Pediatric Liver Tumors Research Articles

Diagnostic and prognostic impact of β-catenin alterations in pediatric liver tumors

Hepatoblastoma (HBL), a major childhood malignant neoplasm, represents the most frequent malignant liver tumor in childhood. Recent reports have shown the CTNNB1 coding beta-catenin protein to be frequently mutated or deleted at hot-spot regions involving exon 3 in HBL. We investigated the genetic alterations of the CTNNB1 coding beta-catenin protein and expression of several genes downstream of Wnt signals in 4 benign and 17 malignant pediatric liver tumors (PLTs) consisting of 15 HBL, 1 hepatocellular carcinoma, and 1 hepatic immature sarcoma. Of 17 malignant PLTs, 10 (56%) revealed pathogenic alterations of the CTNNB1 gene, including 4 with missense mutations at codons 28, 32, 34 or 44, and 6 with interstitial deletions that partially or totally affected exon 3. All 6 deletions were in-frame deletions without a frame shift. The high frequency without any correlation to histological type indicates that the CTNNB1 gene alteration is a crucial event in the tumorigenesis of malignant PLTs. The immunohistochemical studies in 17 malignant PLTs demonstrated the nuclear/cytoplasmic accumulation of beta-catenin to be positive in all tumor specimens except for one hepatic sarcoma. A histological examination revealed all HBL cases involving tumors without detectable CTNNB1 gene alterations to show high expression of beta-catenin, thus indicating the accumulation of beta-catenin to be a common event in malignant PLTs, including HBL and hepatocellular carcinoma. Among the Wnt signal genes downstream of beta-catenin, E-cadherin is expressed in all malignant PLTs, while cyclin D1 expression was significantly detected in malignant PLTs with an advanced stage of disease. An immunohistological examination of nuclear accumulation of beta-catenin may thus be useful for diagnosing malignant PLTs. On the other hand, the expression of cyclin D1, a gene downstream of beta-catenin, might play a role in tumor progression.

147 INVITED Proteomics of lung cancer

This article aims to give an overview of pediatric liver tumors; in particular of the two most frequently occurring groups of hepatoblastomas and hepatocellular carcinomas. Focus lays on achievements gained through worldwide collaboration. We present recent advances in insight, treatment results, and future questions to be asked. Increasing international collaboration between the four major Pediatric Liver Tumor Study Groups (SIOPEL/GPOH, COG, and JPLT) may serve as a paradigm to approach rare tumors. This international effort has been catalyzed by the Children’s Hepatic tumor International Collaboration (CHIC) formation of a large collaborative database. Interrogation of this database has led to a new universal risk stratification system for hepatoblastoma using PRETEXT/POSTTEXT staging as a backbone. Pathologists in this international collaboration have established a new histopathological consensus classification for pediatric liver tumors. Concomitantly there have been advances in chemotherapy options, an increased role of liver transplantation for unresectable tumors, and a web portal system developed at www.siopel.org for international education, consultation, and collaboration. These achievements will be further tested and validated in the upcoming Paediatric Hepatic International Tumour Trial (PHITT).

Pre-operative diagnostic biopsy and surgery in paediatric liver tumours—the Amsterdam experience

Aim To report 24 years of pre-treatment biopsy and surgical experience in primary liver tumours in children. Methods Between 1979 and 2003, 53 children presented with a primary liver tumour of whom 48 who underwent surgical resection were evaluated (two died, two were unresectable, and one was transplanted). Biopsy data, per- and post-operative complications, mortality, and survival were retrospectively reviewed. Results Benign tumours were diagnosed in eight patients. Surgical resection for a malignant tumour was performed in 40 patients (26 hepatoblastomas (HB), eight hepatocellular carcinomas (HCC) (four had fibrolamellar HCC), three rhabdomyosarcomas (RMS), one neuroblastoma, one non-hodgkin lymphoma (NHL), and one teratoma). Primary resection was performed in one HB, and four HCCs. The cumulative survival without evidence of disease was 73% for HB (median 7 years) and 88% for HCC (median 3.5 years). Conclusion The treatment results are comparable with those of larger international series except for HCC. The existing diagnostic pitfalls in differentiating between the various liver malignancies justify the use of a diagnostic biopsy.

