Paraspinal synovial sarcoma as an unusual postradiation complication in pediatric abdominal neuroblastoma

SUMMARY: The development of a soft-tissue sarcoma is an infrequent but well-known long-term complication of radiotherapy. Malignant fibrous histiocytomas, extraskeletal osteosarcomas, fibrosarcomas, malignant peripheral nerve sheath tumors, and angiosarcomas are most frequently encountered. Radiation-associated synovial sarcomas are uncommon and exceedingly rare in pediatric patients. We report an unusual case of paraspinal synovial sarcoma presenting in an adolescent female 13 years after radiation therapy for her neuroblastoma.     

The applicability of immunohistochemistry in the diagnosis and differential diagnosis of malignant soft tissue tumors. A reevaluation based on the material of the Kiel Pediatric Tumor Registry

The diagnosis and differential diagnosis of malignant soft tissue tumors not infrequently poses great difficulties, especially in those cases which lack any feature of differentiation by conventional light microscopy. These difficulties have been partially resolved through the application of ultrastructural investigations. Recently considerable progress has been achieved using immunohistochemistry. At the Kiel Pediatric Tumor Registry we were able to reduce the percentage of unclassified soft tissue sarcomas from 17.6% in 1982 to 4.5% in 1989. Particularly useful were antibodies against the different types of intermediate filaments, muscle-specific actin, myoglobin, and the neural markers neuron-specific enolase and protein S-100. In contrast to the expected immunophenotype rhabdomyosarcomas, malignant peripheral neuroectodermal tumors and malignant schwannomas showed expression of cytokeratins. Moreover, in many cases rhabdomyosarcomas and synovial sarcomas expressed neural markers. Ewing's sarcoma and malignant peripheral neuroectodermal tumor are histogenetically related, but differ in grade of neural differentiation. In all soft tissue sarcomas immunohistochemistry is very useful to obtain information on the cellular heterogeneity. Despite the great achievements not every soft tissue sarcoma can be diagnosed with certainty. There will always be a baseline of unclassified cases due to problems which are not caused by the tumor itself but rather by diagnostic circumstances.     

Overview of sarcomas in the adolescent and young adult population

Based on the data of the Surveillance, Epidemiology and End Results Section of the National Cancer Institute (SEER) program, soft tissue and bone sarcomas account for about 1% of all new malignancies diagnosed in the United States each year. However, there are numerous different histologic types, and any given type of sarcoma is extremely rare. Determining the incidence of sarcomas by age and type is difficult due to the limited data reported. The SEER program collects data regarding age but only limited data on histology, while most series reported in the literature include either adults or pediatric patients, but rarely both. In an effort to estimate the frequency and absolute numbers of different sarcomas in the adolescent and young adult population, the University of Texas M. D. Anderson Cancer Center (MDACC) tumor registry was queried for all soft tissue sarcomas from 1990 through 2003, and all bone sarcomas from 1990 through 2002. Based on this query, an overview of sarcomas that occur predominantly in the adolescent and young adult (AYA) population is presented. These sarcomas include rhabdomyosarcoma, synovial sarcoma, neurogenic sarcoma, epithelioid sarcomas, alveolar soft parts sarcoma, Ewing sarcoma, and osteosarcoma. Using the percentages for occurrence of each histologic type determined from the MDACC database, and the SEER estimate of overall sarcoma incidence, an estimate of the number of new cases in 2004 for the predominant histologic types occurring in the AYA population are presented. Also reviewed are the chromosomal translocations that occur frequently in sarcomas presenting in the AYA population.     

