Age-Dependent Presentation and Clinical Course of 1465 Patients Aged 0 to Less than 18 Years with Ovarian or Testicular Germ Cell Tumors; Data of the MAKEI 96 Protocol Revisited in the Light of Prenatal Germ Cell Biology.

OBJECTIVE: To evaluate prognostic factors in pediatric patients with gonadal germ cell tumors (GCT). METHODS: Patients <18 years with ovarian and testicular GCT (respectively OGCT and TGCT) were prospectively registered according to the guidelines of MAKEI 96. After resection of the primary tumor, patients staged ≥II received risk-stratified cisplatin-based combination chemotherapy. Patients were analyzed in respect to age (six age groups divided into 3-year intervals), histology, stage, and therapy. The primary end point was overall survival. RESULTS: Between January 1996 and March 2016, the following patients were registered: 1047 OGCT, of those, 630 had ovarian teratoma (OTER) and 417 had malignant OGCT (MOGCT); and 418 TGCT, of those, 106 had testicular teratoma (TTER) and 312 had malignant TGCT (MTGCT). Only in MTGCT, older age correlated with a higher proportion of advanced tumors. All 736 teratomas and 240/415 stage I malignant gonadal GCT underwent surgery and close observation alone. In case of watchful waiting, the progression rate of OGCT was higher than that of TGCT. However, death from disease was reported in 8/417 (1.9%) MOGCT and 8/312 (2.6%) MTGCT irrespective of adjuvant chemotherapy and repeated surgery. CONCLUSIONS: The different pathogenesis and histogenesis of gonadal GCT reflects sex- and age-specific patterns that define clinically relevant risk groups. Therefore, gender and age should be considered in further research on the biology and clinical practice of pediatric gonadal GCT.

Leukotriene receptor blockade as a life-saving treatment in severe bronchopulmonary dysplasia.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a major cause of mortality and morbidity in infants with an extremely low birth weight. Because there is no effective therapy, the mortality of this condition in severely affected patients is high. Therapeutic blocking of the leukotriene system seems to be a logical approach due to the known pathophysiology of BPD. OBJECTIVES: The aim of this study was to examine the therapeutic effect of montelukast in preterm children suffering from severe BPD. METHODS: We performed an unblinded, prospective trial including infants born between 23 and 27 weeks of gestation suffering from severe BPD. The study drug was montelukast (1 mg/kg of body weight as a single dose daily in the 1st week of therapy, increasing to 1.5 mg/kg of body weight in the 2nd week and finally to 2 mg/kg of body weight in the 3rd week). Treatment was continued until the radiological signs and the clinical symptoms of BPD disappeared or the patient was discharged from the hospital. Each patient included in this study was matched for gestational age, birth weight, and pulmonary severity score to a control. RESULTS: Until March 2014, a total of 22 infants were enrolled into the study. The rates of the primary outcome differed significantly between the montelukast-treated group and the control group. All but 1 of the children in the treatment group survived (91%), whereas 7 of the 11 children in the control group died (survival rate 36%; p = 0.002 using Fisher's exact test). The mean mechanical ventilation time (41.2 ± 25.3 vs. 103.7 ± 90.6 days) was significantly shorter and the mean preterm complication score (3.0 ± 1.7 vs. 5.6 ± 1.4) was significantly lower in treated patients compared to the control group. (p = 0.05 for both items; Wilcoxon's matched-pairs test). CONCLUSION: Based on the clinical observations, the statistical results, and the relatively low risk of the study drug montelukast, we recommend using this treatment in severe cases of BPD for infants facing a high risk of death.

Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults.