The emerging family of hepatoblastoma tumours: From ontogenesis to oncogenesis

The identification of distinct types and subtypes of hepatoblastoma has led to a successful classification of these lesions. In recent years, and particularly within large tumour trials, the spectrum of paediatric epithelial liver tumours has increased. This, together with the need for defining clinically relevant risk groups, will require a new approach to defining and classifying these cancers. Furthermore, an impressive amount of molecular biological information on liver ontogenesis and growth regulation of hepatic tumours has recently accumulated, which will allow the development of a comprehensive classification system with particular emphasis on prognostics. In this review, novel findings relating to these issues are discussed.

Tumor angiogenesis and its clinical significance in pediatric malignant liver tumor

To investigate the expression of vascular endothelial growth factor (VEGF) and microvascular density (MVD) count in pediatric malignant liver tumor and their clinical significances. Fourteen children with malignant liver tumors including seven hepatocellular carcinomas (HCCs), five hepatoblastomas, one malignant mesenchymoma and one rhabdomyosarcoma were studied. Twelve adult HCC samples served as control group. All samples were examined with streptavidin-biotin peroxidase (SP) immunohistochemical staining for VEGF expression and MVD count. VEGF positive expression in all pediatric malignant liver tumors was significantly higher than that in adult HCC (0.4971+/-0.14 vs 0.4027+/-0.03, P<0.05). VEGF expression in pediatric HCC group was also markedly higher than that in adult HCC group (0.5665+/-0.10 vs 0.4027+/-0.03, P<0.01) and pediatric non-HCC group (0.5665+/-0.10 vs 0.4276+/-0.15, P<0.05). The mean value of MVD in pediatric malignant liver tumors was significantly higher than that in adult HCC (33.66+/-12.24 vs 26.52+/-4.38, P<0.05). Furthermore, MVD in pediatric HCC group was significantly higher compared to that in adult HCC group (36.94+/-9.28 vs 26.52+/-4.38, P<0.05), but there was no significant difference compared to the pediatric non-HCC group (36.94+/-9.28 vs 30.37+/-14.61, P>0.05). All 7 children in HCC group died within 2 years, whereas the prognosis in pediatric non-HCC group was better, in which two patients survived more than 5 years. Children with malignant liver tumors, especially with HCC, may have extensive angiogenesis that induces a rapid tumor growth and leads to a poor prognosis.

Desmoplastic Nested Spindle Cell Tumor of Liver

We describe a distinctive tumor of the liver in four children composed of nested spindled and epithelioid cells with extensive desmoplasia that we have termed "desmoplastic nested spindle cell tumor of the liver." All four patients were previously healthy. One patient had a presumptive diagnosis of hepatic hemangioma 11 years prior to presentation. Grossly, the tumors were well circumscribed, lobular white masses, ranging from 2.8 to 15 cm in diameter. These tumors were characterized by the presence of cohesive nests of plump, bland spindle cells arranged in short fascicles with an accompanying desmoplastic stroma. Epithelioid areas ranging from palisading epithelioid cells at the periphery of some nests to pseudoglandular and polygonal cells with intercellular bridges were invariably present. Mitotic activity was low. Calcification and ossification were present. Non-neoplastic bile ducts and hepatic elements were seen both within and surrounding the tumor cell nests. Each tumor displayed cytoplasmic reactivity for vimentin, pan-cytokeratin, CD57, and nuclear staining for WT1. Neuroendocrine markers were negative. Ultrastructurally, the tumor cells showed focally well-developed cell junctions, basal lamina, and few cytoplasmic organelles. All tumors were confined to the liver and were resected without complication. Two patients received postoperative adjuvant therapy for presumed hepatoblastoma. The patients are doing well without recurrence at 7.5 years, 7 years, 5 years, and 8 months post-surgery. The morphologic appearance and immunohistochemical profile of these lesions are unique in our experience and represent a new category of pediatric liver tumor.

