Childhood soft tissue sarcomas account for approximately 10% of all childhood cancers. About half of all childhood soft tissue sarcomas are rhabdomyosarcoma, which arises from skeletal muscle, these are most common between the ages of 2 and 6. The other soft tissue sarcomas of childhood include a wide range of different histologies including fibrosarcoma, leiomyosarcoma, liposarcoma, schwannoma, soft tissue Ewing's / peripheral neuroectodermal tumours, synovial sarcoma and many other types. These non-rhabdo sarcomas are more common in adults, but these tumours usually behave quite differently in children compared to the same tumours in adults
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MeSH term: Sarcoma
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- Childhood Soft Tissue Sarcoma Treatment
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- Clinical Trials - Childhood Soft Tissue Sarcoma
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- Nonrhabdomyosarcoma Soft Tissue Sarcomas
Referenced article by Justine Walker MD covering background, presentation diagnosis, workup, treatment and follow-up.
Multidisciplinary journal covering all aspects of connective tissue oncology research.
- Soft Tissue Sarcoma
SEER, National Cancer Institute
Part of a SEER report on statistical trends and risk factors associated with childhood cancers. From: Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995. (PDF)
This list of publications is regularly updated (Source: PubMed).
Kuru TH, Roethke MC, Nyarangi-Dix J, et al.Pediatric case report on magnetic resonance imaging/transrectal ultrasound-fusion biopsy of rhabdomyosarcoma of the bladder/prostate: a new tool to reduce therapy-associated morbidity?
Urology. 2013; 81(2):417-20 [PubMed
Rhabdomyosarcomas are the most common soft tissue sarcomas in children. Here we present management of an 18-month-old boy with metastatic rhabdomyosarcoma of the bladder/prostate. After radiochemotherapy, high-spatial-resolution 3-Tesla multiparametric magnetic resonance imaging (MRI) showed regressive systemic disease but a residual mass at the right seminal vesicle. For histologic re-evaluation, 3-dimensional-controlled stereotactic MRI/transrectal ultrasound (TRUS)-fusion biopsy specimens were taken. Because histologic analysis showed nonvital tissue, a decision could be made against adjuvant radical cystoprostatectomy. Advanced 3-Tesla imaging and MRI/TRUS-fusion biopsies in children are feasible and represent an effective tool to examine suspicious pelvic lesions. Depending on histology, this can lead to a significant reduction of therapy-associated morbidity.
Mulder RL, Paulides M, Langer T, et al.Cyclophosphamide versus ifosfamide for paediatric and young adult bone and soft tissue sarcoma patients.
Cochrane Database Syst Rev. 2012; 12:CD006300 [PubMed
BACKGROUND: Alkylating agents, such as cyclophosphamide and ifosfamide, play a major role in the improved survival of children and young adults with bone and soft tissue sarcoma. However, there is still controversy as to their comparative anti-tumour efficacy and possible adverse effects. This is an update of the first systematic review evaluating the state of evidence on the effectiveness of cyclophosphamide as compared to ifosfamide for paediatric and young adult patients with sarcoma.
OBJECTIVES: To compare the possible effectiveness of cyclophosphamide with that of ifosfamide for paediatric and young adult patients with sarcoma.
SEARCH METHODS: We searched CENTRAL (The Cochrane Library 2012, issue 2), MEDLINE/PubMed (from 1966 to March 2012) and EMBASE/Ovid (from 1980 to March 2012) with pre-specified terms. In addition, we searched reference lists of relevant articles, conference proceedings and ongoing trial databases (www.controlled-trials.com; searched April 2012).
SELECTION CRITERIA: Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing cyclophosphamide and ifosfamide for the treatment of different types of sarcoma in paediatric and young adult patients (aged less than 30 years at diagnosis). Chemotherapy other than either cyclophosphamide or ifosfamide should have been the same in both treatment groups.
DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection.
MAIN RESULTS: No studies meeting the inclusion criteria of the review were identified.
AUTHORS' CONCLUSIONS: No RCTs or CCTs comparing the effectiveness of cyclophosphamide and ifosfamide in the treatment of bone and soft tissue sarcoma in children and young adults were identified. Therefore no definitive conclusions can be made about the effects of cyclophosphamide and ifosfamide in these patients. Based on the currently available evidence we are not able to give recommendations for clinical practice. More high quality research is needed.
Fayda M, Kebudi R, Dizdar Y, et al.Spontaneous pneumothorax in children with osteosarcoma: report of three cases and review of the literature.
Acta Chir Belg. 2012 Sep-Oct; 112(5):378-81 [PubMed
Spontaneous pneumothorax is a rare manifestation of primary lung cancer or metastasis. It is estimated that < 1% of all cases of spontaneous pneumothorax are tumor-associated and metastatic osteogenic or soft-tissue sarcomas are associated most commonly with pneumothorax especially in the setting of cytotoxic chemotherapy or radiotherapy. In this article, we report three pediatric cases with osteosarcoma that developed spontaneous pneumothorax during chemotherapy with a review of the literature. Two of them had lung metastasis at the time of the detection of pneumothorax and the remaining patient was found to have a bronchopleural fistula. SPx is an emergency situation and early diagnosis and management can improve prognosis and quality of life of the patient however the optimal management has yet to be determined.
