Pediatric Liver Tumors Research Articles

Childhood liver tumors in Argentina: Incidence trend and survival by treatment center. A report from the national pediatric cancer registry, ROHA network 2000-2015.

Information on the epidemiology of pediatric liver tumors in Latin America is limited. To describe the incidence of liver tumors in a pediatric registry in Argentina according to geographic region, national trends over 16years, and survival related to stage, age, sex, and care center. Newly diagnosed liver tumors cases are registered in the Argentine Pediatric Oncology Hospital Registry (ROHA) with an estimated coverage of 91% of national cases. Age-standardized incidence rate per millon (ASR) was calculated based on the National Vital Statistics Reports. Five-year overall survival (OS) was estimated using the Kaplan-Meier method. The log-rank test was used to compare subgroup survival. Two hundred seven cases of hepatoblastoma (HB) and 73 of hepatocellular carcinoma (HCC) were identified. ASR of liver tumors was 1.8/million (95% confidence Interval [CI], 1.6-2.0) per year. ASR was 1.4 (1.2-1.6) for HB and 0.4 (0.3-0.5) for HCC. For HB, the highest incidence was found in the northwest region including the Altiplano. OS was 60.4% (53.4-66.8) for HB and 36.1% (25.2-47.2) for HCC. Five-year survival rate of children with metastatic HB treated at liver transplant hospitals (LTH) was 54.2% (30.3-73.0) compared to 13.3% (2.2-34.6) for those seen at other hospitals (OH) (P=.02), while for HCC this rate was 46.3% (30.7-60.6) at LTH compared to 17.5% (3.1-41.9) at OH (P=.01). The incidence rate of pediatric liver tumors was stable over the 16-year study period. Patients may benefit if at treatment initiation they are evaluated jointly with LTH specialists to define treatment strategies.

Management of benign liver tumors

Benign liver tumors in children are far less frequent than their malignant counterparts. Recently, there have been advances of diagnostic procedures and novel treatments with improved classification as a result. While malignant pediatric liver tumors have been comprehensively addressed by multicenter international tumor trials, benign tumors have more usually relied upon individualised workup and treatment. Due to the rarity and heterogeneity of these different entities, large studies are lacking. In this article the authors highlight the spectrum of benign liver tumors with special focus on specific clinical features, pathology, and treatment.

Pediatric Hepatoblastoma: What the Sonographer Needs to Know for the Sonographic Evaluation of Complications After Treatment and After Liver Transplantation

Hepatoblastoma (HB) is a common primary pediatric liver tumor, and its typical presentation is a palpable, nontender abdominal mass that is detected through sonographic imaging. The current treatment standard for HB includes chemotherapy followed by liver resection or transplantation. Throughout the management of HB, high-quality sonographic images inform diagnosis, treatment interventions, and detection of surgical treatment complications. It is important that sonographers be familiar with the presentation and complications of HB on imaging examinations. The authors review sonographic detection, evaluation of HB at presentation, and common complications after liver resection and transplantation.

Outcome and Late Complications of Hepatoblastomas Treated Using the Japanese Study Group for Pediatric Liver Tumor 2 Protocol.

We report here the outcomes and late effects of the Japanese Study Group for Pediatric Liver Tumors (JPLT)-2 protocol, on the basis of cisplatin-tetrahydropyranyl-adriamycin (CITA) with risk stratification according to the pretreatment extent of disease (PRETEXT) classification for hepatoblastoma (HB). From 1999 to 2012, 361 patients with untreated HB were enrolled. PRETEXT I/II patients were treated with up-front resection, followed by low-dose CITA (stratum 1) or received low-dose CITA, followed by surgery and postoperative chemotherapy (stratum 2). In the remaining patients, after 2 cycles of CITA, responders received the CITA regimen before resection (stratum 3), and nonresponders were switched to ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC; stratum 4). Intensified chemotherapeutic regimens with autologous hematopoietic stem-cell transplantation (SCT) after resection were an optional treatment for patients with refractory/metastatic disease. The 5-year event-free and overall survival rates of HB patients were 74.2% and 89.9%, respectively, for stratum 1, 84.8% and 90.8%%, respectively, for stratum 2, 71.6% and 85.9%%, respectively, for stratum 3, and 59.1% and 67.3%%, respectively, for stratum 4. The outcomes for CITA responders were significantly better than those for nonresponders, whose outcomes remained poor despite salvage therapy with a second-line ITEC regimen or SCT. The late effects, ototoxicity, cardiotoxicity, and delayed growth, occurred in 61, 18, and 47 patients, respectively. Thirteen secondary malignant neoplasms (SMNs), including 10 leukemia, occurred, correlating with higher exposure to pirarubicin and younger age at diagnosis. The JPLT-2 protocol achieved up-front resectability in PRETEXT I/II patients with no annotation factors, and satisfactory survival in patients who were CITA responders in the remaining patients. However, outcomes for CITA nonresponders were unsatisfactory, despite therapy intensification with ITEC regimens and SCT. JPLT-2 had a relatively low incidence of cardiotoxicity but high rates of SMNs.