Stem-like Cells in Human Hepatoblastoma

Hepatoblastoma is a pediatric liver tumor with epithelial components resembling embryonal and fetal liver cells. The existence of teratoid hepatoblastoma suggests the presence of stem cells in hepatoblastoma. The aim of this study was to analyze the expression of stem cell markers in hepatoblastomas. We studied specimens from 10 hepatoblastomas. Five of the hepatoblastomas were of epithelial and five of mixed type. Immunohistochemistry (IHC) for the stem cell markers CD34, Thy1, c-kit, and the hepatic or biliary lineage markers CK-18, OCH, CK-7, and CD56 was performed. Double IHC for stem cell and lineage markers was used to identify putative liver stem cells. The different markers showed distinct distributions on the tumor cells. Cells in atypical ducts were found to express simultaneously stem cell markers and hepatocytic or biliary lineage markers. Other cells in connective tissue showed c-kit expression, but not hepatic or biliary marker expression. The data show the presence of different cell populations bearing stem cell markers in human hepatoblastoma. Ductal cells co-expressing stem cell markers and hepatic lineage markers phenotypically resemble hepatic stem-like cells. These findings support the thesis that stem cells play a role in the histogenesis of hepatoblastoma.

High expression of telomerase is an independent prognostic indicator of poor outcome in hepatoblastoma

Telomerase, an enzyme related with cellular immortality, has been extensively studied in many kinds of malignant tumours for clinical diagnostic or prognostic utilities. Telomerase activity is mainly regulated by the expression of hTERT (human telomerase reverse transcriptase), which is a catalytic component of human telomerase. To evaluate whether the levels of hTERT mRNA provides a molecular marker of hepatoblastoma malignancy, we examined hTERT mRNA expression levels in the primary hepatoblastoma tissues by fluorescent RT–PCR using LightCycler technology and followed up the clinical outcomes in 63 patients listed in the Japanese Study Group of Pediatric Liver Tumor between 1991 and 2002. The hTERT mRNA expression was detected in 61 (96.8%) specimens and their expression levels ranged between 0.1/1000 and 745.1/1000 copies of PBGD gene that was used as an internal control. Among these cases, frozen 39 tumour samples and 14 adjacent noncancerous liver tissues were analysed for semiquantitative telomerase assay. In the 39 tumour samples, the levels of telomerase activity ranged between 0.11 and 2709 TPG and 12 (30.7%) had high telomerase activity (>100 TPG), whereas only nine of 14 noncancerous liver tissue samples showed telomerase activity which was less than 1.0 TPG. The levels of telomerase activity were significantly correlated with the levels of hTERT mRNA expression (P<0.001). The frequency of high hTERT mRNA expression and/or high telomerase activity did not significantly associate with the clinicopathological factors except for stage of disease. The prognosis of the patients with high hTERT mRNA expression was significantly worse than that of others (P<0.01), as was the patients with high telomerase activity (P<0.01). Multivariate analysis indicated that high levels of hTERT mRNA expression as well as telomerase activity are independent prognosis-predicting factors in patients with hepatoblastoma.

Analysis of treatment outcome for children with recurrent or metastatic hepatoblastoma: T. Matsunaga, F. Sasaki, M. Ohira, et al. Pediatr Surg Int 19:142–146, (May), 2003