PURPOSE: To improve risk-adapted therapy for localized childhood soft tissue sarcoma within an international multicenter setting. PATIENTS AND METHODS: Four hundred forty-one patients younger than 21 years with localized rhabdomyosarcoma and rhabdomyosarcoma-like tumors (ie, extraosseous tumors of the Ewing family, synovial sarcoma, and undifferentiated sarcoma) were eligible. Therapy was stratified according to postsurgical stage, histology, and tumor site. In unresectable tumors, treatment was further adapted depending on response to induction chemotherapy, TN classification, tumor size and second-look surgery. A novel five-drug combination of etoposide, vincristine, dactinomycin, ifosfamide, and doxorubicin (EVAIA) was evaluated for high-risk patients, but cumulative chemotherapy dosage and treatment duration were reduced for the remaining individuals as compared with that of the previous trial CWS-86. Hyperfractionated accelerated radiotherapy (HART) was recommended at doses of either 32 or 48 Gy. RESULTS: At a median follow-up of 8 years, 5-year event-free survival (EFS) and overall (OS) survival for the entire cohort was 63% +/- 4% and 73% +/- 4%, respectively (all survival rates in this abstract are calculated and displayed with +/-95% CI). EFS/OS rates by histology were 60% +/- 5%/72% +/- 5% in rhabdomyosarcoma, 62% +/- 10%/69% +/- 10% for Ewing tumors of soft tissues, 84% +/- 12%/90% +/- 10% for synovial sarcoma, and 67% +/- 38%/83% +/- 30% for undifferentiated sarcoma, respectively. Response to one cycle of the five-drug combination EVAIA was similar to that of the four-drug combination VAIA used in CWS-86. Two hundred twelve patients with rhabdomyosarcoma underwent radiation (EFS, 66% +/- 6%); 53 of those patients had a favorable risk profile and received 32 Gy of HART (EFS, 73% +/- 12%). TN classification, tumor site, tumor size, histology, and age were prognostic in univariate analysis. CONCLUSION: Improved risk stratification enabled decreased therapy intensity for selected patients without compromising survival. Intensified chemotherapy with EVAIA did not improve outcome of localized high-risk rhabdomyosarcoma.

Germ cell tumors of the head and neck: report from the MAKEI Study Group.

BACKGROUND: Germ cell tumors (GCTs) of the head and neck region are rare but may pose significant problems for perinatal management as well as surgical and adjuvant therapy. PROCEDURE: Thirty-two prospectively reported patients from the German MAKEI studies (Maligne Keimzelltumoren) were analyzed with regard to perinatal management and long-term survival. RESULTS: Twenty-three tumors were diagnosed around birth and four during the first 3 months of life. All were primarily diagnosed as teratomas, but in two tumors, yolk sac tumor (YST) foci were identified. Another pure teratoma was diagnosed at 12 months. Four tumors were diagnosed after the first year of life and showed YST as leading histology. Most neonates presented with huge tumors causing external airway obstruction. All tumors were resected (complete resection, 16/26 patients with complete surgical information; incomplete resection, 10/26 patients). Eight tumors including five of six YSTs were treated with chemotherapy. In total, six patients relapsed. Relapse rate was higher after incomplete (5/10 patients) than after complete resection (1/16 patients). Accordingly, more relapses were observed in pharyngeal than in neck tumors due to incomplete resection. Nevertheless, half of the patients with incomplete resection remained in remission. One patient with YST died after multiple relapses. CONCLUSIONS: GCTs of the head and neck region require a multidisciplinary approach in specialized centers. Most patients with antenatal tumor growth are identified by ultrasound and delivered preterm by cesarian section. After delivery, immediate intubation and ventilation aim for respiratory stabilization, followed by elective resection. With this approach, outcome was favorable.

Nonviable tumor tissue should not upstage Wilms' tumor from stage I to stage II: a report from the SIOP 93-01 nephroblastoma trial and study.

