Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

A Novel Standard for Systematic Reporting of Neuroblastoma Surgery: The International Neuroblastoma Surgical Report Form (INSRF): A Joint Initiative by the Pediatric Oncological Cooperative Groups SIOPEN∗, COG∗∗, and GPOH∗∗∗.

OBJECTIVE: To create the first structured surgical report form for NBL with international consensus, to permit standardized documentation of all NBL-related surgical procedures and their outcomes. SUMMARY OF BACKGROUND DATA: NBL, the most common extracranial solid malignant tumor in children, covers a wide spectrum of tumors with significant differences in anatomical localization, organ or vessel involvement, and tumor biology. Complete surgical resection of the primary tumor is an important part of NBL treatment, but maybe hazardous, prone to complications and its role in high-risk disease remains debated. Various surgical guidelines exist within the protocols of the different cooperative groups, although there is no standardized operative report form to document the surgical treatment of NBL. METHODS: After analyzing the treatment protocols of the SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology pediatric cooperative groups, important variables were defined to completely describe surgical biopsy and resection of NBL and their outcomes. All variables were discussed within the Surgical Committees of SIOP Europe International Neuroblastoma Study Group, Children's Oncology Group, and Gesellschaft fuer Paediatrische Onkologie und Haematologie - German Association of Pediatric Oncology and Haematology. Thereafter, joint meetings were organized to obtain intercontinental consensus. RESULTS: The "International Neuroblastoma Surgical Report Form" provides a structured reporting tool for all NBL surgery, in every anatomical region, documenting all Image Defined Risk Factors and structures involved, with obligatory reporting of intraoperative and 30 day-postoperative complications. CONCLUSION: The International Neuroblastoma Surgical Report Form is the first universal form for the structured and uniform reporting of NBL-related surgical procedures and their outcomes, aiming to facilitate the postoperative communication, treatment planning and analysis of surgical treatment of NBL.

11p15.5 epimutations in children with Wilms tumor and hepatoblastoma detected in peripheral blood.

BACKGROUND: Constitutional or somatic mosaic epimutations are increasingly recognized as a mechanism of gene dysregulation resulting in cancer susceptibility. Beckwith-Wiedemann syndrome is the cancer predisposition syndrome most commonly associated with epimutation and is extremely variable in its phenotypic presentation, which can include isolated tumors. Because to the authors' knowledge large-scale germline DNA sequencing studies have not included methylation analysis, the percentage of pediatric cancer predisposition that is due to epimutations is unknown. METHODS: Germline methylation testing at the 11p15.5 locus was performed in blood for 24 consecutive patients presenting with hepatoblastoma (3 patients) or Wilms tumor (21 patients). RESULTS: Six individuals with Wilms tumor and 1 patient with hepatoblastoma were found to have low-level gain of methylation at imprinting control 1, and a child with hepatoblastoma was found to have loss of methylation at imprinting control 2. The loss of methylation at imprinting control 2 was found to be maternally inherited, despite not being associated with any detectable genomic alteration. CONCLUSIONS: Overall, 33% of patients (8 of 24 patients) with Wilms tumor or hepatoblastoma were found to have an epigenetic susceptibility that was detectable in the blood. It is interesting to note that low-level gain of methylation at imprinting control 1 predominantly was detected in females with bilateral Wilms tumors. Further studies in larger cohorts are needed to determine the efficacy of testing all patients with Wilms tumor or hepatoblastoma for 11p15.5 epimutations in the blood as part of DNA analysis because this hallmark of predisposition will not be detected by sequencing-based approaches and detecting a cancer predisposition may modify treatment.

Role of the extent of prophylactic regional lymph node radiotherapy on survival in high-risk neuroblastoma: A report from the COG A3973 study.