The Hippo Effector Transcriptional Coactivator with PDZ-Binding Motif Cooperates with Oncogenic β-Catenin to Induce Hepatoblastoma Development in Mice and Humans

Hepatoblastoma (HB) is the most common pediatric liver tumor. Though Wnt/β-catenin and Hippo cascades are implicated in HB development, studies on crosstalk between β-catenin and Hippo downstream effector transcriptional coactivator with PDZ-binding motif (TAZ) in HB are lacking. Expression levels of TAZ and β-catenin in human HB specimens were assessed by immunohistochemistry. Functional interplay between TAZ and β-catenin was determined by overexpression of an activated form of TAZ (TAZS89A), either alone or combined with an oncogenic form of β-catenin (ΔN90-β-catenin), in mouse liver via hydrodynamic transfection. Activation of TAZ often co-occurred with that of β-catenin in clinical specimens. Although the overexpression of TAZS89A alone did not induce hepatocarcinogenesis, concomitant overexpression of TAZS89A and ΔN90-β-catenin triggered the development of HB lesions exhibiting both epithelial and mesenchymal features. Mechanistically, TAZ/β-catenin-driven HB development required TAZ interaction with transcriptional enhanced associate domain factors. Blockade of the Notch cascade did not inhibit TAZ/β-catenin-dependent HB formation in mice but suppressed the mesenchymal phenotype. Neither Yes-associated protein nor heat shock factor 1 depletion affected HB development in TAZ/β-catenin mice. In human HB cell lines, silencing of TAZ resulted in decreased cell growth, which was further reduced when TAZ knockdown was associated with suppression of either β-catenin or Yes-associated protein. Overall, our study identified TAZ as a crucial oncogene in HB development and progression.

Hepatoblastoma-An Unusual Presentation: A Case Report

Hepatoblastoma (HB) is the most common primary hepatic malignancy in children and accounts for 43% of the pediatric liver tumors. The usual presentation is the presence of an abdominal mass, vomiting, elevated αfetoprotein levels and thrombocytosis and it occurs in infants and children under 3 years of age. A 6-year-old male child presented to the outpatient department with complaints of mild to moderate grade fever, vomiting and loose stools for 3 days. The child was otherwise active and there was no palpable abdominal mass. USG abdomen and CT scan revealed the presence of an encapsulated solid hepatic tumor suggestive of HB. Complete blood count showed an elevated WBC count, high ESR and high α-fetoprotein levels (958 ng/ml) but no thrombocytosis. A nonanatomical excisional biopsy of the tumor confirmed it to be hepatoblastoma. The unusual features noticed in this case was presentation at a slightly later age (6 years), absence of abdominal mass and absence of thrombocytosis.

Liver Transplantation for Pediatric Liver Cancer.