In SIOP trials, Wilms' tumors were labeled as stage II by the presence of nonviable and/or viable tumor in the renal sinus and/or perirenal fat. The aim of this study was to determine if this approach was justified. Stage II Wilms' tumors were reviewed to establish whether staging was due to viable or nonviable tumor, and this was related to clinical outcome. One hundred sixty-nine patients were included: 40 had stage II due to the presence of nonviable tumor and 129 due to viable tumor. Postoperatively, 29 patients were undertreated: 7 with nonviable and 22 with viable stage II tumors. No undertreated patient with nonviable stage II relapsed or died (event-free survival [EFS] and overall survival [OS] 100%), whereas 3 of 22 with viable stage II relapsed, and 2 of them died (EFS 86%, OS 91%). Of 140 correctly treated patients, only 1 of 33 nonviable stage II patients relapsed and died (EFS and OS 97%); 8 of 107 patients with viable stage II relapsed (EFS 92%), and 3 of them died (OS 97%). The presence of nonviable tumor in the renal sinus and/or perirenal fat does not predict an adverse outcome in Wilms' tumors, and alone it does not warrant designation to stage II.

KIT, PDGFRalpha and EGFR analysis in nephroblastoma.

Nephroblastoma prognosis has dramatically improved, but an unfavourable prognostic subgroup warrants development of novel therapeutic strategies. Selective KIT, PDGFRalpha and epidermal growth factor receptor (EGFR) tyrosine kinase inhibition evolved as powerful targeted therapy for gastrointestinal stromal tumours and non-small-cell lung cancer. To investigate a potential role for tyrosine kinase inhibition, we analyzed 209 nephroblastomas for immunohistochemical KIT and EGFR expression, 63 nephroblastomas for mutations in KIT exons 9, 11, 13, EGFR exons 18, 19, 20 and 21, and all 209 nephroblastomas for PDGFRalpha exons 12, 14 and 18. Twenty-two tumours (10.5%) expressed KIT, 31 (14.8%) EGFR, and 10 (4.8%) both KIT and EGFR, respectively. KIT expression was relatively more common among high-risk tumours (6/27; 22.3%) compared to low-/intermediate-risk tumours (26/181; 14.4%). Nine patients deceased, four of which had high-risk tumours with KIT expression in two of four and EGFR expression in one of four. There were no KIT, PDGFRalpha or EGFR mutations. Our results suggest no significant contribution of KIT, EGFR or PDGFRalpha mutations to nephroblastoma pathogenesis. Despite a trend towards association of immunohistochemical KIT and EGFR expression with poor outcome in high-risk nephroblastomas, statistical analysis did not yield significant correlations in this subgroup. Therefore, it remains open if KIT, PDGFRalpha or EGFR tyrosine kinase inhibition constitute a therapeutic target in nephroblastoma in the absence of KIT, PDGFRalpha or EGFR mutations.

Wnt signaling pathway analysis in renal cell carcinoma in young patients.

Renal cell carcinomas in young patients constitute a morphologically and genetically heterogeneous group. Twenty percent belong to the newly recognized Xp11.2 translocation-associated family and rare tumors arise from nephroblastoma. Aberrant Wnt signaling through beta-catenin mutation has been implicated in nephroblastoma pathogenesis and has been found to synergize with WT1 mutations. To characterize Wnt signaling activity in renal cell carcinomas in young patients, we gathered 34 tumors (three clear cell, ten Xp11.2 translocation associated, five papillary, two chromophobe, two collecting duct, one neuroblastoma associated, eight unclassified renal cell carcinomas, and three carcinomas combined with nephroblastoma) from patients less than 22 years. Expression of beta-catenin, its homologue gamma-catenin, and of WT1 was assessed by immunohistochemistry in 30 tumors, and sequence analysis of CTNNB1, CTNNG1, and WT1 genes was performed in 25 tumors. Cytoplasmic beta-catenin accumulation was demonstrated in two papillary carcinomas, one neuroblastoma-associated carcinoma, and two carcinomas arising from nephroblastoma. The pattern of gamma-catenin expression paralleled that of beta-catenin but its signal intensity was lower in 22, equal in 7, and stronger only in 1 tumor, respectively. Four tumors showed nuclear WT1 expression. One Xp11.2 translocation-associated carcinoma presented a rare intronic CTNNB1 single nucleotide polymorphism and cytoplasmic beta-catenin accumulation. There were no further CTNNB1 or CTNNG1 sequence alterations. A WT1 mutation was found in the nephroblastoma component of a carcinoma arising from nephroblastoma. These findings suggest Wnt signaling pathway activation only in a minority of renal cell carcinomas in young patients. CTNNB1 mutations are rare events. Cytoplasmic beta-catenin accumulation in an Xp11.2-associated carcinoma suggests potential interaction of Wnt signaling components with microphthalmia transcription factor family also in Xp11.2 translocation carcinomas. WT1 mutation in the nephroblastoma component of a mixed-type renal cell carcinoma provides direct evidence for clonal independence of nephroblastoma and carcinoma components in this exceptional tumor.