PURPOSE: Neuroblastoma is the most common extracranial solid pediatric malignancy, with poor outcomes in high-risk disease. Standard treatment approaches employ an increasing array of aggressive multimodal therapies, of which local control with surgery and radiotherapy remains a backbone; however, the benefit of broad regional nodal irradiation remains controversial. We analyzed centrally reviewed radiation therapy data from patients enrolled on COG A3973 to evaluate the impact of primary site irradiation and the extent of regional nodal coverage stratified by extent of surgical resection. METHODS: Three hundred thirty high-risk neuroblastoma patients with centrally reviewed radiotherapy plans were analyzed. Outcome was evaluated by the extent of nodal irradiation. For the 171 patients who also underwent surgery (centrally reviewed), outcome was likewise analyzed according to the extent of resection. Overall survival (OS), event-free survival (EFS), and cumulative incidence of local progression (CILP) were examined by Kaplan-Meier, log-rank test (EFS, OS), and Grey test (CILP). RESULTS: The five-year CILP, EFS, and OS for all 330 patients receiving radiotherapy on A3973 were 8.5% ± 1.5%, 47.2% ± 3.0%, and 59.7% ± 3.0%, respectively. There were no significant differences in outcomes based on the extent of lymph node irradiation regardless of the degree of surgical resection (< 90% or ≥90%). CONCLUSION: Although local control remains a significant component of treatment of high-risk neuroblastoma, our results suggest there is no benefit of extensive lymph node irradiation, irrespective of the extent of surgical resection preceding stem cell transplant.

Intracranial metastasis in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver malignancy in adolescents and young adults. Surgery is the mainstay of therapy for primary and metastatic disease. Most patients relapse, with development of both local and distant metastases. Brain metastases from solid tumors are rare in the pediatric and young adult population. Here, we document three patients with brain metastases from FLHCC, confirmed by histology and molecular characterization of the chimeric fusion DNAJB1-PRKACA, each necessitating neurosurgical intervention. These observations highlight the ability of FLHCC to metastasize to the brain and suggest the need for surveillance neuroimaging for patients with advanced-stage disease.

Transcriptomic characterization of fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLHCC) tumors all carry a deletion of ∼ 400 kb in chromosome 19, resulting in a fusion of the genes for the heat shock protein, DNAJ (Hsp40) homolog, subfamily B, member 1, DNAJB1, and the catalytic subunit of protein kinase A, PRKACA. The resulting chimeric transcript produces a fusion protein that retains kinase activity. No other recurrent genomic alterations have been identified. Here we characterize the molecular pathogenesis of FLHCC with transcriptome sequencing (RNA sequencing). Differential expression (tumor vs. adjacent normal tissue) was detected for more than 3,500 genes (log2 fold change ≥ 1, false discovery rate ≤ 0.01), many of which were distinct from those found in hepatocellular carcinoma. Expression of several known oncogenes, such as ErbB2 and Aurora Kinase A, was increased in tumor samples. These and other dysregulated genes may serve as potential targets for therapeutic intervention.

Risk factors and predictors of severity score and complications of pediatric hemorrhagic cystitis.

PURPOSE: We retrospectively analyzed our institutional incidence of hemorrhagic cystitis, identified risk factors, and examined associations of risk factors with disease severity and genitourinary complication rates. MATERIALS AND METHODS: We reviewed charts of all consecutive pediatric patients treated from 1986 to 2010. We analyzed demographics, underlying diagnosis and treatment data to assess risk factors for hemorrhagic cystitis. We also correlated disease severity scores with clinical predisposing factors, and performed univariate and multivariate analyses to examine associations between risk factors and outcomes. RESULTS: Hemorrhagic cystitis was observed in 97 of 6,119 children (1.6%), most of whom (75%) had severity scores of II or III. Mean ± SD age was 12.2 ± 6.3 years for patients with hemorrhagic cystitis and 10.5 ± 7 years for patients without hemorrhagic cystitis (p = 0.017). On univariate analysis increased risk of hemorrhagic cystitis was significantly associated with age greater than 5 years, male gender, cyclophosphamide or busulfan chemotherapy, bone marrow or peripheral blood stem cell transplantation, pelvic radiotherapy and underlying diagnoses of rhabdomyosarcoma, acute leukemia and aplastic anemia. On multivariate analysis age greater than 5 years, allogeneic bone marrow or peripheral blood stem cell transplantation and pelvic radiotherapy were significantly associated with increased risk of hemorrhagic cystitis. Older age, late onset hemorrhagic cystitis, positive urine culture for BK virus and bone marrow or peripheral blood stem cell transplantation were associated with greater disease severity. Patients with higher severity scores more frequently experienced bladder perforation, hydronephrosis, overall hemorrhagic cystitis complications, and increased creatinine and blood urea nitrogen levels during followup. CONCLUSIONS: Older age, previous bone marrow or peripheral blood stem cell transplantation and BK virus in the urine are risk factors for hemorrhagic cystitis and are associated with a higher severity score. Higher severity scores are associated with increased rates of genitourinary complications and renal impairment.