Pediatric malignancies provide unique cancer therapy targets

PURPOSE OF REVIEW: Improving overall survival and reducing morbidity are major goals of childhood cancer research. This review explores an old idea that increased survival in childhood cancer can be achieved by inhibiting specific cancer targets. Specific therapeutic targeting would theoretically cause reduced morbidity as well as increased survival. Tumor-specific translocation-generated fusion proteins appear to be ideal tumor-specific therapeutic targets. This review will describe advances in aspects of target identification, potential for small molecule screening, and the evolution of clinical resistance to this new generation of pharmaceuticals. RECENT FINDINGS: Advances in molecular biology have identified new protein targets along with increased understanding of the biologic role of these proteins. Ewing sarcoma family of tumors research has benefited from new target discovery and enhanced biologic understanding of the EWS-FLI1 fusion protein. Congenital (infantile) fibrosarcoma and cellular mesoblastic nephroma have been grouped based on the presence of a common translocation fusion protein, ETV6-NTRK3. Functional knowledge of ETV6-NTRK3 has advanced so that strategies for screening small molecule inhibitors can proceed. Patients with chronic myeloid leukemia have benefited from the discovery of the BCR-ABL kinase inhibitor imatinib mesylate (Gleevec), thus showing how a molecular therapeutic target can be inactivated for improved therapy. This review will describe challenges raised by clinical resistance to imatinib mesylate as a paradigm for how resistance might evolve in other disease models. This review also describes how patients with synovial sarcoma might benefit from future therapy directed towards the SYT-SSX family of fusion proteins. SUMMARY: The increased utilization of small molecules to disrupt or inactivate tumor-specific molecular targets is rapidly evolving. The use of these small molecules to probe biology and treat disease is advancing towards a new generation of anticancer therapies.     

Synovial sarcoma in the neck of an eleven month old girl

Synovial sarcomas are rare primary tumors of the head and neckin any age group. We present a case of primary synovial sarcoma arising in the neck of an 11-month-old girl.     

Radiation therapy for non-rhabdomyosarcoma soft tissue sarcomas in adolescents and young adults

Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are less responsive to radiotherapy than the more common pediatric soft tissue sarcomas, rhabdomyosarcoma and Ewing sarcoma of soft tissue. However, radiation therapy does play an important role in the treatment of NRSTS, including synovial sarcoma. Little data exists regarding the behavior or treatment of these tumors in adolescents and young adults compared to older populations. Limb-preservation with adjuvant radiation thereby is standard. There is a greater incentive to reduce long-term complications of radiation in younger patients and thus smaller margins, lower doses, and conformal techniques should be considered. Results of anticipated cooperative group studies promise to guide future therapy for the various types of NRSTS.     

Expression of WT-1, Bcl-2, and CD34 by Primary Renal Spindle Cell Tumors in Children

The confident diagnosis of renal spindle cell tumors in children is often difficult. An immunohistochemical study of WT-1, Bcl-2, and CD34 was performed to determine their expression profiles and to assess the potential utility of these immunohistochemical markers in the differential diagnosis of 36 cases of renal spindle cell tumors of childhood. The cases included 11 stromal predominant Wilms tumors, 12 cellular mesoblastic nephromas, 9 clear cell sarcomas of the kidney (CCSK), and 4 monophasic synovial sarcomas. WT-1 was uniformly positive in primitive undifferentiated stromal Wilms tumors (6 of 6) and negative in the differentiating and differentiated stromal elements of Wilms tumors (0 of 5). WT-1 was also negative in cellular mesoblastic nephromas (0 of 12), CCSKs (0 of 12), and synovial sarcomas (0 of 4). Bcl-2 was expressed in all stromal Wilms tumors (11 of 11), all synovial sarcomas (4 of 4), some CCSKs (4 of 9), and none of the cellular mesoblastic nephromas (0 of 12). Although CD34 was absent in the tumor cells of all the tumors studies (0 of 36), CD34 immunohistochemistry nicely demonstrated the evenly distributed septal capillaries characteristic of CCSK in all 9 cases of this tumor. We conclude that a combination of WT-1 and Bcl-2 immunohistochemistry may aid in the distinction of stromal Wilms tumor, monophasic synovial sarcoma, cellular mesoblastic nephroma, and CCSK.     