Pediatric soft tissue sarcomas are rare tumors of childhood, frequently characterized by specific chromosome translocations. Despite improvements in treatment, their clinical management is often challenging due to the low responsiveness of metastatic forms and aggressive variants to conventional therapeutic approaches, which leads to poor overall survival. It is widely thought that soft tissue sarcomas derive from mesenchymal progenitor cells that, during embryonic life, have developed chromosomal aberrations with de-regulation of the main pathways governing tissue morphogenesis. The Notch signaling pathway is one of the most important molecular networks involved in differentiation processes. Emerging evidence highlights the role of Notch signaling de-regulation in the biology of these pediatric sarcomas. In this review, we present an outline of recently gathered evidence on the role of Notch signaling in soft tissue sarcomas, highlighting its importance in tumor cell biology. The potential challenges and opportunities of targeting Notch signaling in the treatment of pediatric soft tissue sarcomas are also discussed.
Odem JL, Oroszi G, Bernreuter K, et al.Deceptively benign low-grade fibromyxoid sarcoma: array-comparative genomic hybridization decodes the diagnosis.
Hum Pathol. 2013; 44(1):145-50 [PubMed
Low-grade fibromyxoid sarcoma (previously known as Evans tumor) is a rare soft tissue neoplasm characterized by a deceptively bland appearance despite the potential for late metastasis or recurrence. We describe a 13-year-old patient with a popliteal fossa mass initially thought to be benign that, because of array-comparative genomic hybridization findings and subsequent immunohistochemistry, was diagnosed as low-grade fibromyxoid sarcoma. The array-comparative genomic hybridization demonstrated a loss of 11p11.2p15.5 and a gain of 16p11.2p13.3 with breakpoints involving the CREB3L1 (cAMP responsive element-binding protein 3-like 1) and FUS (fused in sarcoma) genes, respectively. Subsequent fluorescence in situ hybridization analysis of a dual-labeled break-apart FUS probe on interphase cells was positive. Our case highlights the importance of using genetic information obtained via array-comparative genomic hybridization to classify accurately pediatric soft tissue tumors.
de Souza RR, Oliveira ID, Caran EM, et al.Investigation of PAX3/7-FKHR fusion genes and IGF2 gene expression in rhabdomyosarcoma tumors.
Growth Horm IGF Res. 2012; 22(6):245-9 [PubMed
The purpose of our study was to investigate the prevalence of the PAX3/7-FKHR fusion genes and quantify the IGF2 gene expression in rhabdomyosarcoma (RMS) samples. Soft tissue sarcomas account 5% of childhood cancers and 50% of them are RMS. Morphological evaluation of pediatric RMS has defined two histological subtypes, embryonal (ERMS) and alveolar (ARMS). Chromosomal analyses have demonstrated two translocations associated with ARMS, resulting in the PAX3/7-FKHR rearrangements. Reverse transcriptase-polymerase chain reaction (RT-PCR) is extremely useful in the diagnosis of ARMS positive for these rearrangements. Additionally, several studies have shown a significant involvement of IGF pathway in the pathogenesis of RMS. The presence of PAX3/7-FKHR gene fusions was studied in 25 RMS samples from patients attending the IOP-GRAACC/UNIFESP and three RMS cell lines by RT-PCR. IGF2 gene expression was quantified by qPCR and related with clinic pathological parameters. Of the 25 samples, nine (36%) were ARMS and 16 (64%) were ERMS. PAX3/7-FKHR gene fusions expression was detected in 56% of ARMS tumor samples. IGF2 overexpression was observed in 80% of samples and could indicate an important role of this pathway in RMS biology.
Armeanu-Ebinger S, Herrmann D, Bonin M, et al.Differential expression of miRNAs in rhabdomyosarcoma and malignant rhabdoid tumor.
Exp Cell Res. 2012; 318(20):2567-77 [PubMed
Alveolar rhabdomyosarcoma (RMA) and malignant rhabdoid tumor (MRT) have a frequent metastatic spread and a poor prognosis. Aberrant miRNA expression is often found in metastatic tumors. The aim of this study was to identify specific miRNA expression patterns in these tumors. We analyzed the expression of miRNAs in RMA and MRT in tissue samples and in the rhabdomyosarcoma (RMS) cell lines (Rh30 and RD). Selected target miRNAs were modulated with mimic or inhibitor oligonucleotides. Functional analysis was monitored by flow cytometry and migration assays. A set of 107 differentially expressed miRNAs showed tissue-specific clustering of RMA and MRT. Comparison with the Sarcoma microRNA Expression Database revealed RMA- and MRT-specific miRNAs. Metastatic invasion associated miRNA miR-9 was overexpressed in RMA. miR-200c-inhibiting migration-was lower expressed in RMA than in MRT. Transient transfection of RMS cells with a miR-200c mimic and miR-9( inhibitor did neither increase the expression of the known target E-cadherin nor decrease migration. Expression of E-cadherin could be induced in RD cells using decitabine, but demethylation did not influence cell migration. Despite a comparable high rate of metastatic invasion pediatric RMA and MRT show a different pattern of miRNA expression possibly allowing risk stratification.
