Pediatric Liver Tumors Research Articles

Computer-assisted surgery planning in children with complex liver tumors identifies variability of the classical Couinaud classification

BackgroundIn complex malignant pediatric liver tumors there is an ongoing discussion regarding surgical strategy; for example, primary organ transplantation versus extended resection in hepatoblastoma involving 3 or 4 sectors of the liver. We evaluated the possible role of computer-assisted surgery planning in children with complex hepatic tumors. MethodsBetween May 2004 and March 2016, 24 Children with complex liver tumors underwent standard multislice helical CT scan or MRI scan at our institution. Imaging data were processed using the software assistant LiverAnalyzer (Fraunhofer Institute for Medical Image Computing MEVIS, Bremen, Germany). Results were provided as Portable Document Format (PDF) with embedded interactive 3-dimensional surface mesh models. ResultsMedian age of patients was 33months. Diagnoses were hepatoblastoma (n=14), sarcoma (n=3), benign parenchyma alteration (n=2), as well as hepatocellular carcinoma, rhabdoid tumor, focal nodular hyperplasia, hemangioendothelioma, or multiple hepatic metastases of a pancreas carcinoma (each n=1). Volumetry of liver segments identified remarkable variations and substantial aberrances from the Couinaud classification. Computer-assisted surgery planning was used to determine surgical strategies in 20/24 children; this was especially relevant in tumors affecting 3 or 4 liver sectors. Primary liver transplantation could be avoided in 12 of 14 hepaoblastoma patients who theoretically were candidates for this approach. ConclusionsComputer-assisted surgery planning substantially contributed to the decision for surgical strategies in children with complex hepatic tumors. This tool possibly allows determination of specific surgical procedures such as extended surgical resection instead of primary transplantation in certain conditions.

Pediatric liver transplantation for hepatoblastoma.

Hepatoblastoma is the most common pediatric liver tumor and is usually diagnosed before five years of age. Treatment consists of a combination of chemotherapy and surgery, with the goal being attainment of complete local control by surgical resection and eradication of any extrahepatic disease. Neoadjuvant chemotherapy is utilized and is often beneficial in rendering tumors resectable; however, prolonged chemotherapy administration attempting to render tumors resectable by conventional resection should be avoided. For patients whose tumors are too extensive to be conventionally resected, liver transplantation can be curative and remains the treatment of choice for eligible patients otherwise incurable by conventional resection.

Sildenafil potentiates the cytostatic effect of doxorubicin in pediatric epithelial liver tumors

Sildenafil potentiates the cytostatic effect of doxorubicin in pediatric epithelial liver tumors

Preclinical Evaluation of UAB30 in Pediatric Renal and Hepatic Malignancies.

Rare tumors of solid organs remain some of the most difficult pediatric cancers to cure. These difficult tumors include rare pediatric renal malignancies, such as malignant rhabdoid kidney tumors (MRKT) and non-osseous renal Ewing sarcoma, and hepatoblastoma, a pediatric liver tumor that arises from immature liver cells. There are data in adult renal and hepatic malignancies demonstrating the efficacy of retinoid therapy. The investigation of retinoic acid therapy in cancer is not a new strategy, but the widespread adoption of this therapy has been hindered by toxicities. Our laboratory has been investigating a novel synthetic rexinoid, UAB30, which exhibits a more favorable side-effect profile. In this study, we hypothesized that UAB30 would diminish the growth of tumor cells from both rare renal and liver tumors in vitro and in vivo We successfully demonstrated decreased cellular proliferation, invasion and migration, cell-cycle arrest, and increased apoptosis after treatment with UAB30. Additionally, in in vivo murine models of human hepatoblastoma or rare human renal tumors, there were significantly decreased tumor xenograft growth and increased animal survival after UAB30 treatment. UAB30 should be further investigated as a developing therapeutic in these rare and difficult-to-treat pediatric solid organ tumors. Mol Cancer Ther; 15(5); 911-21. ©2016 AACR.

Magnetic resonance imaging of primary pediatric liver tumors.