Pediatric and adolescent synovial sarcoma: multivariate analysis of prognostic factors and survival outcomes.

PURPOSE: Treatment of synovial sarcoma (SS) is challenging because of its unpredictable clinical behavior. We reviewed our institutional experience with pediatric SS to identify prognostic indicators and survival outcomes. METHODS: We retrospectively reviewed all pediatric/adolescent patients (age<22 years) with confirmed SS treated from 1970 to 2010. Patient and clinical characteristics were evaluated for prognostic significance and survival outcomes. RESULTS: We identified 111 patients. The median age was 15.4 years. Sixty-seven tumors (60%) were monophasic, 42 (38%) were biphasic, and 2 (2%) were of unknown histology. Median follow-up was 5.3 years (range 0.8-36.8 years), 5-year overall survival (OS) was 73%, and 10-year OS was 65%. Greater tumor size (stratified as ≤5 cm, >5 cm, or ≥10 cm) (P=0.001) and depth (P=0.03) correlated with decreased OS. Primary tumor location in the upper extremity correlated with increased OS when compared with lower-extremity and central lesions (P=0.05). Bone and/or neurovascular invasion negatively impacted survival (P=0.02). Multivariate analysis revealed that tumor size (trichotomized) was the dominant and sole factor in discriminating survival risk. Neither radiotherapy nor chemotherapy correlated with improved 5-year survival. CONCLUSIONS: Tumor size, depth, invasion, and primary location affect survival in pediatric SS. The role of radiotherapy and chemotherapy for SS warrants future study.

Intensity-modulated radiation therapy with dose-painting for pediatric sarcomas with pulmonary metastases.

BACKGROUND: We examined patterns of failure in pediatric patients with thoracic sarcoma and pulmonary metastases treated with intensity-modulated radiation therapy with dose-painting (DP-IMRT). PROCEDURE: Eleven pediatric patients, five with Ewing sarcoma family tumors (ESFT) and six with rhabdomyosarcoma (RMS), with primary thoracic tumors and pulmonary metastases underwent DP-IMRT with chemotherapy for definitive treatment. Eight patients also underwent surgery. Median time to RT was 21 (15-31) weeks. Nine patients received 45-50.4-Gy in 1.8 Gy fractions to the primary tumor (n = 3) or post-operative tumor bed (n = 6). Two patients ≤4 years received 12 Gy intraoperative radiation therapy and 30.6-36 Gy IMRT postoperatively to the tumor bed. All patients received 14-16.8 Gy in 0.54-0.88 Gy fractions to the whole lungs (n = 6) or hemithorax (n = 5) using dose-painting technique. A representative case was re-planned with IMRT plus standard AP/PA whole lung irradiation (WLI) for dosimetric comparison. RESULTS: With 27-month median follow-up, 3-year pulmonary relapse-free survival in all patients was 61%: 80% for RMS and 40% for ESFT. Five patients (4 ESFT and 1 RMS) experienced pulmonary relapse at median 16 (9-41) months. There were no local failures. Our representative case demonstrated more homogeneous target volume coverage of the whole lungs and decreased mean dose to esophagus (15%), heart (31%), spinal cord (15%), and liver (19%) with DP-IMRT. CONCLUSIONS: The treatment of children with a primary thoracic tumor and pulmonary metastases poses a significant challenge. DP-IMRT is one solution to this technical problem. Initial data from this small series suggest DP-IMRT is feasible and produces superior sparing of critical normal tissues.

Pancreatic involvement in neuroblastoma with radiologic-pathologic correlation: a single-institution experience.