Hepatoblastoma is the third most common malignant abdominal tumor in children. Favorable prognosis and increased survival rate have been reached by combined surgical and chemotherapeutic treatment. The authors analyzed the outcome of refractory tumors registered by the Japanese study group for pediatric liver tumors. From 1991 to 1999, 134 children were registered with a median follow-up of 75 months for the 98 survivors. The protocol for stage 1 or 2 cases (tumor of 1 or 2 liver segments) included 6 cycles of postoperative chemotherapy with cisplatin and Adriamycin. A subgroup received 1 cycle as intraarterial preoperative chemotherapy. In stage 3 or 4 cases (tumor of 3 to 4 liver segments or distant metastasis), a double dose, 6 cycle chemotherapy was given; 3 to 4 cycles were applied preoperatively via intra-arterial or intravenous lines. One hundred and fourteen nonmetastatic cases had a 3-year survival rate of 76%. The recurrence rate was 13.3% (12 recurrences). In limited disease (stage 1 or 2), total resection was followed by 6 recurrences. Two cases had preoperative; and 4 cases had postoperative chemotherapy. In advanced disease (stage 3 and 4), total resection was possible in 87% of cases with preoperative intra-arterial chemotherapy and in 67% with an intravenous chemotherapy. Six recurrent cases followed intra-arterial (4x; 30%) or intravenous (2x; 5,5%) chemotherapy. Four hepatic recurrences were treated surgically with pre- (1 case) or postoperative (3 cases) chemotherapy and were doing well 17 months later. Seven of 8 pulmonary recurrences were resected with pre- (5 cases) or postoperative (2 cases) chemotherapy. One child with bilateral metastasis was resected on one side only. One bilateral recurrence was not resected and died, as well as the other bilateral and one unilateral case. Five children survived and at 13 months were doing well. Twenty metastatic cases had a 3-year survival rate of 52%. Chemotherapy was applied according to tumor stage as mentioned above. The liver tumor was resected completely in 11 cases. In 7 of them, metastases disappeared with chemotherapy, 2 were resected, and in 2 incomplete resection of metastases was followed by chemotherapy. Nine of these 11 children were alive more than 2 years later. Nine children with incomplete or not resected liver tumors died. Preoperative chemotherapy leads to a higher number of resectable tumors. Concerning this aspect, intra-aterial versus intravenous chemotherapy, there was a considerable, but not significant difference. Recurrent tumors often are resistent to chemotherapy. Therefore, in nonmetastatic cases the authors recommend preoperative intravenous chemotherapy followed by surgery. Recurrences should first be resected followed by chemotherapy. Bilateral pulmonary recurrences seem to be lethal. In metastatic disease, lung metastasis often are controlled by chemotherapy and surgery. Generally, the overall survival rate depends on the extent of the primary tumor.

Impact of surgical and immunological parameters in pediatric liver transplantation: a multivariate analysis in 500 consecutive recipients of primary grafts.

To assess the respective impact of surgical and immunologic factors on patient/graft outcome and rejection after pediatric liver transplantation. Orthotopic liver transplantation (OLT) constitutes a validated therapeutic modality for acute liver failure and end-stage liver disease in children. Only a few large studies of factors influencing outcome of pediatric OLT are available in the literature. Studies considering the impact of rejection on graft outcome are scarce in adult OLT and are not even available for pediatric recipients. Five hundred consecutive pediatric recipients (<15 years) of a primary OLT performed between March 1984 and July 2000 were retrospectively reviewed. The main indication was biliary atresia (n = 328). A living related donor graft was used from July 1993 onwards in 82 children (16%). Survival was calculated and multivariate analysis was performed. Actuarial survival rates at 1, 5, and 10 years were 85%, 81%, and 79% for patients, and 76%, 71%, and 70% for grafts, respectively. At the multivariate analysis, only 3 factors were found to be independently correlated with better patient survival: year of transplantation (P = 0.001), pretransplant diagnosis (P < 0.001, worst results for liver tumors), and ABO matching (P < 0.001, worst results for ABO incompatibility). Similarly, 3 factors were independently correlated with better rejection-free graft survival: tacrolimus as primary immunosuppressant (P < 0.001), a negative T-cell crossmatch (P = 0.016), and younger age of the donor (P < 0.001). Pediatric OLT constitutes a complex undertaking with multifactorial impact on results: (1). a strong learning curve effect was shown to impact on overall results; (2). pediatric liver tumors still represent a challenging indication for OLT; (3). primary immunoprophylaxis with tacrolimus provided a lower rejection incidence; (4). the younger donor age effect deserves further immunologic investigations.