Ovarian small cell carcinoma of the hypercalcemic type in children and adolescents: a prognostically unfavorable but curable disease.

BACKGROUND: Ovarian small cell carcinoma of the hypercalcemic type is a rare neoplasm that is associated with a poor prognosis. The objective of the current study was to investigate the clinicopathologic features of this tumor and to develop preliminary diagnostic and therapeutic guidelines. METHODS: Between 1994 and 2005, 11 girls (ages 9-22 years) who were registered on the German Maligne Keimzelltumoren studies and the Kiel Pediatric Tumor Registry were analyzed. Prior to histopathologic review, 8 patients had been misdiagnosed with either germ cell tumor or juvenile granulosa cell tumor. RESULTS: According to the International Federation of Gynecologic Oncology, 4 patients had Stage IA disease, 3 patients had Stage IC disease, and 4 patients had Stage III disease. After resection, 4 patients were followed without additional therapy, and all 4 patients developed recurrent disease after 3 to 11 months. Seven patients received adjuvant chemotherapy during first-line treatment. One patient with Stage III disease received additional regional deep hyperthermia. During first-line treatment, high-dose chemotherapy was received by 4 patients who achieved a complete response (CR) after conventional chemotherapy. All 4 of those patients remained in CR for 7 to 73 months, whereas the other 3 patients developed recurrent disease. Salvage treatment after recurrence or tumor progression consisted of surgery and chemotherapy. One patient received high-dose chemotherapy in 2nd CR and remained in 2nd CR. In total, 5 patients remained alive with no evidence of disease. CONCLUSIONS: Patients with ovarian small cell carcinoma of the hypercalcemic type require multiagent chemotherapy during first-line treatment. High-dose chemotherapy may be used to consolidate the therapeutic success.

Imbalances of chromosome arm 1p in pediatric and adult germ cell tumors are caused by true allelic loss: a combined comparative genomic hybridization and microsatellite analysis.

Previous studies on childhood germ cell tumors (GCTs) report highly variable frequencies of losses at chromosome arm 1p. Since deletions at 1p portend a poor prognosis in other embryonal tumors, this study aims to clarify the question of the frequency of true allelic loss at 1p and whether it constitutes a prognostic parameter. We analyzed 13 GCTs from different gonadal and extragonadal sites of children (4 teratomas, 9 malignant GCTs) and 18 GCTs of adolescents and adults (3 teratomas; 15 malignant GCTs) using automated microsatellite analysis with 23 polymorphic markers and chromosomal "high resolution" comparative genomic hybridization (HR-CGH). With this combined approach, we detected loss of heterozygosity (LOH) at 1p in 8/9 childhood malignant GCTs with concordant data from HR-CGH and microsatellite analyses. In contrast, LOH at 1p was not detected in childhood teratomas (0/4) and constituted a rare event in GCTs of adolescence and adulthood (3/18). The commonly deleted region was located at distal 1p36-pter, with a proximal boundary between the markers D1S450 and D1S2870. These data unequivocally demonstrate that deletion at 1p is common in childhood GCTs and results in allelic loss. This observation argues for the presence of a classical tumor suppressor at distal 1p. Considering the high frequency of LOH at 1p and the overall favorable prognosis of childhood GCTs, a prognostic impact of LOH at 1p in childhood GCTs appears unlikely. However, since two postpubertal tumors with LOH at 1p progressed, a prognostic relevance in this age group seems possible, warranting a prospective evaluation.