Marburger TB, Gardner JM, Prieto VG, Billings SDPrimary cutaneous rhabdomyosarcoma: a clinicopathologic review of 11 cases.
J Cutan Pathol. 2012; 39(11):987-95 [PubMed
BACKGROUND: Rhabdomyosarcoma is a malignant mesenchymal tumor with skeletal muscle differentiation. Primary cutaneous rhabdomyosarcoma is rare. We report a series of 11 cases of primary cutaneous rhabdomyosarcoma.
METHODS: Cases diagnosed as rhabdomyosarcoma arising in the dermis/subcutis with no identified primary tumor elsewhere were retrospectively reviewed. Follow-up was obtained.
RESULTS: The tumors occurred in five children and six adults. The adult subset consisted of pleomorphic, epithelioid and not otherwise specified (NOS) subtypes while the pediatric subset showed alveolar and embryonal subtypes. All cases showed immunohistochemical staining consistent with the diagnosis of rhabdomyosarcoma. Three adult cases showed immunoreactivity for cytokeratins (one pleomorphic, one epithelioid and one NOS.
CONCLUSIONS: Primary cutaneous rhabdomyosarcoma shows a bimodal age distribution and male predominance, correlating with rhabdomyosarcoma in deep soft tissue. Follow-up, available on all patients, showed aggressive behavior in both children and adults. Primary cutaneous rhabdomyosarcoma should be considered in the differential diagnosis of tumors with abundant eosinophilic cytoplasm and those with "small round blue cell" morphology. Desmin, myogenin and MYOD1 are a trio of markers with high sensitivity and specificity for primary cutaneous rhabdomyosarcoma. Cytokeratin immunoreactivity in primary cutaneous rhabdomyosarcoma represents a potential diagnostic pitfall in the differential diagnosis with sarcomatoid carcinoma.
Masià A, Almazán-Moga A, Velasco P, et al.Notch-mediated induction of N-cadherin and α9-integrin confers higher invasive phenotype on rhabdomyosarcoma cells.
Br J Cancer. 2012; 107(8):1374-83 [PubMed
] Article available free on PMC
BACKGROUND: Rhabdomyosarcoma (RMS) is the commonest type of soft-tissue sarcoma in children. Patients with metastatic RMS continue to have very poor prognosis. Recently, several works have demonstrated a connection between Notch pathway activation and the regulation of cell motility and invasiveness. However, the molecular mechanisms of this possible relationship remain unclear.
METHODS: The Notch pathway was manipulated pharmacologically and genetically. The mRNA changes were analysed by quantitative PCR and protein variations by western blot and immunofluorescence. Finally, the capabilities of RMS cells to adhere, heal a wound and invade were assessed in the presence of neuronal cadherin (N-cadherin)- and α9-integrin-blocking antibodies.
RESULTS: Cells treated with γ-secretase inhibitor showed lower adhesion capability and downregulation of N-cadherin and α9-integrin. Genetic manipulation of the Notch pathway led to concomitant variations in N-cadherin and α9-integrin. Treatment with anti-N-cadherin-blocking antibody rendered marked inhibition of cell adhesion and motility, while anti-α9-integrin-blocking antibody exerted a remarkable effect on cell adhesion and invasiveness.
CONCLUSION: Neuronal cadherin and α9-integrin are postulated as leading actors in the association between the Notch pathway and promotion of cell adhesion, motility and invasion, pointing to these proteins and the Notch pathway itself as interesting putative targets for new molecular therapies against metastases in RMS.
Bektaş-Kayhan K, Karagöz G, Bayrak Ö, et al.Implant-assisted dental rehabilitation of a patient with maxillary rhabdomyosarcoma.
J Craniofac Surg. 2012; 23(5):e384-6 [PubMed
Rhabdomyosarcoma is a malignant, soft tissue neoplasm consisting of cells derived from the primitive mesenchyme that exhibit a profound tendency to undergo myogenesis. Multimodality therapy for tumors in the head and neck regions has a significant effect on maxillofacial skeletal growth, dental development, and the whole ecologic system of the oral cavity. Here we aimed to discuss the influence of head-neck cancer therapy in pediatric patients with long-term follow-up and present a case with implant-assisted dental rehabilitation and also functional and aesthetic outcomes.
Friedrich P, Ortiz R, Strait K, et al.Pediatric sarcoma in Central America: outcomes, challenges, and plans for improvement.
Cancer. 2013; 119(4):871-9 [PubMed
] Article available free on PMC
BACKGROUND: Children with cancer in middle-income countries have inferior outcomes compared with similar children in high-income countries. The magnitude and drivers of this survival gap are not well understood. In the current report, the authors sought to describe patterns of clinical presentation, magnitude of treatment abandonment, and survival in children with sarcoma in Central America.
METHODS: A retrospective review was conducted of hospital-based registries from national pediatric oncology referral centers. Patients with newly diagnosed osteosarcoma, Ewing sarcoma, rhabdomyosarcoma (RMS), and soft tissue sarcoma (STS) between January 1, 2000 and December 31, 2009 were included. Survival analyses were performed first using standard definitions of overall survival (OS) and event-free survival (EFS) and then with abandonment included as an event (abandonment-sensitive OS and abandonment-sensitive EFS).