Unresectable hepatocellular carcinoma (HCC) was first removed successfully with total hepatectomy and liver transplantation (LT) in a child over five decades ago. Since then, children with unresectable liver cancer have benefitted greatly from LT and a confluence of several equally important endeavors. Regional and trans-continental collaborations have accelerated the development and standardization of chemotherapy regimens, which provide disease control to enable LT, and also serve as a test of unresectability. In the process, tumor histology, imaging protocols, and tumor staging have also matured to better assess response and LT candidacy. Significant trends include a steady increase in the incidence of and use of LT for hepatoblastoma, and a significant improvement in survival after LT for HCC with each decade. Although LT is curative for most unresectable primary liver sarcomas, such as embryonal sarcoma, the malignant rhabdoid tumor appears relapse-prone despite chemotherapy and LT. Pediatric liver tumors remain rare, and diagnostic uncertainty in some settings can potentially delay treatment or lead to the selection of less effective chemotherapy. We review the current knowledge relevant to diagnosis, LT candidacy, and post-transplant outcomes for these tumors, emphasizing recent observations made from large registries or larger series.

Downregulation of SFRP1 is a protumorigenic event in hepatoblastoma and correlates with beta-catenin mutations

BackgroundHepatoblastoma (HB) and pediatric hepatocellular carcinoma (HCC) are the most common malignant liver tumors in childhood. Both tumor types exhibit genetic and epigenetic alterations in the WNT/β-catenin signaling pathway, which is a key regulator of liver progenitor cells in embryonic development. The tumors demonstrate a high rate of β-catenin mutations and gene expression changes of several WNT antagonists. However, the role of the WNT inhibitory factor secreted frizzled-related protein 1 (SFRP1) has not been addressed in pediatric liver cancer so far.ResultsIn our study, we investigated the gene expression level, DNA methylation status and functional relevance of SFRP1 in HB cell lines and in pediatric liver tumor patient samples. SFRP1 was downregulated due to DNA promoter methylation in all tested HB cell lines. Overexpression of SFRP1 in HB cell lines diminished tumor cell proliferation, colony formation and migration potential. In addition, the SFRP1-expressing HB cell lines showed reduced WNT/β-catenin signaling pathway activity and decreased expression of WNT target genes. To evaluate the utility of SFRP1 as a biomarker in pediatric liver cancer, we determined the gene expression level and DNA methylation status of SFRP1 in 45 pediatric liver tumor patient samples. The correlation analysis of different clinical parameters and tumor characteristics revealed a significant correlation of reduced SFRP1 expression with the presence of mutant β-catenin. The methylation status of SFRP1 was furthermore associated to a pediatric liver tumor type with HCC-like characteristics, TERT mutations and an older age at diagnosis.ConclusionAltogether, our data demonstrate that the epigenetic suppression of the WNT/β-catenin antagonist SFRP1 has an important impact on the malignant behavior of HB cells. Although SFRP1 methylation is a common event in HCC-like pediatric liver tumors, its potential as a prognostic or diagnostic biomarker needs to be further investigated.

Cytomorphology of hepatoblastoma with histological correlation and role of SALL4 immunocytochemistry in its diagnosis, subtyping, and prognostication.

Hepatoblastoma (HB) is the most common malignant pediatric liver tumor, and cytology material is often the only tissue available for evaluation before definitive therapy. Subcategorization of HB based on cytomorphological features thus carries an important role in its prognostication. Spalt-like transcription factor 4 (SALL4), a marker of embryonic stem cells that is also found in the fetal liver, is reactivated in certain liver tumors. Limited studies have evaluated its role in HB. This study was aimed at evaluating the cytomorphological features of HB and assessing the utility of SALL4 immunocytochemistry (ICC) in its subtyping and prognostication. Pretherapy fine-needle aspiration smears from patients diagnosed with HB over a period of 9years were retrieved. Aspirates were subclassified on the basis of the cytomorphology and were correlated with the histology wherever it was available. ICC for SALL4 was performed in 33 cases, and nuclear staining was considered positive. A total of 53 HB cases were included with 30 available postchemotherapy resection specimens. All the patients were diagnosed asepithelial HB on cytology, and the cases were subclassified as pure fetal (9 of 53), pure embryonal (2 of 53), or combined epithelial HB (42 of 53). There was good concordance between cytology and histology for subtyping. SALL4 immunostaining displayed strong and diffuse nuclear positivity in the embryonal component whilefocal and weak to negative staining in fetal cells. Fine-needle aspiration cytology serves as a rapid and effective tool for a correct diagnosis of HB before the implementation of chemotherapy, and SALL4 may serve as a useful diagnostic and prognostic marker.