Although primary hepatic neoplasms are less common than other intra-abdominal tumors in children, these neoplasms are a significant source of morbidity and mortality in the pediatric population. MRI is increasingly relied upon in the diagnostic evaluation of these lesions, both before and after treatment, and familiarity with the MRI findings associated with these neoplasms is a must for pediatric radiologists. Advances in MRI technology, particularly the advent of hepatocyte-specific gadolinium-based MRI contrast agents, have allowed for accurate characterization of several types of hepatic neoplasms on the basis of imaging appearance. In this review, we provide an overview of the approach to imaging hepatic neoplasms in children using MRI, including a sample imaging protocol. We also discuss the relevant clinical features and MRI findings of the most clinically relevant entities, including their appearance on post-contrast imaging using hepatocyte-specific gadolinium-based MRI contrast agents.

Abstract A27: INI1 negative hepatoblastoma, a vanishing entity representing malignant rhabdoid tumor

Abstract Introduction: Hepatoblastoma (HB) is the most common primary hepatic tumor of childhood. According to the most current Children’s Oncology Group (COG) classification small cell undifferentiated hepatoblastomas (SCU-HB) are a subtype of epithelial hepatoblastomas with adverse outcome. Malignant rhabdoid tumors (MRT) of the liver are a distinct highly aggressive group of tumors with unknown cell of origin diagnosed on the basis of INI1 negative immunoreactivity and rhabdoid morphology. In the absence of rhabdoid morphology, presence of SMARCB1/INI1 deletion on chromosome 22q11.2 is confirmatory. Therefore, MRT lacking classic rhabdoid morphology are often misdiagnosed as SCU-HB, especially on small biopsy samples. We present a case of previously healthy full-term 10 month old female infant with a lobulated heterogeneous right hepatic mass, low serum alpha-fetoprotein (AFP) of 71 ng/ml, and metastatic pulmonary disease. Initial biopsy of mass was consistent with hepatoblastoma, predominantly small cell undifferentiated component. The patient underwent chemotherapy with vincristine, irinotecan, and temsirolimus with less than the 30% response required for partial responder. She subsequently underwent right partial hepatectomy. Results: Histologic evaluation of the biopsy sample revealed solid proliferation of small tumor cells with clear to eosinophilic cytoplasm and prominent nucleoli, compatible with small cell morphology. Immunohistochemistry for INI1 was negative in all tumor cells. In the absence of rhabdoid morphology, the tumor was initially classified as INI1 negative SCU-HB. Subsequently, the resection specimen showed predominantly small cells with only focal areas of rhabdoid morphology. An extensive immunohistochemical panel was performed and the tumor cells were negative for hepatocellular differentiation markers (Hepar-1 and arginase), beta-catenin, desmin, myoD1, cytokeratin 7, cytokeratin 20, and were positive for glypican-3 and cytokeratin in both biopsy and resection specimens. Similar to the biopsy sample, the tumor cells were entirely negative for INI1 on the resection specimen. Cancer Whole-Exome Sequencing (WES) with Transcriptome was performed and showed homozygous deletion of SMARCB1 on chromosome 22q11.23 with evidence of loss of expression of the gene confirming the loss of INI1 expression with IHC. Discussion: MRT of liver are a distinct entity and are in the differential diagnosis of INI-1 negative pediatric liver tumors along with SCU-HB. MRT are also considered in the differential diagnosis of any aggressive liver tumor with low levels of AFP. Current reports indicate that differentiation of MRT from INI1 negative SCU-HB, in the absence of rhabdoid morphology, is mainly based on molecular testing for SMARCB1. In our case, the initial biopsy sample was classified as INI1 negative SCU-HB predominantly based on morphology, and was subsequently reclassified as MRT based on demonstration of SMARCB1 deletion with WES, as well as identification of focal areas of rhabdoid morphology on the resection specimen. Conclusion: Based on this finding, morphology is not a robust method of differentiating MRT from SCU-HB. It is possible that many cases previously classified as SCU-HB mainly based on morphology, if retrospectively analyzed for SMARCB1 would be reclassified as MRT. Citation Format: Ladan Fazlollahi, Susan Hsiao, Mahesh Mansukhani, Julia Glade Bender, Andrew Kung, Darrell Yamashiro, Helen Remotti. INI1 negative hepatoblastoma, a vanishing entity representing malignant rhabdoid tumor. [abstract]. In: Proceedings of the AACR Special Conference: Developmental Biology and Cancer; Nov 30-Dec 3, 2015; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(4_Suppl):Abstract nr A27.