Is a modified central bisegmentectomy a volume-saving operation for pediatric hepatoblastoma?

The authors report on an 11-month-old girl who presented with a hepatoblastoma. The tumor was located in Couinaud’s segments IV, V, VII, and VIII. She received adjuvant chemotherapy in accordance with the Japanese Study Group for Pediatric Liver Tumor Protocol-2, and the tumor thereafter showed a partial response, involving segments IV and VIII. She thereafter underwent a modified central bisegmentectomy (segments IV, VIII, and a part of V). The postoperative course was uneventful, and the patient is now doing well 22 months after the operation. The authors consider the central bisegmentectomy to be a volume-saving operation, and, based on a volumetric analysis, the estimated preserved volume of the functioning liver parenchyma was determined to be 87%. However, if using a right trisegmentectomy, the preserved volume was estimated to only be 44%. The authors consider a central bisegmentectomy to be a useful alternative operation for patients with centrally located hepatoblastoma to minimize both morbidity and mortality.

Hepatectomy in Children under Total Hepatic Occlusion

Major ablative hepatic resection is often indicated in children with solid liver tumors, and reduction of operative blood transfusion is a primary goal. Total hepatic occlusion (THO) is an effective method that is well established in adults, yet its role in children is less well described. We describe our preliminary experience with THO in children assessing surgical outcome. The charts of seven children (ages 5 months to 7 years, weight 6-30 kg) who underwent THO during hepatectomy (four right and three left lobectomies) for liver tumors (hepatoblastoma in three, metastatic Wilm's tumor in two, mesenchymal hamartoma in one, and angiosarcoma in one) between January 1997 and June 2002 were reviewed. THO was established in all cases by clamping the supra- and infrahepatic inferior vena cava and the porta hepatis. Surgical parameters assessed included: 1) warm ischemia time, 2) operative blood transfusion, 3) operative complications, and 4) tumor resection margins. THO was successful in six of the seven cases (85.7%). In one case systemic hypotension unresponsive to fluid resuscitation developed at the outset with THO requiring conversion to pedicle clamping to perform the hepatectomy. Mean warm ischemia time during THO was 26 minutes (range 18-45 minutes). Mean estimated blood loss was 221 cm3 (range 50-800 cm3). Operative blood transfusion was required in one of six patients (15 cm3/kg). Excluding the "failed" THO case (intraoperative hypotension) there were no significant intraoperative or postoperative complications. All seven children had curative resections as indicated by "tumor-free" microscopic margins. We conclude that total hepatic occlusion can be performed safely and successfully for pediatric liver tumors. Operative blood transfusion appears to be minimized.

Pediatric liver tumors

The role of US has not changed significantly in pediatric liver tumors. Detection and characterisation is still the primary role. Follow up the patients after surgery and/or chemotherapy in case of malignancy. Results of interventional radiology treatments (RF, laser, cryoablation) can be followed by US. Characterisation of the liver tumors remains a challenge for US, and additional methods are needed. Tissue harmonic imaging and SonoCT can improve the ability to identify liver masses and analyse their structure. Color Doppler is of little help in the differential diagnosis of solid masses, and power Doppler is seldom useful. Very little data are available about the use of US contrast agents in pediatric patients with liver tumors. Panoramic US images and 3D US may be helpful to present the results for consultation. Helical CT and/or MR are frequently needed for further workup before treatment. One of the most difficult tasks of imaging is the differentiation between residual liver tumors and recurrencies in case of hepatoblastoma or metastatic liver disease. The differentiation between various benign and malignant pediatric liver masses is sometimes extremely difficult due to the overlap of so-called typical signs. To select the imaging modality of choice in a given case needs a clear understanding of the strength and weaknesses of the radiology imaging methods. Learning objectives: 1) overview of the strength and and weaknesses of US in pediatric patients with various liver masses and tumor-like lesions; and 2) brief overview on the US appearance of the most typical pediatric liver tumors.