RESULTS: In total, 785 new cases of pediatric sarcoma were reported (264 diagnoses of osteosarcoma, 175 diagnoses of Ewing sarcoma, 240 diagnoses of RMS, and 106 diagnoses of STS). The rate of metastatic disease at presentation was high (osteosarcoma, 38%; Ewing sarcoma, 39%; RMS, 29%; and STS, 21%). The treatment abandonment rate also was high, particularly among patients with extremity bone sarcomas (osteosarcoma, 30%; Ewing sarcoma, 15%; RMS, 25%; and STS, 15%). Of 559 patients who experienced a first event, 59% had either recurrent or progressive disease. The 4-year OS rate (±standard error) was 40% ± 3%, and the EFS rate was 30% ± 2%; however, these rates decreased further to 31% ± 2% and 24% ± 2%, respectively, when abandonment was taken into account.
CONCLUSIONS: The current results indicated that high rates of metastases and treatment abandonment and difficulty with upfront treatment effectiveness are important contributors to the poor survival of children with pediatric sarcomas in Central America. Initiatives for early diagnosis, psychosocial support, quality improvement, and multidisciplinary care are warranted to improve outcomes.
Ortega-García JA, Soldin OP, López-Hernández FA, et al.Congenital fibrosarcoma and history of prenatal exposure to petroleum derivatives.
Pediatrics. 2012; 130(4):e1019-25 [PubMed
] Article available free on PMC
Congenital fibrosarcoma (CFS) is a rare fibrous tissue malignancy that usually presents in the first few years of life. It is unique among human sarcomas in that it has an excellent prognosis. We describe a temporal clustering of a number of cases of CFS and investigate the possible associated prenatal risk factors. The Pediatric Environmental History, a questionnaire developed in our clinic that is instrumental in determining environmental risk factors for tumor-related disease, was essential in documenting the presence or absence of risk factors considered as human carcinogens. We found a history of exposure to petroleum products in four cases of CFS that occurred at a greater than expected rate in a short time frame-an apparent cancer cluster. We call attention to the possibility that exposure to petroleum products raises the risk of developing CFS. While future studies should focus on systematic investigation of CFS and its underlying mechanisms, this report suggests the need for proactive measures to avoid exposure to solvents and petroleum products during pregnancy.
Clerici CA, Veneroni L, Bisogno G, et al.Videos on rhabdomyosarcoma on YouTube: an example of the availability of information on pediatric tumors on the web.
J Pediatr Hematol Oncol. 2012; 34(8):e329-31 [PubMed
PURPOSE: Video-sharing sites have become increasingly important in recent years in providing information and orienting people's decisions relating to their health. Adolescents and their families use internet to obtain information on pediatric oncological diseases.
METHODS: We describe the availability and type of video content and origin on YouTube relating to a particular set of pediatric neoplastic diseases, that is, rhabdomyosarcoma and soft-tissue sarcoma.
RESULTS: A total of 149 videos were analyzed: 25 were considered as useful; only 1 video was produced by a doctor, whereas 82.5% were produced by patients or their families, in many cases for commemorating the death of a child.
CONCLUSIONS: Our observations indicate that video-sharing sites have become tools, such as blogs and social media, that make it easier for patients to describe their impressions and experiences of the disease, and this could help other patients devise strategies for coping with the disease, providing them with support and opportunities for sharing information and resources.
Divyambika CV, Sathasivasubramanian S, Krithika CL, et al.Pediatric oral leiomyosarcoma: rare case report.
J Cancer Res Ther. 2012 Apr-Jun; 8(2):282-5 [PubMed
Soft tissue sarcomas comprise a group of histologically diverse malignant neoplasms arising from mesenchymal cell lines. Among these, leiomyosarcomas are sarcomas exhibiting smooth muscle differentiation. Occurrence of this neoplasm in the oral cavity is exceedingly rare and its presentation is unusual in children. We present a case report of leiomyosarcoma of the oral cavity in an eight-year old child. Primary oral leiomyosarcoma, being a rare entity in children, this case report emphasizes the prompt recognition of this tumor to institute appropriate multimodality treatment.
Boyd ASChromosomal translocation-negative cellular extraskeletal myxoid chondrosarcoma in an adolescent female.
J Cutan Pathol. 2012; 39(9):872-6 [PubMed
Extraskeletal myxoid chondrosarcoma (EMC) is a relatively uncommon soft tissue sarcoma that typically presents in adults of middle age and affects the proximal thigh and limb girdles. Initially believed to be a low-grade malignancy, long-term patient follow-up has shown a high incidence of local recurrence and metastatic spread. EMC is uniformly resistant to chemotherapy and radiation therapy. These tumors characteristically display fibrous septae with large aggregates of mucin populated by clusters and strands of oval cells exhibiting minimal mitotic activity. A more aggressive cellular subtype has also been defined and exhibits basaloid cells showing the immunohistochemical staining features of neuroendocrine differentiation calling into question their proposed cartilaginous lineage. Most, although not all, examples of EMC possess a unique balanced chromosomal translocation [t(9;22)(q22;q12)] between the EWSR1 and NR4A3 (previously termed TEC) genes. Pediatric and adolescent cases of EMC are rare, as only 15 have been reported and appear to follow a more aggressive clinical course. Reported herein is a case of an EMC arising in the thigh of a 15-year-old female and the first to undergo evaluation of chromosomal translocation.
