Rhabdomyosarcoma, Ewing Sarcoma, and Other Round Cell Sarcomas.

Several recent advances have been made in the diagnosis and therapy of malignant small round cell tumors that affect children, particularly in rhabdomyosarcoma, Ewing sarcoma, and other round cell sarcomas. These advances have provided new insights into the pathologic, histologic, and genomic characterization of specific tumor subtypes, which has led to the identification of novel therapeutic targets and improved stratification of risk. This has, in turn, led to improved efficacy in clinical trials of new drug combinations, thereby increasing the survival of patients with newly diagnosed and refractory or recurrent round cell sarcomas. Here, we review the progress that has been made using genomics to identify novel pathologic genomic rearrangements, as well as therapeutic targets. We also describe how clinical and molecular factors have helped refine risk stratification and therapies that have led to improved clinical outcomes in patients with round cell sarcomas.

Targeted polytherapy in small cell sarcoma and its association with doxorubicin.

A paradigm shift has occurred in the last decade from chemotherapy to targeted therapy for the management of many patients with advanced sarcoma. This work identifies a combination of targeted agents and doxorubicin that are effective against small cell sarcoma cell lines. Three small cell sarcoma cell lines were studied: RD18 (rhabdomyosarcoma), A204 (undifferentiated sarcoma) and TC 71 (Ewing's sarcoma). Each cell line was exposed to increasing concentrations of vorinostat (HDAC inhibitor), 17-DMAG (HSP90 inhibitor), abacavir (anti-telomerase) or sorafenib (tyrosine kinase inhibitor) alone, combined with one another, or combined with doxorubicin. Cell viability, cell cycle analysis and apoptosis were assessed by MTS assay, propidium iodide-Annexin V staining, and caspase 3/7 activity, respectively. The Chou and Talalay combination index (CI) was used to determine whether the effects were additive (CI = 1), synergistic (CI < 1) or antagonistic (CI > 1). In monotherapy, targeted agents achieved 30-90% reductions in viability, with the exception of abacavir. Dual-targeted combination therapies with vorinostat, sorafenib and 17-DMAG demonstrated synergy. Abacavir was antagonistic with every other drug and was not further studied. Both vorinostat and 17-DMAG synergized with doxorubicin, achieving 60% cell killing compared to 12% with doxorubicin alone. No synergy was observed for sorafenib with doxorubicin. The triple therapy vorinostat, 17-DMAG and doxorubicin did not show synergy, but increased the subG1 population at 24H, from 30% to 70% compared to monotherapies with an increase in apoptosis. This work provides evidence of synergy of combinations of vorinostat, 17-DMAG and sorafenib in small cell sarcoma. In addition to doxorubicin, these combinations enhance doxorubicin cytotoxicity at therapeutically relevant concentrations.

High prevalence of CIC fusion with double-homeobox (DUX4) transcription factors in EWSR1-negative undifferentiated small blue round cell sarcomas.

Primitive round cell sarcomas of childhood and young adults have been problematic to diagnose and classify. Our goal was to investigate the pathologic and molecular characteristics of small blue round cell tumors (SBRCT) that remained unclassified after exhaustive immunohistochemistry and molecular screening to exclude known sarcoma-related translocations. As rare examples of EWSR1-negative SBRCT have been shown to carry rearrangements for FUS and CIC genes, we undertook a systematic screening for these two genes. CIC rearrangements by FISH were detected in 15/22 (68%), while none showed FUS abnormalities. RACE, RT-PCR, and/or long-range DNA PCR performed in two cases with frozen material showed that CIC was fused to copies of the DUX4 gene on either 4q35 or 10q26.3. Subsequent FISH analysis confirmed fused signals of CIC with either 4q35 or 10q26.3 region in six cases each. Tumors positive for CIC-DUX4 fusion occurred mainly in male young adult patients (median age: 29 years), with the extremities being the most frequent location. Microscopically, tumors displayed a primitive, round to oval cell morphology with prominent nucleoli, high mitotic count, and areas of necrosis. O13 expression was variable, being either diffuse or patchy and tumors mostly lacked other markers of differentiation. Although CIC-DUX4 resulting in a t(4;19) translocation has been previously described in primitive sarcomas, this is the first report implicating the related DUX4 on 10q26 in oncogenesis. These results suggest the possibility of a newly defined subgroup of primitive round cell sarcomas characterized by CIC rearrangements, distinct from Ewing sarcoma family of tumors.

Desmoplastic small round cell tumour successfully treated with caffeine-assisted chemotherapy: a case report and review of the literature.