Genetic clonality is a feature unifying nephroblastomas regardless of the variety of morphological subtypes.

Nephroblastomas are embryonal tumors exhibiting a wide variety of different morphological features and genetic changes. Some of the genetic aberrations were associated with a certain histological subtype. It is generally assumed that nephroblastomas develop as subclonal proliferations from nephrogenic rests. However, so far, a very limited amount of tumors from only part of the morphological spectrum of nephroblastomas was investigated. We therefore investigated the clonality of 45 tumors of all different histological subtypes. The number of each subtype was in accordance with the percentage of occurrence of the respective subtype. We analyzed a highly polymorphic locus of the human androgen receptor gene for nonrandom X-inactivation of genomic DNA using a methylation-sensitive restriction enzyme. Data were obtained for 39 tumors. Eighteen of the tumors included were noninformative in the genetic locus examined, the remaining 21 tumors were monoclonal regardless of the histological subtype. Our findings therefore support the hypothesis that Wilms' tumors are monoclonal proliferations despite their large variety of morphological features.

Treatment of severe disseminated juvenile systemic xanthogranuloma with multiple lesions in the central nervous system.

Juvenile xanthogranuloma (JXG), one of the most common forms of Langerhans-dendritic cell proliferation in young children, usually presents as spontaneously regressing cutaneous lesions. JXG with systemic (extracutaneous) involvement is a rare histiocytic disorder in which significant morbidity and death may occur. The systemic type, especially combined with multiple central nervous system lesions in young children, has a very poor prognosis. The patient described here presented with disseminated disease including lungs, liver, kidneys, ribs, scalp, and central nervous system. The patient was treated with multiagent chemotherapy based on the Langerhans cell histiocytosis II treatment protocol. The regimen used included an additional intrathecal therapy with methotrexate and prednisolone to control central nervous system lesions. The patient was treated for 28 months and has been in remission for almost 5 years.

Ovarian sex cord-stromal tumors in children and adolescents.

Ovarian sex cord-stromal tumors (OSCSTs) are a heterogeneous group of tumors that develop from the gonadal non-germ-cell component. Despite recent advances in the clinical and histopathologic diagnosis of OSCSTs, a high degree of uncertainty remains with regard to adequate therapy, particularly in patients presenting with microscopic or macroscopic tumor spread. We review the currently available data on the biology and histology of OSCST in children and adolescents. In addition, we summarize the data from our clinical, histopathologic and genetic analyses of patients that were prospectively reported to the German MAKEI protocols for treatment of nontesticular malignant germ cell tumors. Among these patients, juvenile granulosa cell tumors (JGCTs) constitute the most frequent histologic subtype, followed by Sertoli-Leydig cell tumors (SLCTs) and sclerosing stromal tumors. Patients with JGCT and SLCT show greater mitotic activity than do all those with other histologic types. Furthermore, high mitotic activity is associated with adverse outcome. In addition, prognosis correlates with tumor stage according to the International Federation of Obstetrics and Gynecology. Nevertheless, we observed a favorable response to cisplatin-based chemotherapy in the majority of stage II and III tumors. For the whole cohort of 62 patients, event-free survival was 0.87 +/- 0.05 months and overall survival 0.88 +/- 0.05. Genetic analysis of 27 tumors available for comparative genomic hybridization analysis revealed normal profiles in the majority of tumors and whole chromosomal gain, such as a gain of 12 in single tumors, with no consistent pattern with regard to histology or clinical outcome. This analysis confirmed that most OSCSTs present at a low tumor stage and that prognosis in these patients is excellent. Most important, patients at high risk can be identified through clinical and histopathologic analysis, and the majority can be treated successfully with adjuvant cisplatinum-based chemotherapy. Based on this analysis, a prospective study on OSCST in children and adolescents began recruiting cases in 2005.