Robin TP, Smith A, McKinsey E, et al.EWS/FLI1 regulates EYA3 in Ewing sarcoma via modulation of miRNA-708, resulting in increased cell survival and chemoresistance.
Mol Cancer Res. 2012; 10(8):1098-108 [PubMed
] Article available free on PMC
Ewing sarcoma is an aggressive pediatric cancer of the bone and soft tissue, in which patients whose tumors have a poor histologic response to initial chemotherapy have a poor overall prognosis. Therefore, it is important to identify molecules involved in resistance to chemotherapy. Herein, we show that the DNA repair protein and transcriptional cofactor, EYA3, is highly expressed in Ewing sarcoma tumor samples and cell lines compared with mesenchymal stem cells, the presumed cell-of-origin of Ewing sarcoma, and that it is regulated by the EWS/FLI1 fusion protein transcription factor. We further show that EWS/FLI1 mediates upregulation of EYA3 via repression of miR-708, a miRNA that targets the EYA3 3'-untranslated region, rather than by binding the EYA3 promoter directly. Importantly, we show that high levels of EYA3 significantly correlate with low levels of miR-708 in Ewing sarcoma samples, suggesting that this miR-mediated mechanism of EYA3 regulation holds true in human cancers. Because EYA proteins are important for cell survival during development, we examine, and show, that loss of EYA3 decreases survival of Ewing sarcoma cells. Most importantly, knockdown of EYA3 in Ewing sarcoma cells leads to sensitization to DNA-damaging chemotherapeutics used in the treatment of Ewing sarcoma, and as expected, after chemotherapeutic treatment, EYA3 knockdown cells repair DNA damage less effectively than their control counterparts. These studies identify EYA3 as a novel mediator of chemoresistance in Ewing sarcoma and define the molecular mechanisms of both EYA3 overexpression and of EYA3-mediated chemoresistance.
Ferrari A, Bertulli RAt the crossroads of molecular biology, pathology and the clinic.
Expert Rev Anticancer Ther. 2012; 12(6):725-8 [PubMed
This article outlines some of the highlights of the fourth ESMO Conference on Sarcoma and GIST, a broad-based international multidisciplinary educational meeting that focused on recent advances made in molecular biology and genetics, and the state-of-the art diagnosis and treatment of soft tissue sarcoma and gastrointestinal stromal tumors.
Oberlin O, Rey A, Sanchez de Toledo J, et al.Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study.
J Clin Oncol. 2012; 30(20):2457-65 [PubMed
PURPOSE: MMT95 was the fourth of a series of International Society of Pediatric Oncology (SIOP) collaborations for children with high-risk nonmetastatic soft tissue sarcoma (STS). The principal objective was to explore survival advantage for an intensified chemotherapy strategy in a randomized trial.
PATIENTS AND METHODS: From July 1995 to June 2003, 457 previously untreated patients with incompletely resected embryonal rhabdomyosarcoma (RMS), undifferentiated sarcoma, and soft tissue primitive neuroectodermal tumor at all sites except paratesticular, vagina, and uterus, or with alveolar RMS were randomly assigned to receive either ifosfamide, vincristine, and dactinomycin (IVA) or a six-drug combination (IVA plus carboplatin, epirubicin, and etoposide) both delivered over 27 weeks. Cumulative doses were as follows: ifosfamide 54 g/m(2) (both arms), epirubicin 450 mg/m(2), etoposide 1,350 mg/m(2) (six-drug regimen). Poor responders after three courses of IVA were to be switched to the other arm. Delivery of radiotherapy was determined according to site and/or response to chemotherapy with or without surgery.
RESULTS: Overall survival (OS) for all patients was 81% (95% CI, 77% to 84%) at 3 years. No significant difference in outcome in either OS or event-free survival was noted between the two arms (3-year OS: 82% [95% CI, 76% to 86%] for IVA and 80% [95% CI, 74% to 85%] for the six-drug arm). Toxicity was significantly greater (infection, myelosuppression, and mucositis) in the six-drug arm. Overall burden of local therapy was consistent with data from previous SIOP studies and showed no difference between the two chemotherapy regimens.
CONCLUSION: Intensification of chemotherapy for nonmetastatic RMS and other chemotherapy-sensitive STS provides no survival advantage or reduction in the intensity of local therapy and adds toxicity.
Cruz FD, Matushansky ISolid tumor differentiation therapy - is it possible?