Desmoplastic small round cell tumour (DSRCT) is a rare tumour, usually arising in the abdominal cavity. DSRCT remains an aggressive malignancy, with a poor prognosis despite multi-modality treatments. In the published literature, there has been no patient who lived for three years or more without surgical excision. This report describes a case of DSRCT arising from the brachial plexus and successfully treated with caffeine-assisted chemotherapy. A 29-year-old male presented with pain and numbness in his left forearm. Radiological findings were suggestive of malignant tumour. Histology, immunohistochemical stain and fluorescence in situ hybridisation (FISH) results confirmed the diagnosis of DSRCT. He underwent caffeine-potentiated chemotherapy and the tumour disappeared. The tumour was not removed surgically as it was intertwined in the brachial plexus. Four years after the initial diagnosis, no local relapse and no distant metastases have been observed. Therefore, it is concluded that caffeine-assisted chemotherapy should be one of the treatment options for DSRCT.

Desmoplastic small round cell tumor in the ovary: Report of two cases and literature review.

Desmoplastic small round cell tumor (DSRCT) is a rare intra-abdominal tumor of uncertain histogenesis that occurs predominantly in young males. We report two cases of DSRCT in young women that presented clinically as ovarian tumor with extensive pelvic and abdominal dissemination. Both patients underwent debulking surgery and combined chemotherapy. After primary therapy, the tumors recurred and both women died of the disease. The clinical presentation and differential diagnosis, as well as the treatment, including surgical debulking and combined chemotherapy are discussed.

Reverse transcriptase-polymerase chain reaction as an ancillary molecular technique in the diagnosis of small blue round cell tumors by fine-needle aspiration cytology.

We evaluated the feasibility and usefulness of reverse transcriptase-polymerase chain reaction (RT-PCR) on fine-needle aspirates for categorization of small blue round cell tumors (SBRCTs). A total of 51 cases, including 25 Ewing sarcoma/peripheral primitive neuroectodermal tumors (PNETs), 11 rhabdomyosarcomas, 13 neuroblastomas, and 2 desmoplastic small round cell tumors (DSRCTs) were analyzed. The detection of the EWS-FLI1 (20/25) and EWS-ERG (4/25) fusion transcripts resolved 24 of 25 cases of Ewing sarcoma/PNET. The PAX3/7-FKHR fusion transcript was detected in 2 of 4 cases of alveolar rhabdomyosarcoma and the EWS-WT1 transcript in both cases of DSRCT. Tyrosine hydroxylase and 3,4-dihydroxyphenylalanine (dopa) decarboxylase transcripts were demonstrated in 10 of 13 cases of neuroblastoma. In comparison, immunocytochemical analysis resolved 19 (76%) of 25 Ewing sarcomas, 9 (82%) of 11 rhabdomyosarcomas, 6 (46%) of 13 neuroblastomas, and 1 (50%) of 2 DSRCTs. Overall, RT-PCR resolved 38 (86%) of 44 vs 35 (69%) of 51 cases by immunocytochemical analysis. RT-PCR is easily applied to fine-needle aspirates of SBRCT and greatly facilitates accurate tumor typing.

Intra-abdominal desmoplastic small round cell tumour in a 39-year-old man.

Desmoplastic small round cell tumor is a very rare neoplasm, that usually appears in children and young adolescents. There is no standard therapy, and responses to chemotherapy are infrequent. Surgery is still the main treatment for this disease. We report the case of a 39 year-old man and briefly summarize the evidence about this tumor.

Desmoplastic small round cell tumor in children: a new therapeutic approach.

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare, highly aggressive malignancy with distinctive histologic and immunohistochemical features occurring in a young population with a male predominance. The tumor appears to arise as masses in the abdominal cavity without a clear visceral origin. Five patients with DSRCT were treated as usual with combined chemoradiation and surgery. In addition, in our center, patients underwent autologous bone marrow transplant (BMT), which is a novel approach to this disease. METHODS: Charts of 5 patients (4 males, mean age of 11 years) treated between 2000 and 2007 were reviewed. The diagnosis of DSRCT was made on the basis of clinical examination, computed tomographic scan, and explorative laparotomy with biopsy, and biochemical markers were negative. All patients were treated with aggressive chemoradiation and surgery. Three patients also had autologous BMT. RESULTS: Three patients (BMT recipients) responded to treatment. The responding patients had surgery with the intent of removing all disease. Two patients died of their cancer, neither of whom underwent BMT. CONCLUSION: The patients DSRCT are sensitive to an aggressive combination of chemotherapy, surgical debulking, and radiation therapy, followed by autologous BMT. It appears that this new multifaceted treatment offers good palliation, which may prolong survival and a possible cure.

Translocation (4;19)(q35;q13.1)-associated primitive round cell sarcoma: report of a case and review of the literature.