Hypermethylation of the p16 Gene and Lack of p16 Expression in Hepatoblastoma

Hepatoblastoma is the most frequent pediatric liver tumor that develops mostly in young children. Abnormal regulation of cell cycle regulatory genes including p16 has been described, displaying no p16 mRNA and p16 protein in hepatoblastomas. The inactivation of p16, leading to the disruption of cell cycle control is involved in many types of human malignancies. However, the mechanism of the p16 inactivation in hepatoblastomas has not yet been elucidated. In this present study, we examined the methylation status of the p16 gene promoter by using methylation-specific PCR in 24 cases of hepatoblastomas and in 20 cases of corresponding non-neoplastic liver tissue. Aberrant methylation of 5′ CpG islands of p16 was present in 12 of 24 (50.0%) cases of hepatoblastoma. Clinicopathologic parameters were not associated with the methylation status of p16. To correlate the methylation status of p16 with the expression of p16, immunohistochemical staining was done in tumors and non-neoplastic liver tissue. All non-neoplastic liver tissues displayed moderate, but heterogeneous immunoreactivity for p16. Eight of 12 (66.6%) methylation-positive hepatoblastomas showed a complete lack of immunoreactivity for p16. The other 4 methylation-positive hepatoblastomas had heterogeneous immunoreactivity. Nine of 12 (75.0%) unmethylated cases of hepatoblastoma displayed diffuse immunoreactivity, whereas 3 cases of unmethylated hepatoblastoma were not immunostained for p16. Our data indicate that the hypermethylation of p16 is a major mechanism of the transcriptional repression of p16 in hepatoblastomas, and we suggest that the inactivation of p16, leading to the lack of p16, may play an important role in the tumorigenesis of hepatoblastomas.

Pediatric liver tumors and hepatic ontogenesis: common and distinctive pathways.

Several types of pediatric liver tumors exhibit structural features apparently reflecting processes which normally occur during hepatic ontogenesis: some hepatoblastomas mimic distinct phases of hepatogenesis, including the formation of mesenchymal structures closely associated with immature epithelia, and there are tumors almost exclusively consisting of complex mesenchymal patterns. Current classifications of hepatoblastomas refer to the identification of more or less mature (differentiated) single or mixed components seen in histologic preparations. These do not, however, attempt to integrate ontogenic pathways, in contrast for example, to nephroblastoma and associated lesions, where such a view has proved to be highly fruitful. Based on the fact that an enormous amount of knowledge has recently been accumulated regarding hepatic ontogenesis, time may have come to look at these tumors with a new eye. In what follows, we aim at trying to analyze distinct features of pediatric hepatic tumors (except vascular tumors) within the background of ontogenesis. Some key steps of hepatogenesis and the regulatory factors involved may, in the future, deliver an armamentarium to search for novel molecular mechanisms involved in tumorigenic pathways.

The influence of preoperative chemotherapy and surgical technique in the treatment of hepatoblastoma--a report from the German Cooperative Liver Tumour Studies HB 89 and HB 94.