Malignant Rhabdoid Tumor, an Aggressive Tumor Often Misclassified as Small Cell Variant of Hepatoblastoma.

The clinical management of pediatric liver tumors involves stratification into risk groups. One previously defined, high-risk group of hepatoblastomas is the small cell undifferentiated variant. In light of molecular studies showing SMARCB1 deletion in these tumors, it is now recognized that most small cell, undifferentiated liver tumors represent an aggressive unrelated tumor—the malignant rhabdoid tumor (MRT). SMARCB1 is a member of the chromatin remodeling SWI/SNF complex and encodes the INI1 protein. The histologic diagnosis of MRT is currently based on INI1 negative immunoreactivity and the presence of rhabdoid morphology. INI1-negative small cell liver tumors lacking classic rhabdoid morphology are often misclassified as small cell undifferentiated hepatoblastomas (SCUD-HB), according to the current classification. Pediatric liver tumors diagnosed between 2003–2017 as SCUD-HB (four cases) or MRT (two cases) were identified from the Columbia University Pathology Department Archives. All tumors were associated with normal or low serum alpha fetoprotein levels, and showed an absence of immunohistochemical staining of hepatocellular markers (Hep-par1, Arginase) and loss of INI1 staining. Two cases were initially diagnosed as MRT, one with prominent rhabdoid morphology, the other with predominant small cell morphology. The remaining four cases with small cell morphology were classified as SCUD-HB. Ancillary molecular studies confirmed the loss of SMARCB1, supporting the diagnosis of MRT in all cases, proving morphology an unreliable criterion. It is critical to eliminate the term INI1-negative hepatoblastoma from the current classification scheme, and classify INI1-negative tumors as MRT, particularly since high-risk HB-chemotherapy regimens are not effective for treating MRT.

Late toxicities, especially second malignancies, with GWAS analysis in hepatoblastoma cases treated in the Japanese study group for pediatric liver tumor protocol-2.

10043 Background: This study focused on late toxicities, especially second malignancies (SMNs), experienced by patients with hepatoblastoma (HB) treated with CITA (cisplatin and pirarubicin) in the Japanese Study Group for Pediatric Liver Tumor protocol-2 (JPLT-2). Methods: In the JPLT-2, 361 children with HB were eligible for inclusion. We evaluated late effects including ototoxicity, cardiotoxicity and SMN in these patients. PRETEXT I/II patients were typically treated by initial resection at diagnosis followed by CITA. Otherwise, patients received preoperative CITA, followed by surgery and postoperative chemotherapy. Non-responders to CITA received ITEC (ifosfamide, pirarubicin, etoposide, and carboplatin) or intensified chemotherapeutic regimens. In 267 patients whose germline DNA samples were available, genotyping analysis was performed using the Illumina Human Omni Express Exome-8 v.1.3 BeadChip. Associations between single nucleotide polymorphisms (SNPs) and toxicities were assessed using logistic regression analysis. Results: Among the patients (n = 300) who survived more than 5 years, ototoxicity was detected in 61 and cardiotoxicity in 18. The presence of ototoxicity was associated with a significantly higher dose of cisplatin, and the Brock grade of ototoxicity was correlated with the total dose of cisplatin (P < 0.01). SMNs occurred in 13 patients (9 leukemia, 1 myelodysplastic disease, 1 lymphoma, 1 Ewing sarcoma and 1 thyroid tumor). The total dose of pirarubicin in SMN cases was significantly higher than those without SMNs (P = 0.035). The mean age at onset of HB was 13 months in the patients with SMNs and 23.3 months in the other patient (P = 0.12). However, two-way analysis of variance showed that SMN occurrence was significantly correlated with the age of HB onset and the total dose of pirarubicin (P < 0.0001). We identified ten inherited SNPs, including six SNPs associated with ototoxicity such as ACYP2, two SNPs associated with cardiotoxicity and two candidate SNPs associated with SMNs. Conclusions: The total dose of cisplatin was significantly associated with ototoxicity development. A low incidence of cardiotoxicity but high rates of SMTs, which were correlated with a high dose of pirarubicin and younger age at diagnosis, were found in this study. We also identified SNPs associated with SMNs in HB. Our study provides strong evidence that germline mutation may modify the effect of chemotherapy for childhood cancers on late toxicities, especially during early childhood. Clinical trial information: UMIN000001116.