Abdominal inflammatory masses mimicking neoplasia in children-experience of two centers.

Despite progress in modern imaging, some inflammatory masses are difficult to distinguish clinically from neoplastic processes. In such cases the pathology report has a great distinctive value, but even then the final diagnosis may be difficult to reach. Eight patients with abdominal tumors of inflammatory origin were treated in two institutions, the Department of Pediatric Surgery of the Medical University of Gdansk, Poland, and Helios Center of Pediatric Surgery in Berlin, Germany, during the last 10 years. Four tumors were located in the pelvis, two in the liver, and two in the colonic mesentery. Five of them were inflammatory pseudotumors (two subclassified as inflammatory fibrosarcoma), one had nonspecific inflammatory changes, one was diagnosed as idiopathic retroperitoneal fibrosis, and one was diagnosed as bacillary angiomatosis. All patients underwent surgical tumor biopsy, excisional in four and incisional in four. All but two children underwent macroscopically complete tumor excision (four primarily, two secondarily). In one case the tumor resolved with antibiotherapy. Surgery in retroperitoneal masses was often extensive and associated with significant complications because of invasive tumor growth. In conclusion, intraabdominal inflammatory lesions may closely mimic neoplasia in children. Clinical doubts result in repeated biopsies, and for this reason excisional biopsy should be preferred. In some cases, when excisional biopsy is not feasible due to invasive growth of the tumor, delayed complete mass excision should follow, despite occasional significant morbidity. The etiology and exact nature of inflammatory pseudotumors are still obscure, and it is unknown whether they represent inflammatory lesions or true neoplasia.

Juvenile xanthogranuloma in childhood and adolescence: a clinicopathologic study of 129 patients from the kiel pediatric tumor registry.

Juvenile xanthogranuloma (JXG) is an uncommon non-Langerhans cell histiocytosis. We investigated 148 biopsy specimens from 129 patients collected in the Kiel Pediatric Tumor Registry (KPTR) between 1965 and 2001. The clinical, histologic, and immunohistochemical characteristics of JXG were evaluated to gain more and deeper insights into the morphology and clinical behavior of JXG. Conventionally stained lesions were classified into the following morphologic subtypes: early JXG (EJXG), classic JXG (CJXG), transitional JXG (TJXG), or combined lesions with more than one basic pattern (combined JXG). Immunohistochemistry included antibodies against macrophages (Ki-M1P), S-100 protein, CD1a, and factor XIIIa (FXIIIa). Clinical data were obtained by means of a standardized questionnaire. The relative incidence of JXG in the KPTR is 0.52%. The male/female ratio was 1.4:1. The mean age was 22.4 months (median, 5 months; range, 0-244 months). A total of 34.5% of the cases of JXG were congenital, and 71.0% of the lesions were diagnosed within the first year of life. Most cases of cutaneous JXG were solitary (81.0%). Five cases (3.9%) presented with visceral (systemic) involvement. Histologically, CJXG was most frequent (47.2%), followed by EJXG (27.1%) and TJXG (16.0%). A total of 9.7% of the lesions represented combined JXG. Histiocytes, including giant cells, were positive for Ki-M1P (100%) and in most cases for FXIIIa (99%). The CD1a and S-100 protein reactions were generally negative. Clinical and follow-up data showed a generally favorable prognosis with a low relapse rate (7.0%) and even complete involution after incomplete resection. Only 1 of 5 patients with widespread congenital systemic disease died after 34 days. JXG is an uncommon, mostly cutaneous, and prognostically favorable histiocytic tumor of infancy. Simple tumor excision is the therapy for choice except in the very rare systemic JXG, in which multimodal chemotherapy is indicated.