Cyclooxygenase-2 Expression in Pediatric Sarcomas

Therapies for metastatic pediatric sarcomas have reached maximum tolerated doses, but continue to provide suboptimal cure rates. Additionally, these treatments are associated with numerous short- and long-term side effects. Therefore, the search for newer, less toxic therapeutic agents is warranted. Overexpression of the inducible enzyme, cyclooxygenase-2 (COX-2), has been discovered in a variety of adult solid tumors and numerous studies have shown COX-2 inhibitors to have significant antiproliferative effects. Therefore, we sought to determine the expression of COX-2 in pediatric sarcomas. We evaluated rhabdomyosarcoma (RMS), osteosarcoma (OS), and Ewing sarcoma (EWS) samples for COX-2 expression by immunohistochemical analysis as well as by cDNA microarray analysis. COX-2 expression was detected in 48/58 (82.8%) tumors by immunohistochemistry and in an additional 52/59 (88.1%) tumors tested by microarray gene analysis. There was a trend toward increased COX-2 expression in metastatic rhabdomyosarcoma and osteosarcoma, though it did not reach clinical significance. The degree of COX-2 immunoreactivity did not vary significantly with other clinicopathologic features such as age, gender, or histologic classification. We conclude that the majority of these pediatric sarcoma samples express COX-2 to varying degrees. Therefore, studies testing the efficacy of COX-2 inhibitors in the treatment of pediatric sarcomas are warranted.     

Granulocytic sarcoma presenting as pneumonia in a child with t(8;21) acute myelogenous leukemia: diagnosis by fluorescent in situ hybridization

Granulocytic sarcoma is a soft tissue collection of leukemic cells. The authors describe a 4-year-old boy with M2 acute myelogenous leukemia (AML) who presented with fever, mild nonproductive cough, and hematemesis. Although he was initially diagnosed with nodular pneumonia, rapid resolution of a pulmonary infiltrate following induction chemotherapy was suggestive of a pulmonary granulocytic sarcoma. Interphase fluorescent in situ hybridization (FISH) of the lung biopsy specimen for the t(8;21)(q22;q22) translocation confirmed the retrospective diagnosis of a well-differentiated pulmonary granulocytic sarcoma. Pulmonary granulocytic sarcomas may be underrecognized in children with AML; this may delay anti-leukemic therapy and may lead to ineffective therapy if misdiagnosed as pneumonia.     

Pilot trial of tumor-specific peptide vaccination and continuous infusion interleukin-2 in patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma: an inter-institute NIH study

BACKGROUND: Patients with recurrent Ewing sarcoma and alveolar rhabdomyosarcoma have poor prognoses and limited therapeutic options. We have investigated the use of peptide pulsed vaccination in an attempt to immunologically target the breakpoint region of tumor specific fusion proteins expressed in these tumors. PROCEDURE: Sixteen patients with recurrent, translocation positive, Ewing sarcoma, and alveolar rhabdomyosarcoma underwent apheresis for collection of peripheral blood mononuclear cells. Following countercurrent centrifugal elutriation, an apheresis product comprised predominantly of monocytes but containing small numbers of circulating immature dendritic cells was pulsed with peptides derived from the breakpoint region of the fusion proteins. Vaccines were administered intravenously concomitant with continuous intravenous rhIL-2 at 9 x 10(6) IU/m(2)/day. RESULTS: Toxicity was limited to IL-2 related effects and was generally mild. Following vaccination, all patients showed progressive disease, most in a rapid fashion following the first vaccine. One patient showed evidence of an immunologic response and another showed a mixed clinical response. Patients enrolled on this tumor vaccine trial showed significant immunosuppression and large bulky tumors. CONCLUSIONS: Peptide vaccination as administered in this trial did not alter the dismal clinical outcome for patients with recurrent pediatric sarcomas. Future trials of tumor vaccines in this population should target patient populations with improved immune competence and smaller tumor burdens. Furthermore, optimization of the antigen presenting cell populations may be important for inducing immune responses to peptide antigens.     