Modeling and identifying therapeutic targets in Hepatoblastoma.

e21518 Background: Hepatoblastoma, an aggressive pediatric liver tumor, most often affects young children under five years of age. Surgical resection and chemotherapy have saved many children’s lives; yet, the overall five-year survival rate is 70%, and worse for children who present with unresectable tumors. Addressing the clinical need for HB-targeted therapies requires a better understanding of how HB tumors maintain their tumorigenic potential. Recent studies suggest that YAP1, the transcriptional co-regulator, and the Wnt/β-catenin pathway cooperate for HB tumor initiation. Further YAP1 is hyperactivated in nearly 80% of children’s HB tumors; however, will YAP1 inhibition result in therapeutic benefit for pediatric patients? Methods: To assess the role of YAP1 signaling in HB tumor maintenance, we generated a conditional mouse model of HB driven by doxycycline-inducible YAP1S127A and constitutively active β-Catenin. Delivery of doxycycline induces YAP1S127A expression and mice develop HB tumors within six weeks. After tumor formation, doxycycline is withdrawn, turning off YAP1 expression, and tumor progression is monitored using in vivo bioluminescent imaging. Results: Here we show in our conditional mouse model of HB that YAP1 is essential for tumor maintenance. In vivo YAP1 withdrawal leads to > 90% tumor regression within 10 weeks. Transcriptional analyses reveal that YAP1 withdraw in regressing tumors potently induces hepatocyte differentiation and metabolism genes, including HNF4a and FoxA2 target genes. Conclusions: Establishment of a luminescent conditional model of HB provides a new platform to critically address and explore therapeutic vulnerabilities in HB. Specifically, our data suggest HB tumor maintenance requires YAP1. Finally, in vivo tumor regression following YAP1 withdraw serves as preclinical evidence for the therapeutic potential of YAP1 inhibitory therapies in children with HB.

Evaluation of the diagnostic biopsy approach for children with hepatoblastoma: A report from the children’s oncology group AHEP 0731 liver tumor committee

BackgroundThe histopathological assessment of pediatric liver tumors at presentation is critical to establish a diagnosis, guide treatment, and collect appropriate research samples. The purpose of this study was to evaluate complications associated with different approaches to liver biopsy for newly diagnosed hepatoblastoma. MethodsChildren with hepatoblastoma were enrolled on Children's Oncology Group study AHEP0731 (September 2009–March 2012). This analysis evaluated the study cohort of initially unresectable patients who therefore underwent a biopsy procedure at diagnosis. The primary endpoint was clinically significant postbiopsy hemorrhage, defined as requiring red blood cell transfusion. ResultsWe identified 121 children who underwent open (n = 76, 63%), laparoscopic (n = 17, 14%), or percutaneous (n = 28, 23%) liver biopsies. All biopsy procedures yielded adequate tissue for diagnosis. Postbiopsy hemorrhage requiring transfusion occurred after 26% (n = 31) of biopsies. Need for blood product transfusion most frequently occurred following open (n = 27/76, 36%) and laparoscopic (n = 4/17, 24%) biopsies, compared with percutaneous (n = 0/28, 0%) biopsies (p < 0.01). ConclusionsPretreatment biopsy of pediatric liver tumors via a percutaneous approach yielded the lowest frequency of clinically significant hemorrhage requiring transfusion, without evidence of sacrificing diagnostic accuracy. Level of EvidenceLevel I.

PP2A activation alone and in combination with cisplatin decreases cell growth and tumor formation in human HuH6 hepatoblastoma cells.