Abstract A33: Discovery of chimeric transcripts involving APC and TERT in pediatric HCC by RNA sequencing

Abstract Background: Hepatocellular carcinoma (HCC) is a rare pediatric liver tumor with a poor prognosis. A characteristic DNAJB1-PRKACA gene fusion has been identified in a specific subtype, fibrolamelar HCC (FL-HCC). In the majority of pediatric cases of non-FL-HCC, a genetic cause has not been identified. We hypothesize that gene fusions could play a role in the tumorigenesis of pediatric HCC. The goal of this project is to utilize RNA sequencing to identify chimeric transcripts in pediatric HCC that could improve molecular characterization and identify potential oncogenic drivers of this disease. Materials and Methods: We have used RNA sequencing (RNA-seq) to survey a cohort of 8 FL-HCCs, 4 pediatric HCCs, and 6 normal liver samples for chimeric transcripts. High quality RNA (RIN: 6.6-9.7) was extracted from fresh-frozen tissue and strand-specific, poly-A+ RNA-seq libraries were prepared for Illumina sequencing. Approximately 85 million paired-end reads (42.5 million fragments) of 2 x 100 bp length were generated per sample. Fusion transcripts in the tumor samples were detected using deFuse (v.0.6.1) on FASTQ files followed by subtraction of fusions also called in the normal liver dataset. The remaining calls in the HCC dataset were then filtered for the COSMIC Cancer Gene Census list to identify fusions involving known oncogenes or tumor suppressor genes. Candidate fusions were verified using BLAST and validated by RT-PCR. Results: On average, 150 fusion transcripts were predicted per tumor sample using the deFuse algorithm. Further filtering by the normal liver dataset reduced the number of calls in the tumor datasets by ~60%. As expected, DNAJB1-PRKACA fusions were identified in the FL-HCC cohort with no additional fusions detected. Filtering by the COSMIC Cancer Gene Census list resulted in five additional fusion calls in HCC (three unique events in two tumors) two of which were confirmed by RT-PCR. The first event is an inversion within the APC and AP3B1 genes that results in the two in-frame fusion transcripts, APC-AP3B1 and APC3B1-APC, but no full-length APC transcript. The second event is a deletion encompassing the TERT promoter that results in the in-frame fusion LPCAT1-TERT. An increase in TERT expression is seen in this tumor as compared to both normal liver and other pediatric HCC tumors. Filtering for in-frame fusions involving non-COSMIC genes did not reveal any fusions in the two remaining HCCs and further analysis of these cases is ongoing. Conclusion: The detection of chimeric transcripts by RNA-seq has allowed us to identify two unique structural events involving known cancer genes in two pediatric non-fibrolamellar HCCs. The chimeric transcripts found in these tumors provide further insight into the tumorigenic events of pediatric HCC. Supported by research grants from Cancer Prevention and Research Institute of Texas RP101195 and RP120715 and National Institute of General Medical Sciences T32GM008307. Citation Format: Katherine Haines, Angshumoy Roy, Linghua Wang, Pavel Sumazin, Kyle R. Covington, Donna M. Muzny, Vijetha Kumar, Harsha Doddapaneni, Hsu Chao, David A. Wheeler, Gail Tomlinson, D. Williams Parsons, Sharon E. Plon, Dolores Lopez-Terrada. Discovery of chimeric transcripts involving APC and TERT in pediatric HCC by RNA sequencing. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A33.

The paediatric hepatic international tumour trial (PHITT): clinical trial design in rare disease

Hepatoblastoma is a comparatively uncommon paediatric solid tumour, while hepatocellular carcinoma is very rare. The Paediatric Hepatic International Tumour Trial will be the single largest clinical trial undertaken in paediatric liver cancer patients as collaboration between the European Study Group for Paediatric Liver Tumours, Children’s Oncology Group and Japanese Study Group for Pediatric Liver Tumors. In the context of the low incidence paediatric cancer, an overarching study with therapeutic questions for the separate tumour types and risk groups will be more efficient than setting up separate studies for each group. Hence, the design will incorporate randomised comparisons for five different patient groups. It is difficult to obtain feasible sample sizes based on conventional frequentist design criteria. Therefore, Bayesian methods based on probability distributions will be used with event-free survival as the primary outcome measure for each comparison summarised by hazard ratio. Posterior probability distributions, with non-informative priors, based on the number of events will be used to give probabilities of one treatment being better than another. Operating characteristics are explored through simulations of various scenarios given pre-specified decision criteria. The level of evidence needed will depend on the clinical question: for example, a stronger level of evidence is likely to be needed if treatment is being intensified than if two regimens of comparable intensity are being compared. It is important to investigate promising approaches in randomised trials. The design will enable quicker and more efficient identification of effective therapies, leading to improved outcomes for children with liver cancer.