Morphologic and molecular characterization of renal cell carcinoma in children and young adults.

A new WHO classification of renal cell carcinoma has been introduced in 2004. This classification includes the recently described renal cell carcinomas with the ASPL-TFE3 gene fusion and carcinomas with a PRCC-TFE3 gene fusion. Collectively, these tumors have been termed Xp11.2 or TFE3 translocation carcinomas, which primarily occur in children and young adults. To further study the characteristics of renal cell carcinoma in young patients and to determine their genetic background, 41 renal cell carcinomas of patients younger than 22 years were morphologically and genetically characterized. Loss of heterozygosity analysis of the von Hippel-Lindau gene region and screening for VHL gene mutations by direct sequencing were performed in 20 tumors. TFE3 protein overexpression, which correlates with the presence of a TFE3 gene fusion, was assessed by immunohistochemistry. Applying the new WHO classification for renal cell carcinoma, there were 6 clear cell (15%), 9 papillary (22%), 2 chromophobe, and 2 collecting duct carcinomas. Eight carcinomas showed translocation carcinoma morphology (20%). One carcinoma occurred 4 years after a neuroblastoma. Thirteen tumors could not be assigned to types specified by the new WHO classification: 10 were grouped as unclassified (24%), including a unique renal cell carcinoma with prominently vacuolated cytoplasm and WT1 expression. Three carcinomas occurred in combination with nephroblastoma. Molecular analysis revealed deletions at 3p25-26 in one translocation carcinoma, one chromophobe renal cell carcinoma, and one papillary renal cell carcinoma. There were no VHL mutations. Nuclear TFE3 overexpression was detected in 6 renal cell carcinomas, all of which showed areas with voluminous cytoplasm and foci of papillary architecture, consistent with a translocation carcinoma phenotype. The large proportion of TFE3 "translocation" carcinomas and "unclassified" carcinomas in the first two decades of life demonstrates that renal cell carcinomas in young patients contain genetically and phenotypically distinct tumors with further potential for novel renal cell carcinoma subtypes. The far lower frequency of clear cell carcinomas and VHL alterations compared with adults suggests that renal cell carcinomas in young patients have a unique genetic background.

Expression of the c-kit receptor characterizes a subset of neuroblastomas with favorable prognosis.

Expression of the c-kit proto-oncogene product in neuroblastomas has been reported, but its clinical relevance is unclear. We determined the expression of c-kit by immunohistochemistry in a series of 155 neuroblastomas with long-term follow-up. The specificity of the reaction was verified by Western blot analysis and quantitative RT-PCR, and exon 11 of the kit gene was screened for mutations by PCR and capillary electrophoresis. No mutations were detected, and transcription of the kit gene correlated with protein expression. c-kit expression was associated with lower tumor stages and a low rate of MYCN amplification. More importantly, it coincided with tumor differentiation (P<0.0001), and portended a favorable outcome with a relative risk of 0.18 (P<0.0001). In a multivariate analysis of event-free survival, loss of c-kit (relative risk 4.25, P<0.0001) was an independent prognostic factor next to INSS stage 4 and before MYCN amplification. It is concluded that c-kit is transcriptionally regulated in neuroblastomas. Its expression likely identifies a subset of neuroblastomas with conserved capacity for differentiation, which may represent the embryonal variety of the disease. Assessment of c-kit may improve prognostic models for neuroblastoma and provide a basis for new therapy concepts.

Epidemiologic analysis of 1,442 children and adolescents registered in the German germ cell tumor protocols.