Despite an increase in incidence, treatments for hepatoblastoma remain virtually unchanged for the past 20 years, emphasizing the need for novel therapeutics. FTY720 (fingolimod) is an immunomodulator approved for use in multiple sclerosis in children that has been demonstrated to have anti-cancer properties in multiple cancer types. We have demonstrated that FTY720 activates PP2A in hepatoblastoma, but does not do so via inhibition of the endogenous inhibitors, CIP2A and I2PP2A, as previously observed in other cancers. PP2A activation in hepatoblastoma decreased cell viability, proliferation, and motility and induced apoptosis. In a subcutaneous xenograft model, FTY720 decreased tumor growth. FTY720 in combination with the standard chemotherapeutic, cisplatin, decreased proliferation in a synergistic manner. Finally, animals bearing subcutaneous hepatoblastoma xenografts treated with FTY720 and cisplatin in combination had significantly decreased tumor growth compared to those treated with either drug alone. These findings show that targeting PP2A with FTY70 shows promise in the treatment of hepatoblastoma and that combining FTY720 with cisplatin may be a novel and effective strategy to better treat this devastating pediatric liver tumor.

Targeting excessive MYCN expression using MLN8237 and JQ1 impairs the growth of hepatoblastoma cells.

Hepatoblastoma (HB) is the most common liver tumor in children under the age of 3years worldwide. While many patients achieve good outcomes with surgical resection and conventional chemotherapy, there is still a high‑risk population that exhibits a poor treatment response and unfavorable prognosis, which warrants the search for novel treatment options. In recent years, it has become clear that genetic events alone are not sufficient to explain the aggressive phenotype of this embryonal malignancy. Instead, epigenetic modifications and aberrant gene expression seem to be key drivers of HB. In the present study, expression analyses such as reverse transcription‑quantitative polymerase chain reaction revealed that the oncogene, MYCN proto‑oncogene basic‑helix‑loop‑helix transcription factor (MYCN) was upregulated in HB and other pediatric liver tumors, due to the transcriptional activity of its antisense transcript MYCN opposite strand (MYCNOS). Pyrosequencing demonstrated the hypomethylated regions in the promoter of MYCN and MYCNOS, suggesting that an epigenetic mechanism may underlie the induction of aberrant expression. Transient MYCN knockdown in HB cells resulted in growth inhibition over time. In addition, treating HB cells with the MYCN inhibitors JQ1 and MLN8237 led to the significant downregulation of MYCN either at the mRNA or protein levels, respectively. The underlying mechanism of action of the two inhibitors was revealed to be associated with the induction of dose‑dependent growth arrest, by arresting cells at either the G1/G0 or G2 phase. Furthermore, MLN8237 and JQ1 were able to cause spindle disturbances and/or apoptosis in HB cells. The present results suggest that MYCN may be a promising biomarker for HB and a potential therapeutic target in patients with tumors overexpressing MYCN.

03:00 PM Abstract No. 411 A slice of normal liver in pediatric liver tumors: do we need it?

Histologic evaluation of focal liver disease and mass lesions can be challenging. In a pediatric population, inadequate sampling or unclear diagnosis can lead to repeat biopsies that require general anesthesia. Adding non-lesional liver tissue (NLT) or transitional liver tissue (TLT) to standard biopsy procedures may aid pathologists in reaching a diagnosis. We aim to evaluate the safety, outcomes, and utility of adding NLT/TLT to evaluate pediatric liver lesions. Chart review revealed 36 liver lesion biopsies occurred from January 2016 to July 2018 at a tertiary care children’s hospital. Results were screened for NLT and TLT cases with exclusion of transplant patients (n=14). TLT was defined as the interface between radiologically NLT and the lesion of concern. A non-lesional liver sample was obtained using a 16- or 18-gauge coaxial system, before positioning the needle into the lesion. Among 10 boys and 4 girls (mean age 9.0 years, range 1–19 years), fine-needle aspiration (FNA) (mean 2.1 FNAs per procedure), NLT core biopsy (mean 1.6 cores), TLT core biopsy (mean 2.0 cores), and lesional core biopsy (mean 5.9 cores) were performed. NLT/TLT sample utility was subjectively evaluated by a pathologist. NLT was abnormal in 3 patients and normal in 11 patients. The pathologist reviewing these patients found NLT/TLT helpful in all cases, even if the tissue was normal. Only a single case (7.1%) required 2 separate incisions to obtain NLT and lesional tissue. On average, 2.6 additional core biopsies were performed to obtain NLT or TLT. All biopsies led to a final diagnosis without further tissue sampling. Pre- and post-procedural hemoglobin demonstrated no significant changes over 24 hours (p>.05). No intraprocedural or post-procedural complications were observed. In one case, comparison of NLT to the lesion enabled pathologists to identify malignant features within the NLT, aiding in the diagnosis of early metastatic neuroendocrine tumor. Obtaining additional NLT/TLT during a liver mass biopsy is not only safe, but also beneficial in making an accurate diagnosis. However this study is limited due to the small sample size and possible subjective bias of pathologists.