Oncotarget. 2012; 3(5):559-67 [PubMed
] Article available free on PMC
Genetic and epigenetic events within a cell which promote a block in normal development or differentiation coupled with unregulated proliferation are hallmarks of neoplastic transformation. Differentiation therapy involves the use of agents with the ability to induce differentiation in cells that have lost this ability, i.e. cancer cells. The promise of differentiation-based therapy as a viable treatment modality is perhaps best characterized by the addition of retinoids in the treatment of acute promyelocytic leukemia (APML) revolutionizing the management of APML and dramatically improving survival. However, interest and application of differentiationbased therapy for the treatment of solid malignancies have lagged due to deficiencies in our understanding of differentiation pathways in solid malignancies. Over the past decade, a differentiation-based developmental model for solid tumors has emerged providing insights into the biology of various solid tumors as well as identification of targetable pathways capable of re-activating blocked terminal differentiation programs. Furthermore, a variety of agents including retinoids, histone deacetylase inhibitors (HDACI), PPARγ agonists, and others, currently in use for a variety of malignancies, have been shown to induce differentiation in solid tumors. Herein we discuss the relevancy of differentiation-based therapies in solid tumors, using soft tissue sarcomas (STS) as a biologic and clinical model, and review the preclinical data to support its role as a promising modality of therapy for the treatment of solid tumors.
Minard-Colin V, Ichante JL, Nguyen L, et al.Phase II study of vinorelbine and continuous low doses cyclophosphamide in children and young adults with a relapsed or refractory malignant solid tumour: good tolerance profile and efficacy in rhabdomyosarcoma--a report from the Société Française des Cancers et leucémies de l'Enfant et de l'adolescent (SFCE).
Eur J Cancer. 2012; 48(15):2409-16 [PubMed
AIM: This phase II study evaluated efficacy, safety and pharmacokinetics (PK) profile of combination intravenous vinorelbine (VNL) and continuous low doses oral cyclophosphamide (CPM) combination in children and young adults with a recurrent or refractory solid tumour.
METHODS: A total of 117 patients (median age, 12 years) within six disease strata received intravenous VNL 25mg/m(2) on days 1, 8 and 15 of each 28-day cycle combined with continuous daily oral CPM 25mg/m(2). Tumour response was assessed every two cycles according to WHO (World Health Organisation) criteria. PK of VNL was investigated in a subset of 18 patients aged 4-15 years.
RESULTS: In rhabdomyosarcoma (RMS) (n=50), the best overall response rate (ORR) was 36% with four complete (8%) and 14 partial responses (28%). The best ORR was 13% in Ewing's sarcoma (n=15), 6% in non-RMS soft tissue sarcoma (n=16) and 6% in neuroblastoma (n=16). No response was observed in osteosarcoma (n=10) and medulloblastoma (n=7). The main grade 3/4 toxicity was neutropenia (38%). Other severe toxicities were limited with 3% of peripheral neuropathy and no haemorrhagic cystitis. The PK analysis revealed equivalent blood exposure to VNL between children >4 years and adult series when the VNL dose was based on the body surface area-based dosing. CONCLUDING STATEMENT: In heavily pre-treated children, VNL combined with CPM showed an interesting response rate in RMS and an acceptable toxicity profile supporting further evaluation of these agents in phase III trials.
Ferrari A, Orbach D, Sultan I, et al.Neonatal soft tissue sarcomas.
Semin Fetal Neonatal Med. 2012; 17(4):231-8 [PubMed
Soft tissue tumors in very young children pose diagnostic and therapeutic challenges. Vascular tumors are the most prevalent soft tissue neoplasms in the neonatal period. They are generally benign tumors, but may exhibit aggressive behaviour and cause life-threatening complications. Fibroblastic tumors of intermediate prognosis, more prevalent in very young children (especially infantile fibrosarcoma), are locally aggressive. Since metastases are unusual in this group of tumors, complete surgical resection is generally curative. However, these tumors often present a therapeutic challenge because of the location which makes complete surgical resection difficult. Among the malignant soft tissue tumors, rhabdomyosarcoma is most frequent. It is an aggressive high-grade tumor, with local invasiveness and a propensity to metastasize. These tumors respond to chemotherapy and radiotherapy. Neonates with rhabdomyosarcoma seem to have a worse prognosis than in older age groups. This may be a result of inappropriate dosing of chemotherapeutic agents and decreased use of radiation therapy among other factors.
Salman M, Tamim H, Medlej F, et al.Rhabdomyosarcoma treatment and outcome at a multidisciplinary pediatric cancer center in Lebanon.
Pediatr Hematol Oncol. 2012; 29(4):322-34 [PubMed
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Outcome of patients treated on standard protocols, in a multidisciplinary cancer center setting outside of clinical trials, is not well reported. We reviewed characteristics and outcome of 23 pediatric patients treated at a single, multidisciplinary cancer center in Lebanon, between April 2002 and December 2010. Median follow-up was 41 months. The most commonly affected primary site was the head and neck (48%, n = 11). Nineteen tumors (82.6%) were of embryonal histology. Tumor size was ≥5 cm in eight (34.8%) patients. Sixteen patients (69.6%) had localized disease, and one (4.4%) had metastatic disease. Fifteen (65.2%) had Group III tumors. All patients received chemotherapy, for a duration ranging 21-51 weeks. Upfront surgical resection was performed in 10 patients (43.5%). Eighteen patients (78.3%) received radiation therapy. The 5-year overall and disease-free survival rates were 83% and 64%, respectively. Relapse correlated with absence of surgery. Treatment of childhood RMS in a multidisciplinary cancer center in Lebanon results in similar survival to that in developed countries when similar protocols are applied. There was a higher incidence of local relapse, but those were salvageable with further therapy and surgical local control.
