Fibrolamellar variant of hepatocellular carcinoma does not have a better survival than conventional hepatocellular carcinoma--results and treatment recommendations from the Childhood Liver Tumour Strategy Group (SIOPEL) experience.

PURPOSE: Fibrolamellar hepatocellular carcinoma (FL-HCC) and conventional hepatocellular carcinoma (HCC) cases in two consecutive paediatric HCC trials were analysed to compare outcome and derive treatment implications. PATIENTS AND METHODS: Data of 24 FL-HCC (24% PRETEXT IV) and 38 HCC (42% PRETEXT IV) cases from SIOPEL-2 and -3 (1995-1998, 1998-2006) were analysed. Patients were treated according to SIOPEL-2 and -3 high-risk protocol (carboplatin+doxorubicin alternating with cisplatin; seven preoperative, three postoperative cycles) or with primary surgery followed by chemotherapy as indicated. RESULTS: Thirteen of 24 FL-HCC (54%) and 32/38 HCC (84%) were initially treated with chemotherapy. Eight FL-HCC (33%) and five HCC patients (13%) had primary surgery. Partial response was observed in 31% of FL-HCC versus 53% of HCC patients (p=0.17). Complete resection was achieved in ten FL-HCC and seven HCC patients (p=0.08). Three-year event free survival (EFS) was 22% for FL-HCC versus 28% for HCC. Overall survival (OS) was not significantly different at 3 years follow up (42% for FL-HCC versus 33% for HCC, p=0.24). EFS/OS Kaplan-Meier curves did not differ significantly, with median follow up of 43 (FL-HCC) and 60 (HCC) months. No significant correlation was found between potential prognostic factors and OS. In the entire cohort nine out of 23 (39%) patients with complete resection or orthotopic liver transplantation versus 34/39 (87%) without successful surgical treatment, died. CONCLUSIONS: Long-term OS in FL-HCC and HCC is similar. With low response rates, complete resection remains the treatment of choice.

Risk-adapted treatment for childhood hepatoblastoma. final report of the second study of the International Society of Paediatric Oncology--SIOPEL 2.

SIOPEL 2 was a pilot study designed to test the efficacy and toxicity of two chemotherapy (CT) regimens, one for patients with hepatoblastoma (HB) confined to the liver and involving no more than three hepatic sectors ('standard-risk (SR) HB'), and one for those with HB extending into all four sectors and/or with lung metastases or intra-abdominal extra hepatic spread 'high-risk (HR) HB'. SR-HB patients were treated with four courses of cisplatin (CDDP), at a dose of 80 mg/m(2) every 14 days, delayed surgery, and then two more similar CDDP courses. HR-HB patients were given CDDP alternating every 14 days with carboplatin (CARBO), 500 mg/m(2), and doxorubicin (DOXO), 60 mg/m(2). Two courses of CARBO/DOXO and one of CDDP were given postoperatively. Between October 1995 and May 1998, 77 SR-HB (10 of whom were actually treated with the HR protocol) and 58 HR-HB patients were registered and all 135 could be evaluated. Response rates for the entire SR-HB and HR-HB groups were 90% (95% CI 80-96%) and 78% (95% CI 65-87%), and resection rates were 97% (95% CI 87-99%) and 67% (95% CI 54-79%) including several children undergoing liver transplantation. For SR-HB patients, 3-year overall and progression-free survivals were 91% (+/-7%) and 89% (+/-7%) and for the HR-HB group 53% (+/-13%) and 48% (+/-13%), respectively. The short-term toxicity of these regimens was acceptable, with no toxic deaths. A treatment strategy based on CDDP monotherapy and surgery thus appears effective in SR-HB but, despite CT intensification, only half of the HR-HB patients are long-term survivors. For SR-HB patients, the efficacy of CDDP monotherapy and the CDDP/DOXO ('PLADO') combination are now being compared in a prospective randomised trial (SIOPEL 3).