BACKGROUND: Germ cell tumors (GCTs) constitute a heterogeneous group of tumors that significantly vary with respect to their clinical presentation and biology. The objective of this analysis was to analyze a large population-based pediatric cohort of GCTs and to evaluate the parameters age, sex, site of the tumor, histology, and potential correlations between these parameters. PROCEDURE: Between 1981 and 2000, 1,442 patients were prospectively enrolled onto the German protocols for testicular and non-testicular GCTs. Tumors were histologically classified according to the WHO. RESULTS: We observed a bimodal age distribution with a first peak during infancy and a second after the onset of puberty. At birth, almost all tumors were teratomas, sometimes with microfoci of yolk sac tumor, which on the other hand, was the predominant histology during childhood. After the onset of puberty, germinomatous GCTs represented the most frequent histological subtype, and malignant non-germinomatous GCTs often presented as mixed tumors with choriocarcinoma and embryonal carcinoma components. During infancy, non-gonadal GCTs accounted for the majority of GCTs, while after the onset of puberty, gonadal GCTs predominated. Notably, among non-gonadal GCTs, there was a female predominance during childhood and a strong male predominance during adolescence. CONCLUSIONS: Two separate groups of GCTs with distinct clinical features relevant for differential diagnosis and the diagnostic assessment can be distinguished. This observation correlates with genetic studies that reveal different genetic changes in childhood and adolescence GCTs. Further studies are needed to elucidate the molecular mechanisms of germ cell and GCT development that account for the age- and sex-dependent clinical manifestation.

Group II rhabdomyosarcoma and rhabdomyosarcomalike tumors: is radiotherapy necessary?

PURPOSE: In the prospective Cooperative Soft Tissue Sarcoma Study Group (CWS) 81, 86, 91, and 96 trials, radiotherapy was omitted in some patients with rhabdomyosarcoma and rhabdomyosarcoma-like tumors within Intergroup Rhabdomyosarcoma Study (IRS) group II. This analysis evaluates whether subgroups can be defined for which radiotherapy is not necessary. PATIENTS AND METHODS: Two hundred three patients who were registered between January 1981 and December 1998 were eligible for evaluation. Radiotherapy was given depending on tumor location, histology, and whether a secondary complete resection could be performed. The recommended radiation doses ranged from 32 to 54 Gy. RESULTS: One hundred ten patients did receive and 93 patients did not receive radiotherapy. The calculated local control after 5 years was 83% with and 65% without radiotherapy (P <.004). Event-free survival (EFS) at 5 years was 76% and 58%, respectively (P <.005). Overall survival (OS) at 5 years was 84% and 77% (P = not significant). The differences in local control were significant for the subgroups of irradiated patients with favorable histology, favorable site, and initial tumor size of less than 5 cm. A trend for improved local control with irradiation was observed for patients with unfavorable site, unfavorable histology, and large primary tumors. EFS was significantly improved for irradiated patients who had unfavorable histology, both favorable and unfavorable tumor sites, and small initial tumors. OS was significantly improved for patients with unfavorable histology through radiation. CONCLUSION: Local control and EFS in group II patients are improved with radiotherapy. No subgroup could be defined for which the omission of radiotherapy produced outcome equivalent to that of patients who were irradiated.

Low occurrence of familial neuroblastomas and ganglioneuromas in five consecutive GPOH neuroblastoma treatment studies.

Familial neuroblastoma is of special interest in view of the oncogenesis of this tumour with its early manifestation in childhood. The inheritance seems to follow an autosomal-dominant mendelian trait with incomplete penetrance. Familial neuroblastomas and ganglioneuromas have not been reported in detail within large treatment studies. A retrospective clinicopathological survey of patients reported to the German neuroblastoma treatment studies over 24 years was performed. Among 2863 patients (2752 neuroblastomas, 111 ganglioneuromas) included in five consecutive trials, only 22 hereditary cases in ten families were observed. Neuroblastomas were found in 18 patients and ganglioneuromas in four, accounting for less than one percent of all cases. Six patients with neuroblastomas had localised disease, seven had stage 4, three had stage 4S, and stage was unknown in two patients. Two families had three affected patients. Contrary to previous reports, age distribution and number of primary tumours in patients with familial data confirm the low prevalence of familial neuroblastoma and may help in counselling the affected families.