Despite the success of chemotherapy in the treatment of hepatoblastoma (HB), the complete surgical resection of the primary liver tumour and metastases is the most important factor for survival. From 1989 to 1998, 141 children with HB were treated in the German Cooperative Paediatric Liver Tumour Study HB 89 and HB 94. The study determines the results of surgical strategy, which adapts the procedure at the initial operation to the tumour extension in the liver and the occurrence of metastases. The median follow-up of the survivors was 72 months (range 24 - 132 months). 98/141 (78 %) patients were alive and 31/141 (22 %) died. 12/141 (8.5 %) children had no surgical treatment. A complete resection of the primary tumour was achieved in 107/129 (83 %) cases. Forty-eight children were primary resected and eighty-one children were operated on after initial chemotherapy. In 36 cases, an atypical tumour resection, in 90 cases an anatomical liver resection, was performed. Three children were transplanted. There was no perioperative death. 14/48 (30 %) children with primary tumour resection had microscopical or macroscopical residual tumour in the liver. Despite the larger number of advanced HB in the primary chemotherapy group, an incomplete tumour resection was performed in only 15/78 (19 %) cases after liver resection (p < 0.044). 14/36 (38 %) cases with atypical tumour resection and only 16/90 (18 %) cases with anatomical liver resection had residual tumours in the liver (p < 0.019). These results underline the necessity for preoperative chemotherapy in all HB, which was accepted in the following study HB 99. Atypical tumour resection should be avoided because of the higher rate of incomplete tumour resections and local relapse compared to the group with anatomical tumour resection.

Pretreatment prognostic factors and treatment results in children with hepatoblastoma: a report from the German Cooperative Pediatric Liver Tumor Study HB 94.

In the past 20 years, a dramatic improvement in the prognosis of patients with hepatoblastoma (HB) has been achieved by combining surgery with chemotherapy in several national and international trials. A worldwide, unsolved problem remains the treatment of patients with advanced or metastatic HB. The German Cooperative Pediatric Liver Tumor Study HB 94 was a prospective, multicenter, single-arm study. The study ran from January 1994 to December 1998. The protocol assessed the efficiency of chemotherapy consisting of cisplatin, ifosfamide, and doxorubicin (CDDP/IFO/DOXO) and/or etoposide and carboplatin (VP16/CARBO). The prognostic significance of the surgical strategy, pretreatment factors, and tumor characteristics for disease free survival (DFS) were analyzed. Sixty-nine children with HB were treated in the HB 94 study. The median follow-up of survivors was 58 months (range, 32-93 months). Fifty-three of 69 patients (77%) remained alive, and 16 of 69 patients (23%) died. Long-term DFS was as follows: 26 of 27 patients had Stage I HB, 3 of 3 patients had Stage II HB, 19 of 25 patients had Stage III HB, and 5 of 14 patients had Stage IV. A complete resection of the primary tumor was achieved in 54 of 63 patients (86%). Six children (8%) had no surgical treatment. Twenty-two tumors were resected primarily, and 41 children underwent surgery after initial chemotherapy. Two children underwent liver transplantation. There was no perioperative death. Forty-eight children received primary chemotherapy with CDDP/IFO/DOXO. Forty-one of 48 children achieved partial remission after CDDP/IFO/DOXO. Eighteen children with advanced or recurrent HB underwent VP16/CARBO chemotherapy, with a response achieved by 12 children. The relevant pretreatment prognostic factors were growth pattern of the liver tumor (P = 0.0135), vascular tumor invasion (P = 0.0039), occurrence of distant metastases (P = 0.0001), initial alpha-fetoprotein level (P = 0.0034), and surgical radicality (P < 0.0001). The current results underline the necessity of preoperative chemotherapy in all children with HB. Complete tumor resection is one of the main prognostic factors.

Outcome of hepatoblastoma treated with the JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: A report from the Japanese Study Group for Pediatric Liver Tumor