Liver transplantation for hepatoblastoma: results from the International Society of Pediatric Oncology (SIOP) study SIOPEL-1 and review of the world experience.

BACKGROUND: For hepatoblastoma (HB) that remains unresectable by partial hepatectomy after chemotherapy, total hepatectomy with orthotopic liver transplantation (LTX) has been advocated as the best treatment option. The role of LTX in the overall management of HB is still, however, unclear. PROCEDURE: The results of LTX from the first study of HB by the International Society of Pediatric Oncology, SIOPEL-1, were analyzed. In addition, the world experience of LTX for HB was extensively reviewed. Twelve patients in the SIOPEL-1 study underwent a LTX. Median (range) follow-up at Dec. 31, 2001 was 117 months (52-125) since LTX. RESULTS: Overall survival at 10 years post-LTX was 85% for the seven children who received a "primary LTX" and 40% for the 5 children who underwent a "rescue LTX" after previous partial hepatectomy. In the world experience (147 cases), the overall survival rate at 6 year post-LTX was 82% for 106 patients who received a "primary LTX" and 30% for 41 patients who underwent a "rescue LTX." Multivariate analysis of patients undergoing primary LTX showed that only macroscopic venous invasion had a significant impact (P-value: 0.045 with a hazard ratio of 2.96) on overall survival. CONCLUSIONS: Orthotopic LTX has added a new dimension to the treatment of HB unresectable by partial hepatectomy. Because of the rarity of the disease and to optimize results, children with extensive HB should be treated in centers with surgical expertise in pediatric major liver resection and LTX, in close collaboration with pediatric oncologists, radiologists, and histopathologists.

The epidemiology of neonatal tumours. Report of an international working group.

Neonatal tumours occur every 12,500-27,500 live births and comprise 2% of childhood malignancies, but there is little clarity as to their real prevalence, sites of origin and pathological nature as reported series vary. As an entity, neonatal tumours provide a unique window of opportunity to study tumours in which minimal environmental interference has occurred. The majority of tumours present with a mass at birth (e.g., teratomas, neuroblastomas, mesoblastic nephroma, fibromatosis), which are not infrequently identified on antenatal ultrasound. Histologically, teratoma and neuroblastoma remain the two main tumour types encountered with soft tissue sarcoma, renal tumours, CNS tumours and leukaemia being the next most common tumour types identified. Malignant tumours are uncommon in the neonatal period per se and benign tumours may have malignant potential. A particular problem exists in clinical classification, as histological features of malignancy do not always correlate with clinical behaviour. Benign tumours may also be life threatening because of their size and location. Other tumours may demonstrate local invasiveness, but no metastatic potential, and tumours that are clearly malignant may demonstrate unpredictable or uncertain behaviour. Screening programmes have brought more tumours to light, but do not appear to affect the overall prognosis. They may provide clues to the stage at which tumours develop in foetu. The aetiology of cancer in children is multifactorial and includes both genetic and environmental factors. The association between congenital abnormalities and tumours is well established (15% of neonatal tumours). Genetic defects are highly likely in neonatal tumours and include those with a high risk of malignancy (e.g., retinoblastoma), but also genetically determined syndromes with an increased risk of malignancy and complex genetic rearrangements. Tumours are mostly genetically related at a cellular level and factors influencing cellular maturation or apoptosis within the developing foetus may continue to operate in the neonatal period. Cytogenetics of neonatal neoplasms appear to differ from neoplasms in older children, thus possibly explaining some of the observed differences in clinical behaviour. Certain constitutional chromosome anomalies, however, specifically favour tumours occurring in the foetal and neonatal period. In support of this hypothesis, certain cytogenetic anomalies appear to be specific to neonates, and a number of examples are explored. Other environmental associations include ionizing radiation, drugs taken during pregnancy, infections, tumours in the mother and environmental exposure.

Hepatoblastoma and low birth weight: a trend or chance observation?