Primary liver tumours in childhood

The reported prevalence of focal liver lesions in adult patients and children is different. The article discusses pediatric liver tumors under the criteria of histopathology and contrast enhanced ultrasound (CEUS) features. Aim of this article is also to support the already established Pediatric Registry of the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) to collect data on safety and applications of ultrasound contrast agents in children (www.efsumb.org).

Effects of curcumin in pediatric epithelial liver tumors: inhibition of tumor growth and alpha-fetoprotein in vitro and in vivo involving the NFkappaB- and the beta-catenin pathways.

In children with hepatocellular carcinoma (pHCC) the 5-year overall survival rate is poor. Effects of cytostatic therapies such as cisplatin and doxorubicin are limited due to chemoresistance and tumor relapse. In adult HCC, several antitumor properties are described for the use of curcumin. Curcumin is one of the best-investigated phytochemicals in complementary oncology without relevant side effects. Its use is limited by low bioavailability. Little is known about the influence of curcumin on pediatric epithelial hepatic malignancies. We investigated the effects of curcumin in combination with cisplatin on two pediatric epithelial liver tumor cell lines. As mechanisms of action inhibition of NFkappaB, beta-catenin, and decrease of cyclin D were identified. Using a mouse xenograft model we could show a significant decrease of alpha-fetoprotein after combination therapy of oral micellar curcumin and cisplatin. Significant concentrations of curcuminoids were found in blood samples, organ lysates, and tumor tissue after oral micellar curcumin administration. Micellar curcumin in combination with cisplatin can be a promising strategy for treatment of pediatric HCC.

Liver Transplantation for Pediatric Hepatoblastoma and Hepatocellular Carcinoma: Out of the Unknown.

Withadvances inchemotherapy, surgical treatment, andpostoperative care, the prognosis for children with hepatoblastoma (HBL) has improved significantly during the past 3 decades. The combined use of liver transplantation and chemotherapy isnowthepreferred treatment option for unresectableHBL.1 Inpediatric patientswithhepatocellular carcinoma (HCC), transplantationhasbeenassociatedwith improved disease-free survival compared with conventional treatment with chemotherapy and resection, particularly in children with advanced-stage tumors or chronic underlying liver disease.2 In this issue of JAMA Surgery, Pham et al3 report excellent long-term outcomes at their center after liver transplantation for childhood HBL and HCC, with 5-year disease-free survival rates of 82% and 78%, respectively. Similar to other published reports in the literature, this study is limited by its retrospective nature and the small numbers of patients. The authors proposed several risk factors associated with tumor recurrence after transplantation, but proper multivariable analysis was not performed. Furthermore, patient selection protocols can vary from one transplant center to another, which may lead to notable differences in observed outcomes. The Pediatric Liver Unresectable Tumor Observatory (PLUTO) registry was initiated in 2006 by the International Childhood Liver Tumors Strategy Group (SIOPEL) and now contains prospectively collected data on more than 200 pediatric patients who have undergone transplant for unresectable liver tumors in 79 centers around the world. The primary objectives of the registry are (1) to fully define the indications for liver transplantation in the treatment of pediatric liver tumors, (2) to identify the optimal timing for transplantation, (3) to define the role of pretransplant and posttransplant chemotherapy, and (4) to determine the best strategy for immunosuppression.4 An interim report of the registry5 has demonstrated an expected long-term survival rate of approximately 90% after liver transplantation for unresectable HBL. For children with HCC in the setting of underlying liver disease, liver transplantation produces excellent long-term survival and cure rates, even without the use of chemotherapy. In pediatric patients without chronic liver disease who develop unresectable HCC tumors, Related article page 1150 Research Original Investigation Survival in ChildrenWith Hepatoblastoma and Hepatocellular Cancer

OP14 - Influence of curcumin on a pediatric hepatocellular carcinoma model in vitro and in vivo: significant reduction of alpha-fetoprotein and curcuminoid levels in mice