Purpose: Hepatoblastoma is the most common malignant liver tumor in childhood. Multicenter studies elucidate the optimal pre- or postoperative chemotherapeutic regimens. This report reviews the results of the Japanese Study Group for Pediatric Liver Tumor Protocol-1 (JPLT-1) and compares its outcomes with published reports of other studies. Methods: From March 1991 to December 1999, 154 patients with malignant liver tumor including 145 cases of hepatoblastomas were enrolled in the JPLT study. Data from 134 cases were analyzed in this study. JPLT-1 protocol 91A was used for patients with stage I or II hepatoblastoma. The chemotherapy regimen consisted of repeated courses of cisplatin (CDDP), 40 mg/m2, and tetrahydropyranyl (THP)-Adriamycin, 30 mg/m2. JPLT-1 protocol 91B was administered to patients with stage IIIA, IIIB, or IV hepatoblastoma. The chemotherapy regimen consisted of repeated courses of CDDP, 80 mg/m2, and THP-Adriamycin, 30 mg/m2/day for 2 days. Courses were repeated every 4 weeks as tolerated. Results: Seven patients died of chemotherapy-related side effects. Six of them died of sepsis caused by leukopenia and 1 case of liver failure. Overall survival rate (3-year/6-year) was 100%/100% for stage I (n = 9), 100%/95.7% for stage II (n = 32), 76.6%/73.8% for stage IIIA (n = 48), 50.3%/50.3% for stage IIIB (n = 25), 64.8%/38.9% for stage IV (n = 20), and 77.8%/73.4% overall. For stage IIIA and B disease, intravenous chemotherapy was better than intraarterial chemotherapy (66.4% v 38.1% for event-free survival and 69.3% v. 57.1% for overall survival). Patients less than 1 year of age had a better prognosis than older patients, but age was not a significant prognostic factor by multivariate analysis. Conclusions: The overall and event-free survival rates of the JPLT-1 study of hepatoblastoma were comparable with the results of other multicenter studies in Europe and the United States. The event-free survival rate at 3 years for stage IIIB and IV disease was under 50%. New treatment strategies are needed for patients with advanced hepatoblastoma. J Pediatr Surg 37:851-856. Copyright 2002, Elsevier Science (USA). All rights reserved.

Surgical view of the treatment of patients with hepatoblastoma

Surgical resection is the cornerstone of treatment for patients with hepatoblastoma (HB). The Society of Pediatric Oncology Liver Tumor Study Group launched its first prospective trial (SIOPEL-1) with the intention to treat all patients with preoperative chemotherapy and delayed surgical resection. The objective of this article was to assess the assumed surgical advantages of primary chemotherapy. Between 1990 and 1994, 154 patients age < 16 years with HB were registered on SIOPEL-1. The pretreatment extent of disease was assessed, and, after undergoing biopsy, patients were treated with cisplatin 80 mg/m(2) intravenously over 24 hours and doxorubicin 60 mg/m(2) intravenously over 48 hours by continuous infusion (PLADO). Generally, tumors were resected after four of a total of six courses of PLADO. One hundred twenty eight patients underwent surgical resection (13 patients underwent primary surgery, and 115 patients underwent delayed surgery after PLADO). A pretreatment surgical biopsy was performed in 96 of 128 patients (75%). Biopsy complications occurred in 7 of 96 patients (7%). Twenty-two patients showed pulmonary metastases at the time of diagnosis, and 7 patients underwent thoracotomy. Operative morbidity and mortality were 18% and 5%, respectively. Complete macroscopic surgical resection was achieved in 106 patients (92%), including 6 patients who underwent orthotopic liver transplantation. The actuarial 5-year event free survival (EFS) rate for all 154 patients in the study was 66%, and the overall survival (OS) rate was 75%. For the 115 patients who were included in the surgical analysis that followed the exact protocol, the EFS and OS rates were 75% and 85%, respectively. Biopsy is a safe procedure and should be performed routinely. Preoperative chemotherapy seems to make tumor resection easier. Reresection of a positive resection margin does not necessarily have to be performed, because postoperative chemotherapy showed good results. Resection of lung metastases can be curative if there is local control of the primary tumor; however, results showed that the patient's prognosis was worse. Surgical morbidity or mortality rates were not necessarily higher in large multicenter studies. More importantly, countries of lesser economic status also can contribute effectively to these trials.

Stromal predominant type mesenchymal hamartoma of liver: CT and MR features

Mesenchymal hamartoma is a rare pediatric liver tumor. The tumor is mainly cystic but occasionally a solid component is seen. Therefore the tumor can be divided into two forms: (a) cystic predominant, and (b) stromal predominant. In this report, CT and MR features of stromal predominant type mesenchymal hamartoma are presented.