Primary pericardial synovial sarcoma confirmed by molecular genetic studies: a case report

Primary pericardial synovial sarcoma is an extremely rare tumor. The awkward tumor site and clinical features associated with quite advanced disease at presentation make obtaining adequate biopsy material challenging. Ambiguous histologic features may also make diagnosis difficult. We present a case of a 15-year-old patient with an original diagnosis of a spindle cell thymoma. After definitive surgery the diagnosis was amended to a primary pericardial synovial sarcoma. Molecular confirmation of the SYT-SSX fusion gene was critical in reaching an accurate diagnosis. This highlights the necessity for routine molecular genetic studies, so that patient therapy can be directed accordingly.     

Prolonged 14‐day continuous infusion of high‐dose ifosfamide with an external portable pump: Feasibility and efficacy in refractory pediatric sarcoma

Background

Ifosfamide is currently used to treat pediatric sarcomas and increasing its dosage may be associated with a better response rate. Prolonged continuous infusion seems an attractive administration modality.

Methods

Ifosfamide 14 g/m² (with mesna 14 g/m²) was administered through an ambulatory portable pump over 14 days as a continuous infusion, starting every 3 weeks, in 14 patients with relapsing sarcomas. No growth factors were given.

Results

Acute grade 3 hematological toxicity was observed in only 13/66 cycles and red cell transfusions were given in two patients. Hematuria and dysuria occurred in three cases. The response rate was: five partial responses, five stable disease. The median time to progression was 3 months (range: 2–19 months). The best response rate was seen for synovial sarcoma and Ewing sarcoma.

Conclusion

Prolonged 14‐day continuous infusion of high‐dose ifosfamide is well tolerated. Potentially interesting preliminary responses in pediatric patients already treated with ifosfamide are reported. Pediatr Blood Cancer. 2010;55:617–620. © 2010 Wiley‐Liss, Inc.     

Pathology of soft tissue sarcomas: 238 cases of the childhood tumor registry

Until April 1981 malignant soft tissue sarcomas were registered from 238 patients. Rhabdomyosarcoma was the most common tumor (115/238 = 48.3%). The embryonal subtype was predominantly seen among the rhabdomyosarcomas (83/115 = 72.2%). Rhabdomyosarcomas were localized most frequently in the head and neck area (40/115 = 34.8%), followed by genitourinary system (15/115), pelvis soft tissue (12), abdomen (10) and extremities (10). Non-rhabdomyosarcomatous soft tissue sarcomas (123/238 = 51.7%) were synovial sarcomas (20 = 8.4%), fibrosarcomas including spindle cell sarcoma (17 = 7.4%), leiomyosarcomas (12 = 5.0%), malignant tumors of the vascular system (11 = 4.6%) and neurofibrosarcomas (9 = 3.8%). Other types of sarcoma were extremely rare. 42 (17.6%) of all soft tissue sarcomas could not be classified histogenetically. Rhabdomyosarcomas could be diagnosed much more accurately (105/115 = 91.3%), compared to all other soft tissue sarcomas (99/121 = 81.8%). At present, the most difficult diagnostic problems remain with the tumors of connective tissue, in particular with fibrosarcomas and with the differential diagnosis of juvenile fibrosarcomas versus juvenile fibromatoses.     

Recurrent atrial ectopic tachycardia following chemotherapy with ifosfamide

In most pediatric tumors, particularly sarcomas, cyclophosphamide or ifosfamide represent essential first-line chemotherapeutic agents [1]. Whereas cyclophosphamide is known to be associated with a well-defined cardiomyopathy [2], only a few cardiac complications following ifosfamide chemotherapy have been observed to date. Here we report a patient treated for Ewing sarcoma with multiple pulmonary and osseous metastases who repeatedly developed a supraventricular tachyarrhythmia following administration of ifosfamide as part of a polychemotherapy regimen.