Introduction In children with hepatocellular carcinoma (pHCC) overall survival is poor. In adult HCC several antitumor properties are described in in vitro models for the use of curcumin (CUR). Methods Hepatoma cell lines (HuH6, HepT1, HepG2, HC-AFW1) were treated with CUR or, and Cisplatin (PDDT), cultures were either kept in the dark or exposed to blue light (PDT; 480 nm, 300W, 10 seconds), MTT-tests were performed. ROS production was measured. Reduction of cancer stem cells (CSC) was investigated with FACS analyses. Orthotopic growth of the pediatric hepatocellular carcinoma cell line HC-AWF1 in NSG mice was induced. By the increase serum alpha fetoprotein AFP >5 U/mL mice were treated with micellar CUR, PDDT, or CUR PDDT and compared to controls. Curcuminoid levels in serum and organ lysates as well as AFP serum levels were investigated. Results In all cell lines IC50 were significantly lower after blue light exposure than after CUR alone (p Conclusion These data prove the potential of micellar curcumin as a complementary agent in pediatric oncology to enhance the overall survival of patients with pediatric liver tumors.

Mortality and morbidity in primarily resected hepatoblastomas in Japan: Experience of the JPLT (Japanese Study Group for Pediatric Liver Tumor) trials

BackgroundIn the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocols (JPLT-1 and 2) for evaluating the cure rate of risk-stratified hepatoblastoma, primary resection was permitted in PRETEXT I and II cases, followed by postoperative chemotherapy. MethodsIn approximately 500 enrolled cases, resection was performed as the initial treatment in 60 cases, including all 18 PRETEXT I, 30 PRETEXT II, and 12 ruptured cases. The clinical features, surgical procedures, complications, and survival rates were compared in these three groups. ResultsAll 18 PRETEXT I cases underwent complete resection by lobectomy or segmentectomy (n=14) or nonanatomical partial hepatectomy (NPH) (n=4). The 30 PRETEXT II cases underwent primary resection by right or left lobectomy (n=16), NPH (n=10), or other procedures (n=4). Of these 30 cases, operational death occurred in 1 newborn, and recurrence occurred in 7 cases (14.6%), including 6 NPH cases and 4 older cases (aged >3years). Of the 12 ruptured cases, 7 (58.3%) showed recurrence. Event-free survival rates at 5years in the 3 groups were 88%, 70%, and 32%, respectively. ConclusionsPrimary resection for PRETEXT I or II HB cases should be performed by anatomical resection according to strict surgical guidelines. More intensified chemotherapy is required for primary resected cases whose tumors have ruptured.

Abstract 2107: YAP protein expression and subcellular localization in pediatric liver tumors

Abstract Purpose: Currently, there is no effective chemotherapy for the treatment of hepatocellular carcinoma (HCC). Both HCC and hepatoblastoma (HB) remain lethal in their metastatic forms. Therefore, understanding the molecular mechanisms of tumor survival and proliferation is critical for developing novel therapies. Our lab has shown that YAP, a transcription factor, is involved in liver regeneration. Specifically, increases in nuclear YAP have been coupled with expression of genes important for cell proliferation. We therefore sought to examine whether there is increased nuclear localization of YAP in liver tumors. Methods: Tumor tissue and normal liver tissue from 3 pediatric patients with HCC (all males, mean age 10.63 years), and 6 HB patients (4 males and 2 females, mean age 2.99 years) were stained for YAP using immunohistochemistry. Multiple high-power fields were photographed for each sample. Using ImageJ software, the number of YAP-positive nuclei were counted and expressed as a mean percentage of total nuclei. Results: The percentage of nuclei staining positive for YAP was increased in tumor cells compared to normal liver in 3/3 of the HCC tumors. In addition, YAP nuclear staining was significantly increased in 2/6 of the HB tumors. Conclusion: All HCC tumors and 33% of the HB showed an increase in the nuclear localization of transcription factor YAP. The increased activity of YAP in the nuclei of tumor cells may indicate a crucial role for YAP in tumor proliferation and survival. Targeting YAP or its upstream pathway (Hippo) may provide a novel target for therapy. Citation Format: Michael J. LaQuaglia, James Grijalva, Kaly Mueller, Antonio Perez-Atayde, Heung Bae Kim, Ghazaleh Sadri-Vakili, Khashayar Vakili. YAP protein expression and subcellular localization in pediatric liver tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2107. doi:10.1158/1538-7445.AM2015-2107