OBJECTIVE: Pancreatic involvement in neuroblastoma is extremely rare, with few cases reported in the literature. We present imaging findings of pancreatic involvement in neuroblastoma with clinical and pathologic correlation in the largest documented series to date. SUBJECTS AND METHODS: We prospectively reported pancreatic involvement evident on multimodality imaging in neuroblastoma patients presenting to our institution from 1997 to 2011. Lesions were classified according to location within the pancreas, and imaging features were correlated with cytogenetic and surgicopathologic findings. RESULTS: Neuroblastoma involving the pancreas was evident on imaging of seven of 1031 patients (mean age, 6.6 years). One patient had pancreatic involvement at presentation, and six developed pancreatic disease at relapse or disease progression. Pancreatic lesions were most frequently initially identified on concurrent CT and (123)I-metaiodobenzylguanidine scintigraphy, and additional lesions initially were found on MRI and ultrasound. Five of seven patients had focal lesions, one had diffuse pancreatic involvement, and one had pancreatic extension from contiguous disease. The distribution of lesions favored the pancreatic body and tail. All patients had International Neuroblastoma Staging System stage 3 or 4 disease, Children's Oncology Group intermediate- or high-risk disease, and unfavorable histology at initial diagnosis. For the five patients with surgical correlation, pancreatic surgical specimens revealed neuroblastoma in three cases and ganglioneuroblastoma in two cases. CONCLUSION: Although rare, pancreatic involvement in neuroblastoma occurs. Its variable imaging appearance should be considered when evaluating the retroperitoneum in patients with known or suspected neuroblastoma, particularly because increased patient survival holds the potential for uncommon patterns of recurrence.

Prognostic factors and survival in pediatric and adolescent liposarcoma.

Purpose. Liposarcoma is extremely rare in the pediatric population. To identify prognostic factors and determine treatment outcomes, we reviewed our institutional experience with pediatric liposarcoma. Methods. We retrospectively reviewed all pediatric patients (age <22 years) with confirmed liposarcoma treated at Memorial Sloan-Kettering Cancer Center. Histologic subtype, tumor location, margin status, recurrence, and adjuvant therapy were analyzed and correlated with overall survival. Results. Thirty-four patients (56% male) with a median age of 18.1 years were identified. Twenty-two (65%) had peripheral tumors and 12 (35%) had centrally located tumors. Histologically, 29 (85%) tumors were low grade, and 5 (15%) were high grade pleomorphic. Eleven (32%) had recurrent disease, 9 patients with central tumors and 2 patients with peripheral lesions. Eight deaths occurred, all in patients with central disease. Five-year overall survival was 78%, with a median follow-up time of 5.4 years (range, 0.3-30.3 years). Tumor grade (P = .003), histologic subtype (P = .01), and primary location (P < .001) all correlated with survival, as did stage (P < .001) and margin status (P = .001). Conclusions. Central location of the primary tumor, high tumor grade, and positive surgical margins are strongly correlated with poor survival in pediatric patients with liposarcoma.

Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.

Clinical sequencing of soft tissue and bone sarcomas delineates diverse genomic landscapes and potential therapeutic targets.

The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.

Extracellular vesicle and particle isolation from human and murine cell lines, tissues, and bodily fluids.

We developed a modified protocol, based on differential ultracentrifugation (dUC), to isolate extracellular vesicles and particles (specifically exomeres) (EVPs) from various human and murine sources, including cell lines, surgically resected tumors and adjacent tissues, and bodily fluids, such as blood, lymphatic fluid, and bile. The diversity of these samples requires robust and highly reproducible protocols and refined isolation technology, such as asymmetric-flow field-flow fractionation (AF4). Our isolation protocol allows for preparation of EVPs for various downstream applications, including proteomic profiling. For complete details on the use and execution of this protocol, please refer to Hoshino et al. (2020).

Colorectal cancer in young adults.

Colorectal cancer (CRC) is rare in young adults. It presents more frequently with stage 3 or 4 disease, underscoring its relevance in this population. Prognosis, matched for stage of disease at presentation, is likely similar to that in older adults, although survival is clearly lower for the youngest subgroups within this population. This article reviews the literature on the etiology, presentation, treatment, and outcome of CRC in young adults. New chemotherapeutic regimens have demonstrated survival benefits and the introduction of new biological agents has offered ways to control metastatic disease that may eventually show promise in the treatment of earlier-stage CRC. The benefit of these newer agents in young adults is assumed but currently unproven. Molecular genetic studies are increasing the understanding of the pathobiology of CRC and may ultimately allow at-risk patients to be identified at an earlier stage.

Chest wall tumors in childhood and adolescence.