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.

Reactive Ductules Are Associated With Angiogenesis and Tumor Cell Proliferation in Pediatric Liver Cancer.

While reactive ductules (RDs) have been observed in viral hepatitis, biliary atresia, nonalcoholic fatty liver disease, and adult hepatocellular carcinoma (HCC), RDs in pediatric liver cancer remain uncharacterized. This study investigated the relationship of RDs with angiogenic paracrine factors, the extent of angiogenesis, and tumor cell proliferation in pediatric hepatoblastoma (HBL)/HCC livers. We quantified the extent of RDs and their expression of paracrine factors that include vascular endothelial growth factor (VEGF), vascular endothelial growth factor D (VEGFD), platelet‐derived growth factor C, and angiopoietin 1 (ANGPT1). In addition, we performed immunohistochemical detection of the endothelial marker clusters of differentiation (CD)34 and the proliferation marker Ki67 followed by correlation analyses. In HBL, we found the percentage of RDs with Ki67 expression (% Ki67+ RDs) significantly correlated with intratumoral Ki67+ areas (r = 0.5138, P = 0.0349) and % ANGPT1+ RDs positively correlated with % Ki67+ RDs (r = 0.5851, P = 0.0136). In HCC, the high ANGPT1+ RDs group (i.e., cases with % ANGPT1+ RDs ≥50) exhibited high intratumoral Ki67+ areas compared to the low ANGPT1+ RDs group. In the combined HBL and HCC liver tumor group, there was a positive association between % platelet‐derived growth factor C+ RDs and intratumoral Ki67+ areas (r = 0.4712, P = 0.0099) and the high VEGFD+ RDs group (≥50%) exhibited a high number of peritumoral CD34+ vessels compared to the low VEGFD+ RDs group. Conclusion: Paracrine factor‐expressing RDs are associated with angiogenesis and proliferation of pediatric liver tumors.

Survival and delayed effects of risk-stratified hepatoblastoma patients treated in the JPLT-2 trial.

10524Background: The Japanese Study Group for Pediatric Liver Tumor (JPLT) -2 trial (2000-2012) has been conducting to evaluate the efficacy of the CITA regimen, consisting of cisplatin/pirarubicin...

Tracking cellular and molecular changes in a species-specific manner during experimental tumor progression in vivo.

Hepatoblastoma (HBL) is a pediatric liver cancer with defined molecular alterations driving its progression. Here, we describe an animal model for HBL on the chick chorioallantoic membrane (CAM), which recapitulates relevant features of HBL in patients. Expression of classic tumor-associated proteins such as β-catenin, EpCAM and CK19 was maintained in acini-like organized tumors on CAM, as was synthesis of AFP, a tumor marker used for monitoring patient response. RNA sequencing revealed an unexpected molecular evolution of HBL cells on the CAM, with significant deregulation of more than 6,000 genes including more than half of all HOX genes. Bioinformatic analysis distinguish between tumor cell-expressed genes and chick genes, thereby shedding new light on the complex interactions taking place during HBL progression. Importantly, human tumor suppressive ribosomal genes were downregulated after implantation, whereas mitochondrial genes encoding for anti-apoptotic peptides were strongly induced in vivo. Meprin-1α expression was increased during evolution of CAM tumors and confirmed by immunohistochemistry. Cisplatin, a commonly used chemotherapeutic agent for HBL, showed significant anti-tumoral effects. Our results broaden the understanding of the molecular adaptation process of human cancer cells to the microenvironment and might help to elaborate novel therapeutic concepts for the treatment of this pediatric liver tumor.