Abstract 3536: Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model

Abstract Hepatoblastoma (HB), the commonest pediatric liver tumor is frequently associated with an N-terminal deletion in the CTNNB1 gene, which encodes stable β-catenin and promotes nuclear localization and transactivation activity. In 80% of patients, nuclear localization of β-catenin and Yes Associated Protein (YAP), a Hippo-related transactivator, is seen together. Further, stable hepatic co-expression of Δ90-CTNNB1 and active-YAP in mice causes rapid and aggressive HB. Dicer-substrate siRNAs (DsiRNAs) are potent RNA interference (RNAi) triggers that that are efficacious in preclinical tumor models of diverse origin, and are currently under clinical evaluation. To determine if CTNNB1-targeting DsiRNAs have potential as a therapy in HB, we encapsulated this oligonucleotide payload into lipid nanoparticles (LNPs), and systemically administered into mice bearing CTNNB1/YAP-induced HB. The LNP platform used, termed EnCore (because of its specific Envelope and Core lipid components), enables high encapsulation efficiency, long-term stability, and consistent analytical criteria. Downstream of LNP-mediated DsiRNA delivery, both qPCR and in situ hybridization were used to visualize changes in CTNNB1 expression in both tumor and normal liver. Robust and specific silencing of CTNNB1 mRNA was achieved in the tumors. The distribution of mRNA knockdown within each tumor nodule suggests efficient extravasation and internalization of the LNP and its payload into the tumor parenchyma, in contrast to previous reports of vascular-channel limited nanoparticle accumulation in tumors. Intriguingly, a “liver-centric” LNP formulation, which delivers cargo efficiently to a normal liver due to rapid hepatic extraction and apolipoprotein-mediated internalization, was inactive in the tumors. Further evaluation demonstrated efficacy of β-catenin targeting in this model. In conclusion, we report a highly relevant modality of RNAi delivery in a mouse model of hepatoblastoma to target a classically-undruggable oncogene. Citation Format: Marc T. Abrams, Junyan Tao, Shanthi Ganesh, Wendy Cyr, Bo Ying, Martin Koser, Rokhand Arvan, Girish Chopda, Hank Dudek, Cheng Lai, Weimin Wang, Bob Brown, Satdarshan Monga. Targeting β-catenin with a Dicer-substrate siRNA (DsiRNA) in a sleeping beauty transposon-driven murine hepatoblastoma model. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3536. doi:10.1158/1538-7445.AM2015-3536

Quantification of glypican 3, β-catenin and claudin-1 protein expression in hepatoblastoma and paediatric hepatocellular carcinoma by colour deconvolution.

To identify an immunohistochemical panel for paediatric malignant epithelial liver tumours. Forty-five hepatoblastomas (HBs), 13 paediatric hepatocellular carcinomas (HCCs) and two hepatocellular malignant neoplasms not otherwise specified (NOS) were chosen for immunohistochemical staining of glypican 3 (GPC3), β-catenin, claudin-1, delta-like protein (DLK), and forkhead box protein G1 (FOXG1). Immunostaining was quantitatively analysed with NIH imagej software coupled with colour deconvolution. Different subtypes of HB and HCC showed distinct staining patterns ofGPC3, β-catenin, and claudin-1. Moreover, GPC3, β-catenin and claudin-1 all showed higher expression in classic HCC and embryonal HB than in fetal HB; GPC3 showed complete negativity in small-cell undifferentiated (SCU) HB and fibrolamellar HCC (FLC); β-catenin showed the strongest expression in SCU HB but the weakest expression in FLC. A panel of these three immunomarkers was useful for the diagnosis of hepatocellular malignant neoplasms NOS. The expression of DLK and FOXG1 was inconstant among fetal and embryonal HB and classic HCC. A panel of GPC3, β-catenin and claudin-1 is helpful for differentiating HB subtypes and distinguishing HB from HCC.