BACKGROUND: Several reports have suggested an association between prematurity and hepatoblastoma (HB). PROCEDURE: Data were collected by questionnaires from 105 children with HB enrolled in a Children's Cancer Group (CCG) study. RESULTS: Observed over expected rates were increased about 2- and 15+-fold for prematurity (<37 weeks at birth) and low birth weight (<1,000 g) respectively. Similar data were derived from a later CCG study of 36 HB children. CONCLUSIONS: Early reports of a possible association between prematurity and HB have been confirmed.

Hepatocellular carcinoma in children: results of the first prospective study of the International Society of Pediatric Oncology group.

PURPOSE: To improve survival and reduce operative morbidity and mortality in children with primary epithelial liver tumors by using preoperative chemotherapy, as well as to collect information on the epidemiology, natural history, and prognostic factors. PATIENTS AND METHODS: Forty children with hepatocellular carcinoma (HCC) were registered onto the Group for Epithelial Liver Tumors International Society of Pediatric Oncology's first study from January 1990 to February 1994. The outcome could be analyzed in 39 of those patients. Disease was often advanced at the time of diagnosis; metastases were identified in 31% of the children and extrahepatic tumor extension, vascular invasion, or both in 39%. Multifocal tumors were common (56%). Thirty-three percent of tumors were associated with hepatic cirrhosis. All but two patients received preoperative chemotherapy (cisplatin and doxorubicin). RESULTS: Partial response was observed in 18 (49%) of 37 patients; there was no response or progression in the remainder. Complete tumor resection was achieved in 14 patients (36%). Twenty patients (51%) never became operable. Overall survival at 5 years was 28%, and event-free survival was 17%. Most deaths resulted from tumor progression (26 of 28). Presence of metastases and pretreatment extent of disease system grouping at diagnosis had an adverse influence on overall survival in multivariate analysis. CONCLUSION: Survival for pediatric HCC patients is significantly inferior to that for children with hepatoblastoma. Complete tumor excision remains the only realistic chance of cure, although it is often prevented by advanced disease. The presence of metastases is the most potent predictor of poor prognosis. A prospective worldwide cooperation in the field of pediatric HCC should be encouraged to look for novel therapeutic concepts.

Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology.

PURPOSE: Hepatoblastoma (HB) is a rare malignant liver tumor which occurs almost exclusively in childhood. In the 1970s, survival was approximately 20% to 30%. Since the introduction of cisplatin (PLA) and doxorubicin (DO) into the chemotherapy regimens used to treat these patients, the survival rate has improved dramatically. In most recent studies, primary surgery preceded chemotherapy. In this study by the liver group of the International Society of Pediatric Oncology the aim was to improve survival and reduce operative morbidity and mortality by using preoperative chemotherapy. PATIENTS AND METHODS: After biopsy and assessment of pretreatment extent of disease all patients were treated with continuous 24-hour intravenous infusion of PLA 80 mg/m(2) followed by DO 60 mg/m(2) over 48 hours (PLADO). After four courses of this chemotherapy, patients were reassessed. Where possible, the primary tumor was resected and treatment completed with two more courses of chemotherapy. RESULTS: One hundred fifty-four patients were registered in the study, and 138 received preoperative chemotherapy. One hundred thirteen (82%) showed a partial response with tumor shrinkage and serial decrease of serum alpha-fetoprotein levels. One hundred fifteen patients had delayed surgery, and 106 (including six with liver transplants) had complete resection of primary tumor. Five-year event-free survival was 66%, and overall survival was 75%. CONCLUSION: This study demonstrates that international collaboration on a large scale is feasible. The toxicity of chemotherapy and morbidity of surgery were acceptable and the overall survival gratifyingly high. We now regard PLADO chemotherapy and delayed surgery to be the best available treatment for children with HB. Other treatment programs should be measured against this standard.

Hepatoblastoma presenting with lung metastases: treatment results of the first cooperative, prospective study of the International Society of Paediatric Oncology on childhood liver tumors.