Arndt CA, Rose PS, Folpe AL, Laack NNCommon musculoskeletal tumors of childhood and adolescence.
Mayo Clin Proc. 2012; 87(5):475-87 [PubMed
] Article available free on PMC
Osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma are the most common malignant musculoskeletal tumors in children and adolescents. Today, most patients can be cured. Numerous factors have contributed to improved outcome for these patients over the past several decades. These include multidisciplinary care involving oncologists, radiation oncologists, surgeons, pathologists, and radiologists and enrollment of patients in clinical trials. Better understanding of molecular mechanisms of disease have resulted in studies using molecular targets in addition to standard chemotherapeutic agents, which hopefully will lead to better outcomes in the future. Moreover, new orthopedic techniques and devices as well as new technologies in radiation oncology hold promise for better local control of primary tumors and the potential for fewer late adverse effects. Despite this progress, patients must undergo lifelong follow-up for possible late effects of intense chemotherapy and radiation therapy. We review the diagnosis, prognosis, staging, multidisciplinary therapy, new directions in therapy, and long-term complications of treatment for these tumors. For this review, we searched MEDLINE using the terms rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, biology, and humans and limited the search to articles from 2000 to September 2011. Additional references found in these articles were utilized as appropriate, as well as references from the background information in current therapeutic studies of the Children's Oncology Group. The same database and time frame were searched for articles written by leading authorities in the field.
Anderson JL, Denny CT, Tap WD, Federman NPediatric sarcomas: translating molecular pathogenesis of disease to novel therapeutic possibilities.
Pediatr Res. 2012; 72(2):112-21 [PubMed
Pediatric sarcomas represent a diverse group of rare bone and soft tissue malignancies. Although the molecular mechanisms that propel the development of these cancers are not well understood, identification of tumor-specific translocations in many sarcomas has provided significant insight into their tumorigenesis. Each fusion protein resulting from these chromosomal translocations is thought to act as a driving force in the tumor, either as an aberrant transcription factor (TF), constitutively active growth factor, or ligand-independent receptor tyrosine kinase. Identification of transcriptional targets or signaling pathways modulated by these oncogenic fusions has led to the discovery of potential therapeutic targets. Some of these targets have shown considerable promise in preclinical models and are currently being tested in clinical trials. This review summarizes the molecular pathology of a subset of pediatric sarcomas with tumor-associated translocations and how increased understanding at the molecular level is being translated to novel therapeutic advances.
Dantonello TM, Leuschner I, Vokuhl C, et al.Malignant ectomesenchymoma in children and adolescents: report from the Cooperative Weichteilsarkom Studiengruppe (CWS).
Pediatr Blood Cancer. 2013; 60(2):224-9 [PubMed
BACKGROUND: Malignant ectomesenchymoma (MEM) is a soft tissue tumor with heterologous rhabdomyoblastic components believed to arise from pluripotent migratory neural crest cells. To date merely 50 cases have been published and the knowledge about the course of disease and optimal treatment is limited.
METHODS: Six patients with MEM were registered 1996-2009. The diagnosis was confirmed according to current criteria. Their treatment and outcome was analyzed.
RESULTS: The median age of the three females and three males was 0.6 years (range, 0.2-13.5). The mesenchymal component in all tumors was rhabdomyosarcoma (RMS), the neural component ganglioneuroblastoma/neuroblastoma (n = 5) and peripheral primitive neuroectodermal tumor in one case. Five patients presented with localized, one with metastatic disease. All but one patient received multiagent chemotherapy during their initial treatment. The tumors of 4/5 patients with localized MEM were at least grossly resected at best surgery; the patient without gross resection was additionally irradiated. Three of four evaluable tumors responded well to induction chemotherapy. All patients achieved a first complete remission (CR), but three recurrences (two local, one systemic) occurred. The individual with metastatic MEM did not survive, but all five patients with localized MEM are currently alive in CR with a median follow-up of 5 years (range: 2.1-13.7).
CONCLUSIONS: Risk-factors and outcome of MEM appear to be comparable with other highly malignant pediatric soft tissue sarcoma when a multimodal treatment strategy including chemotherapy and adequate local treatment is pursued. We propose that treatment of patients with MEM be done according to pediatric protocols similar to other rhabdomyosarcoma-like soft tissue sarcoma.
Ray A, Huh WWCurrent state-of-the-art systemic therapy for pediatric soft tissue sarcomas.