We report the 4th case of a primitive round cell sarcoma with the translocation (4;19)(q35;q13.1) as the primary cytogenetic abnormality. This undifferentiated sarcoma shows some features of Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET), including a diffuse reactivity for FLI1, but it shows only focal and weak reactivity for CD99 and is negative for a rearrangement of EWS, the molecular signature of ES/PNET. Recognition of the histopathologic and cytogenetic features of this entity is necessary to avoid its misdiagnosis as ES/PNET, especially in small biopsy samples.

High-dose chemotherapy and autologous peripheral blood stem cell transfusion for adult and adolescent patients with small round cell sarcomas.

The treatment of small-round-cell tumors (SRCT) in adult patients remains a challenge to clinicians. In the present study, we analyzed the feasibility and efficacy of high-dose chemotherapy (HDCT) followed by autologous peripheral blood stem-cell rescue as a consolidation therapy exclusively for patients with good disease control through a single regimen of induction chemotherapy and local therapy. Twenty-one patients (12 females, median age 22.0 years) were analyzed, including seven cases with rhabdomyosarcoma (RMS) and 14 cases with Ewing's family tumors (EFT). Overall, survival was 46% and failure-free survival (FFS) was 33% at 3 years. Patients with EFT had better FFS than those with RMS, with an estimated 3-year FFS of 50% (P<0.01). There was a single case of possible treatment-related death and two cases of secondary malignancies. This study cannot conclusively determine the beneficial effects of HDCT for improving treatment outcomes in adult SRCTs due to the small number of subjects. However, study findings suggest that a subgroup of patients with EFT may obtain prolonged survival benefits from this therapy.

Response to vinorelbine and low-dose cyclophosphamide chemotherapy in two patients with desmoplastic small round cell tumor.

We report two cases of abdominal desmoplastic small round cell tumor (DSRCT) that showed a clinical response to the vinorelbine/low-dose cyclophosphamide combination that has been claimed to be effective for rhabdomyosarcoma. This observation may prompt further investigation into the activity of such a regimen in DSRCT patients with recurrent or refractory disease, with a view to a possible future role as maintenance therapy in controlling minimal residual disease in patients who achieve complete remission with intensive induction multimodality therapy.

[Intra-abdominal desmoplastic small round cell tumor in childhood: case report and review of the literature]. / Tumeur desmoplastique à petites cellules rondes intra-abdominale de l'enfant : à propos d'une observation et revue de la littérature.

Desmoplastic small round cell tumor (DSRCT) correspond to a recent clinicopathological entity, individualized in 1989 into the group of tumors with small round cells. This pathology puts ethiopathogenic, diagnostic, therapeutic and prognosis problems. Indeed, the ethiopathogenic is still unknown, diagnosis is asserted only by immuno-histochimic and cytogenetic study because of the big number of differential diagnoses and the anatomopathologic polymorphism. Its treatment is not well codified and its outcome remains dark in spite of therapeutic progress. The objective of this work is to report a personal observation of a DSRCT and to proceed to a review of the literature to clarify the epidemiological, clinical, paraclinical and therapeutic aspects of this rare tumor.

Desmoplastic small round cell tumor presenting in the ovaries: report of a case and review of the literature.

Desmoplastic small round cell tumor is a recently recognized clinical entity with specific morphologic, immunocytochemical, and genetic features. Though this tumor is mostly described to involve serosal surfaces, we report a case with ovarian involvement. The clinical presentation and differential diagnoses as well as the treatment including aggressive surgical debulking and multiagent chemotherapy are discussed.

Desmoplastic small round cell tumour in children and adolescents.

BACKGROUND: Desmoplastic small round cell tumour (DSRCT) is a rare highly aggressive neoplasm, and clinical studies are scarce. PROCEDURE: We report six cases of children and adolescents (median age 14 years, range 6.9-17.5) with DSRCT (5 abdominal, 1 paratesticular) registered by the Italian Cooperative Group (ICG) for soft tissue sarcoma over a 9-year period. Patients received a multidisciplinary treatment, including aggressive initial or delayed surgery and radiotherapy. Chemotherapy regimen was based on the use of ifosfamide, vincristine, dactinomycin, and a few doses of antharacyclines (doxorubicin or epirubicin). RESULTS: Complete surgical resection was possible only for the paratesticular tumour. Among the patients with abdominal lesions, macroscopically radical excision was possible in only one case. All patients received multidrug chemotherapy, and tumour reduction was obtained in the 4 evaluable patients. No relapses were evident in the irradiated fields in the 4 patients who received radiotherapy. Two patients remained progression-free 22 and 63 months after diagnosis, one is in third complete remission, whereas three died 10-25 months after diagnosis. CONCLUSIONS: DSRCT is a chemosensitive tumour, but survival rates remain disappointing despite aggressive multimodality therapy. Our results support surgical tumour removal and radiotherapy to achieve local control. Our experience and a review of the literature suggest that patients with localised abdominal tumours or a paratesticular primary may have a better prognosis.