Chest wall tumors in childhood and adolescence can be very heterogeneous and may appear at any age from infancy to late adolescence. They can be benign or malignant and secondary or primary. A careful history and physical examination should be followed by adequate imaging studies to delineate the primary tumor and identify possible sites of dissemination. Diagnosis usually requires either a needle or open biopsy which minimizes dissection so that a complete resection can be done later. Most neoplastic lesions require a complete resection, whereas secondary and infectious processes are treated with chemotherapy or antibiotics. Rigid chest wall re-construction has the advantage of eliminating paradoxical respiration and obviating the need for postoperative ventilation. Another advantage is maintenance of chest wall contour.

Sentinel node biopsy for melanocytic tumors in children.

Sentinel node biopsy is as pivotal for the staging of pediatric melanoma patients as it is for adults. However, pediatric patients frequently present the clinician with pigmented lesions-such as atypical Spitz tumors or Spitzoid melanomas-that are not easy to classify as benign or malignant, and often fall into a diagnostic gray area when assessed with light microscopy alone. For these lesions, the performance of sentinel node biopsy can contribute to an understanding of the lesion's biology. We present a strategy for incorporating sentinel node biopsy into the overall management approach to children with atypical pigmented lesions with features suspicious for melanoma. With the inclusion of additional adjunctive techniques such as comparative genomic hybridization, this algorithm may lend more diagnostic precision to difficult-to-classify lesions.

Non coding RNA analysis in fibrolamellar hepatocellular carcinoma.

Fibrolamellar hepatocellular carcinoma (FLC) is a rare primary liver cancer found in adolescents and young adults without underlying liver disease. A deletion of ~400 kD has been found in one copy of chromosome 19 in the tumor tissue of all patients tested. This produces a fusion of the genes DNAJB1 and PRKACA which, in turn, produces a chimeric transcript and protein. Transcriptomic analysis of the tumor has shown upregulation of various oncologically relevant pathways, including EGF/ErbB, Aurora Kinase A, pak21 and wnt. To explore other factors that may contribute to oncogenesis, we examined the microRNA (miRNA) and long non-coding RNA (lncRNA) expression in FLC. The non-coding RNA expression profile in tumor tissue samples is distinctly different from the adjacent normal liver and from other liver tumors. Furthermore, miRZip knock down or over expression of certain miRNAs led to changes in the levels of coding genes that recapitulated changes observed in FLC, suggesting mechanistically that the changes in the cellular levels of miRNA are not merely correlative. Thus, in addition to serving as diagnostic tools for FLC, non-coding RNAs may serve as therapeutic targets.

Prognostic factors and survival in non-central nervous system rhabdoid tumors.

INTRODUCTION: Non-central nervous system (non-CNS) rhabdoid tumors tend to present at a young age and have an extremely aggressive course, with dismal overall survival rates. Inactivation of the tumor suppressor gene SMARCB1 has been shown in rhabdoid tumors regardless of anatomic location, suggesting a common genetic basis. We retrospectively analyzed our institutional experience with non-CNS rhabdoid tumors to determine overall survival and prognostic variables. METHODS: We reviewed records of pediatric patients (age<22y) with non-CNS rhabdoid tumor at our institution between 1980 and 2014. Variables evaluated for correlation with survival included: age > or <1.5years (median) at diagnosis, M1 status, and radiation therapy. The log-rank test was used to compare Kaplan-Meier probability distributions with P values adjusted for multiple testing using the false discovery rate approach. RESULTS: Nineteen consecutive patients (10 female) with histologically verified rhabdoid tumor were identified. Mean age at diagnosis was 3.2years (median 1.5y, range 1.3mo-21.8y). Primary tumors were located in the kidney (n=10), head and neck (n=5), and in the liver, thigh, mediastinum and retroperitoneum (n=1 each). SMARCB1 expression was absent in all 10 patients tested. Eight patients had distant metastases at diagnosis. Median overall survival was 1.2years. Age greater than the median and radiation therapy were associated with better outcome, with a median overall survival of 2.7years (P=0.049 and P=0.003, respectively). CONCLUSION: Survival rates for rhabdoid tumor remain poor, but prognosis is better in older children, regardless of primary tumor location. Because of its rarity, clinical trials with present agents are difficult to conduct. Further progress will require a focus on therapies targeted at tumor biology rather than anatomic location for non-CNS rhabdoid tumors.