Curr Oncol Rep. 2012; 14(4):311-9 [PubMed
Pediatric soft tissue sarcomas (STS) are a heterogeneous group of tumors. Rhabdomyosarcomas (RMS) are the most common histologic subtype, while synovial sarcomas and undifferentiated sarcomas are among the more common non-rhabdomyosarcomatous soft tissue sarcomas (NRSTS) encountered. While the survival outcome for certain groups of RMS patients is quite good, the prognosis for those with alveolar histology or those with metastatic or relapsed disease remains dismal. Also, the response rate for some NRSTS to conventional chemotherapy is suboptimal. Thus increased understanding of involved molecular pathways, such as the insulin growth factor and mammalian target of rapamycin pathways, may indicate potential targets for therapy. In addition, immunotherapy-based approaches that include both non-specific activation with interleukins as well as targeted tumor antigen specific T lymphocytes are emerging avenues in the treatment of children with soft tissue sarcomas.
McGovern SL, Mahajan AProgress in radiotherapy for pediatric sarcomas.
Curr Oncol Rep. 2012; 14(4):320-6 [PubMed
Pediatric sarcoma includes a diverse group of pathologies classified, based on the cell of origin, as primary bone or soft tissue sarcomas. Radiotherapy plays an integral role in the multidisciplinary approach required for optimal therapy in these patients. The particular challenges faced by the radiation oncologist while treating these patients include the age of the patient and the location of these tumors, as they are very often adjacent to critical or growing organs. Technical advances in radiation oncology, including highly conformal planning and improved tumor delineation, may allow a reduction in radiation related toxicities with excellent tumor control. In this chapter, the role of radiotherapy will be reviewed as well as modern technologies that are currently available and under development, with an emphasis on the application of these strategies in the pediatric and young adult population.
Parida L, Morrisson GT, Shammas A, et al.Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma.
Pediatr Surg Int. 2012; 28(6):571-8 [PubMed
] Article available free on PMC
PURPOSE: The purpose of this study was to describe the use of lymphoscintigraphy and sentinel lymph-node biopsy (SLNB) for the management of children with melanoma and sarcomas. We report the experience of two children's hospitals that utilize this technique to identify sentinel lymph nodes for lymph-node biopsy and dissection.
METHODS: We identified 56 patients (median age 10.8 years) who underwent 58 lymphoscintigraphy procedures. There were 33 patients with melanoma and melanocytic lesions, and 23 with sarcomas.
RESULTS: Of 58 lymphoscintigraphy procedures, sentinel lymph nodes were identified in 52 (90% success rate). Using the combination of intraoperative blue dye injection and lymphoscintigraphy, the success rate was 95% (55/58). Metastatic disease was found in 14 sentinel lymph nodes (13 patients with melanoma and melanocytic lesions, and 1 patient with rhabdomyosarcoma).
CONCLUSION: We have found that lymphoscintigraphy with SLNB is an effective method to identify patients who may benefit from more extensive lymph-node dissection and to identify those patients who are unlikely to benefit from further lymph-node exploration.
DeRosa J, Smit JRMyxoid malignant fibrous histiocytoma presenting as a midline nasal mass.
Ear Nose Throat J. 2012; 91(4):E3-5 [PubMed
Myxoid malignant fibrous histiocytoma is a rare type of pediatric non-rhabdomyosarcoma soft-tissue sarcoma. The case of a 5-year-old girl is presented, highlighting the potential for multiple pitfalls and aberrant differential diagnoses that need to be identified for successful treatment of pediatric myxofibrosarcomas. An awareness of these tumors and a call for standardized postsurgical treatment protocols is necessary in order to successfully treat children with this disease.
Citti A, Boldrini R, Inserra A, et al.Expression of multidrug resistance-associated proteins in paediatric soft tissue sarcomas before and after chemotherapy.
Int J Oncol. 2012; 41(1):117-24 [PubMed
Expression of multidrug resistance (MDR) proteins is thought to significantly contribute to the different biological/clinical behaviour of soft tissue sarcomas (STS) of various histological types and clinicopathological stages, as they are responsible for active efflux of cytotoxic drugs from tumour cells. We investigated the expression of 3 MDR proteins, i.e., permeability glycoprotein 1 (P-gp), multidrug resistance-associated protein 1 (MRP1) and multidrug resistance 3 (MDR3), in 43 STS specimens from newly-diagnosed paediatric patients, 31 with rhabdomyosarcoma (RMS) and 12 with non-RMS STS. To assess the influence of chemotherapy on STS drug resistance, the number of MDR-associated protein-positive cells was determined in 15 patients on both primary lesions before chemotherapy and on residual tumour after chemotherapy. At least one of the MDR-associated proteins tested was detected in 84% of primary untreated STS specimens. In these specimens, MRP1 was detected in a high percentage (70%) of the cases, followed by MDR3 in 58% and P-gp in 44%. Many specimens showed co-expression of two different MDR proteins. Interestingly, MDR3 was significantly associated with the presence of PAX3/PAX7-FKHR transcripts in RMS (p<0.05). Moreover, expression of MRP1 and MDR3 was significantly more frequent in group III and IV tumours as compared with those of groups I and II (p<0.01). After chemotherapy MRP1, MDR3 and, to a lesser extent, P-gp expression was found to be increased in most of the samples. The frequent expression of these MDR-associated proteins in primary tumour cells before chemotherapy and the increase of their levels after chemotherapy, suggest that these proteins play a pivotal role in conferring drug resistance and in producing therapy-induced differentiation on STS.
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