BACKGROUND: The prognosis of children who are affected by hepatoblastoma (HB) that presents with lung metastases has always been considered very poor. In light of the overall improvement in the survival of HB patients since the introduction of cisplatin (CDDP) in the therapeutic armament of this tumor, the question has been raised whether patients with metastatic HB also would benefit from this drug. The purpose of the current study was to address this issue by analyzing the treatment outcome of those patients presenting with metastases who entered into the first HB study on childhood liver tumors conducted by the International Society of Paediatric Oncology (SIOPEL 1). METHODS: SIOPEL 1 was a prospective, international, multicentric, single-arm study based on preoperative chemotherapy that was open to patient registration from January 1990 to February 1994. After undergoing a biopsy, patients received four courses of CDDP (80 mg/m(2) in a 24-hour, continuous infusion) on Day 1 followed by doxorubicin (60 mg/m(2) in a 48-hour, continuous infusion) on Days 2 and 3 (PLADO). Surgery was performed after four courses of PLADO and was followed by two more courses. Untreated children age < 16 years with biopsy-proven HB were eligible for the study. Metastatic spread was assessed by chest X-ray and, where available, lung computed tomography scan. RESULTS: Thirty-one of 154 children that entered into the trial presented with metastases. Eight children presently are alive with no evidence of disease (NED) after being treated with protocol therapy only (median follow-up, 60 months); nine children are alive with NED after having failed PLADO and having been rescued with alternative therapies (median follow-up, 80 months). The 5-year overall and event free survival rates for these children were 57% (95% confidence interval, 39-75%) and 28% (95% confidence interval, 12-44%), respectively. Persistent lung disease was the main reason for PLADO failure (17 of 23 patients; 74%). CONCLUSIONS: The SIOPEL 1 therapeutic strategy seems to cure 25% of the HB patients who present with metastases. However, further chemotherapy and the use of thoracotomies still can save significant numbers of these children.

Pretreatment prognostic factors for children with hepatoblastoma-- results from the International Society of Paediatric Oncology (SIOP) study SIOPEL 1.

The aim of this study was to investigate the prognostic significance of pretreatment patient and tumour characteristics for overall (OS) and event-free (EFS) survival in 154 children affected by hepatoblastoma (HB) in the first prospective liver tumour study run by the International Society of Paediatric Oncology. The pretreatment characteristics studied were age, alpha-fetoprotein, platelet count, histology; from radiology: intrahepatic tumour extension (PRETEXT), lung metastases, enlarged hilar lymph nodes, vena cava or extrahepatic vena porta tumour extension and tumour focality. Five-year OS was 75% (95% confidence interval (CI) 68-82%) and EFS 66% (95% CI 59-74%). Both were univariately associated with PRETEXT and the presence of metastases. Additionally tumour focality and enlargement of hilar lymph nodes at diagnosis were univariately associated with EFS. In multivariate analysis, PRETEXT was the only predictor of OS; PRETEXT and metastases were predictors of EFS. There is a need to investigate further these factors to confirm their validity.

SIOPEL trials using preoperative chemotherapy in hepatoblastoma.

Hepatoblastoma is a rare, malignant liver tumour of childhood. Until the mid 1980s only around 30% of patients were cured, but with modern chemotherapy, and of course surgery, the cure rate is now at least 70%. This dramatic improvement in survival has been achieved by the national and international cooperation of paediatric oncology centres. The International Society of Paediatric Oncology Liver Tumour Group, in contrast to most other groups, has used preoperative chemotherapy in all patients, followed by delayed surgery. The group has also developed a novel staging system, called PRETEXT (PRE Treatment EXTent of disease), based on the anatomy of the liver and radiological findings at diagnosis, to try to predict resectability and outcome.