Conduite à tenir devant une tumeur hépatique de l’enfant

Two-thirds of pediatric liver tumors are malignant, but pseudotumors such as abscesses or hematoma can simulate a tumor. The pediatrician is often the first to discover a hepatic mass in a child. The diagnostic gamut varies depending on the child's age. Before the age of three years, the main diagnoses are hepatoblastoma and hemangioma, while after the age of three, hepatocarcinoma, sarcoma, focal nodular hyperplasia, and adenoma are more frequent. The laboratory findings to search for are alpha-fetoprotein whatever the age (increased in hepatoblastoma and hepatocarcinoma), beta-hCG, and urinary catecholamines in infants. Liver function is usually normal. Ultrasonography is the first-line examination to request. It confirms the hepatic location of the mass, differentiates solid from cystic tumors (cystic mesenchymal hamartoma and undifferentiated sarcoma), hypervascular findings (hemangioma in the infant, focal nodular hyperplasia in the older child), portal or hepatic thrombosis suggesting a malignant tumor, and findings of portacaval fistula predisposing to focal nodular hyperplasia and adenoma. At the end of this clinical, biological, and ultrasound examination, the pediatrician will refer the patient to a specialized center for further investigation and management, which are at best performed by pediatric oncologists, surgeons, and radiologists. Diagnostic confirmation and extension work-up will require CT or MRI depending on the patient's age and clinical state and the availability of equipment.

Hepatoblastoma in Children—Analysis of Treatment Outcome from a Tertiary Care Referral Centre in South India

Aim: To look at demography, clinical features, management modalities and outcome of children who presented with hepatoblastoma (HB) to our centre. Methods: Retrospective review of case notes of children (<16 yrs) with HB who presented to our hospital between Jan 2011 and Dec 2014. Results: Twenty four children with HB presented at a median age of 2 years (range – 3 months to 12 years), with a M:F ratio of 2.4:1. Of the 24, one child had phenotype of Beckwith Wiedemann syndrome. Abdominal mass was the main presenting complaint in 71% (n = 17) of children. All had normal liver function tests with preserved synthetic function. 37.5% (n = 9) were PRETEXT 4, 25% (n = 6) were PRETEXT 3, 33% (n = 8) of them were PRETEXT 2 and 4.5% (n = 1) was PRETEXT 1. All children were treated with standard chemotherapy regimen suggested by “The International Society of Pediatric Oncology Epithelial Liver Tumor Group (SIOPEL)” (Cisplatin/Doxorubicin) before surgery except for two. Sixteen children had complete resection, while four underwent living donor liver transplantation, of which three had unresectable tumor and one had recurrence following resection. All children received two cycles of chemotherapy post resection/transplantation. Of the 16 children who underwent surgery, 3 had lung metastasis. Four children poorly responded to chemotherapy so surgical resection or liver transplantation was not feasible in them. All these four children died. The children who underwent resection/transplantation were followed up for a median of 18 months (range, 1 month to 36 months) and all of them are healthy except two, who had metastasis in lung and diaphragm. Conclusion: Lung metastasis is not an absolute contraindication for resection/transplantation in HB. HB is a potentially curable disease with good long-term outcome and best managed in centres with multidisciplinary team with a liver transplant back up.

Survival and late effects in the risk-stratified hepatoblastoma patients treated by JPLT-2 protocol.

10021 Background: The Japanese Study Group for Pediatric Liver Tumor (JPLT) has conducted cooperative treatment studies on hepatoblastoma (HB) since 1991. The main aim in JPLT-2 study launched in 1...

Intraoperative ultrasound for liver tumor resection in children

BackgroundPrimary hepatic neoplasms in children are rare tumors. All malignant and medically refractive benign primary pediatric liver tumors ultimately require surgical resection for cure. Accurate preoperative imaging including multidetector helical computerized tomography or magnetic resonance imaging (MRI) is necessary to determine resectability. In the literature intraoperative ultrasound (IOUS) has proven to be a vital adjunct to liver surgery in adults, but this is not well established in children. Materials and methodsBetween April 2003 and November 2014, children (<18-y-old) with a primary liver neoplasm, preoperatively evaluated with multidetector helical computerized tomography or MRI, who had IOUS used at the time of surgery were retrospectively reviewed. ResultsPreoperative evaluation with high-resolution MRI and IOUS were discordant in 4 of 19 patients (21%). In one case, right hepatic vein involvement was not accurately assessed with MRI. Two cases showed tumor involvement in segment IV by MRI; however, IOUS revealed no medial segment involvement. The final patient had a large (>5 cm), solitary hepatic adenoma on MRI, but IOUS in this case revealed diffuse adenomatosis. The operative management was altered in three of these cases. ConclusionsAlthough MRI can provide a detailed view of the hepatic anatomy and is an invaluable tool for preoperative planning for the pediatric patient with a primary liver neoplasm, IOUS may provide further and more up to date delineation of tumor extent and should be considered a crucial element in operative planning for hepatectomy in children.