver lesions identified in children include benign and malignant neoplasms, inflammatory masses, cysts and metastatic lesions. Two-thirds of liver lesions in children are malignant. Hepatoblastoma accounts for two-thirds of malignant liver tumors in children. Benign lesions of the liver in children include vascular lesions, hamartomas, adenomas, and focal nodular hyperplasia. Although benign and malignant liver masses share some clinical manifestations, however treatment and prognosis differ. Evaluation involves physical examination, imaging evaluation and laboratory investigations such as serological markers [alpha-fetoprotein (AFP)] for malignant liver lesions. Ultrasound is the initial imaging modality of choice because it can detect, characterize, and provide the extent of liver lesions. However, CT or MRI are often subsequently performed for further characterization, assessment of precise extent, and detection of associated metastatic disease in cases of malignant hepatic neoplasm. Serological markers (such as alpha fetoprotein) can be useful in narrowing the differential diagnosis when they are markedly elevated but a substantial number of patients unfortunately do not have high levels of these markers at the time of presentation or cautious interpretation is warranted as AFP level is frequently elevated in infants up to 6 mo of age and may be slightly elevated with benign tumors and with hepatic insult or regeneration. Therefore, a tissue diagnosis is often required to guide subsequent management. The histology and anatomy of a pediatric liver tumor guides the treatment and prognosis.

Hepatoblastoma modeling in mice places Nrf2 within a cancer field established by mutant β-catenin.

Aberrant wnt/β-catenin signaling and amplification/overexpression of Myc are associated with hepatoblastoma (HB), the most prevalent type of childhood liver cancer. To address their roles in the pathogenesis of HB, we generated mice in which Myc and mutant β-catenin were targeted to immature cells of the developing mouse liver. Perinatal coexpression of both genes promoted the preferential development of HBs over other tumor types in neonatal mice, all of which bore striking resemblance to their human counterparts. Integrated analysis indicated that tumors emerged as a consequence of Myc-driven alterations in hepatoblast fate in a background of pan-hepatic injury, inflammation, and nuclear factor (erythroid-derived 2)-like 2/Nrf2-dependent antioxidant signaling, which was specifically associated with expression of mutant β-catenin but not Myc. Immunoprofiling of human HBs confirmed that approximately 50% of tumors demonstrated aberrant activation of either Myc or Nfe2l2/Nrf2, while knockdown of Nrf2 in a cell line-derived from a human HB with NFE2L2 gene amplification reduced tumor cell growth and viability. Taken together, these data indicate that β-catenin creates a protumorigenic hepatic environment in part by indirectly activating Nrf2 and implicate oxidative stress as a possible driving force for a subset of β-catenin-driven liver tumors in children.