Hepatoblastoma Presenting with Lung Metastases Treatment Results of the First Cooperative, Prospective Study of the International Society of Paediatric Oncology on Childhood Liver Tumors

The prognosis of children who are affected by hepatoblastoma (HB) that presents with lung metastases has always been considered very poor. In light of the overall improvement in the survival of HB patients since the introduction of cisplatin (CDDP) in the therapeutic armament of this tumor, the question has been raised whether patients with metastatic HB also would benefit from this drug. The purpose of the current study was to address this issue by analyzing the treatment outcome of those patients presenting with metastases who entered into the first HB study on childhood liver tumors conducted by the International Society of Paediatric Oncology (SIOPEL 1). SIOPEL 1 was a prospective, international, multicentric, single-arm study based on preoperative chemotherapy that was open to patient registration from January 1990 to February 1994. After undergoing a biopsy, patients received four courses of CDDP (80 mg/m(2) in a 24-hour, continuous infusion) on Day 1 followed by doxorubicin (60 mg/m(2) in a 48-hour, continuous infusion) on Days 2 and 3 (PLADO). Surgery was performed after four courses of PLADO and was followed by two more courses. Untreated children age < 16 years with biopsy-proven HB were eligible for the study. Metastatic spread was assessed by chest X-ray and, where available, lung computed tomography scan. Thirty-one of 154 children that entered into the trial presented with metastases.

Eight children presently are alive with no evidence of disease (NED) after being treated with protocol therapy only (median follow-up, 60 months); nine children are alive with NED after having failed PLADO and having been rescued with alternative therapies (median follow-up, 80 months). The 5-year overall and event free survival rates for these children were 57% (95% confidence interval, 39-75%) and 28% (95% confidence interval, 12-44%), respectively. Persistent lung disease was the main reason for PLADO failure (17 of 23 patients; 74%). The SIOPEL 1 therapeutic strategy seems to cure 25% of the HB patients who present with metastases. However, further chemotherapy and the use of thoracotomies still can save significant numbers of these children.

Focal nodular hyperplasia of the liver in children: review of follow-up and outcome.

The authors used a conservative approach to treat focal nodular hyperplasia of the liver (FNH) and were interested in the long-term results of different therapeutic approaches in order to establish the most appropriate treatment. A review of the literature was conducted, and 31 pediatric case reports were identified in which follow-up and outcome data were noted. Tumor resection was performed in 18 cases (58%), operative biopsy alone in nine (29%), vascular ligation in two, and embolization of hepatic arteries in two. The outcome appears to be good for both groups of patients, ie, those with observation alone and those with resection. More information is to be collected regarding the new procedures (embolization and ligation). This is a retrospective analysis, and data from future international prospective studies are needed.

[Rhabdomyosarcoma of the prostate and bladder in a child: radical or conservative surgery?]. / Rhabdomyosarkom der Prostata und Blase beim Kind: radikale oder konservative Chirurgie?

Rhabdomyosarcoma is the most common soft-tissue tumor in childhood. In infants it is frequently localized in the pelvis and in the prostata or bladder region. The aim of treatment should be to eradicate the tumor and yet maintain as normal function as possible. Effective preoperative chemotherapy has enabled one to frequently achieve this aim. We report on two patients both with a rhabdomyosarcoma of the bladder-prostata. One of them in 1983 was operated and treated with chemotherapy and cysto-prostatectomy and the other in 1991 with chemotherapy and eradication of the tumor without cystectomy. Both children are now tumor-free after 10 years/2 years resp. Both approaches are discussed.

Prostatic utricle: an unusual case report.

A 3-year-old white patient was hospitalized for the second recurrence of an epididymitis but this time with a left scrotal abscess. He was known to have a perineoscrotal hypospadias associated with bilateral undescended testis. Cystoscopy with cytourethrography releaved the presence of a "prostatic utricle". At operation after treatment of the infection the utricle was exised. Surprisingly a vagina masculinus (vagina, uterus and fallopian tubes without ovaries) more than a conventional utricle was found.