Childhood Soft Tissue Sarcomas
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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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Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Kerouanton A, Jimenez I, Cellier C, et al.
Synovial sarcoma in children and adolescents.
J Pediatr Hematol Oncol. 2014; 36(4):257-62 [PubMed] Related Publications
Synovial sarcoma (SS) is a high-grade soft tissue sarcoma characterized by local invasiveness and a propensity to metastasize, affecting pediatric, adolescent, and adult populations. The peak incidence is observed in the third decade of life and SS is the most common nonrhabdomyosarcoma soft tissue sarcoma in childhood and adolescence. Although pediatric and adult SS appear clinically and radiologically identical, treatment modalities may differ according to the patient's age. For many years, pediatric oncologists have treated SS as a chemosensitive tumor according to the "rhabdomyosarcoma philosophy." In contrast, adult oncologists generally treat this tumor as a poorly chemosensitive tumor and focus on local control. The authors propose an update of SS in the pediatric population and analyze their results to those obtained in adults.

Related: Synovial Sarcoma

Rudzinski ER, Anderson JR, Lyden ER, et al.
Myogenin, AP2β, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children's oncology group.
Am J Surg Pathol. 2014; 38(5):654-9 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Pediatric rhabdomyosarcoma (RMS) is traditionally classified on the basis of the histologic appearance into alveolar (ARMS) and embryonal (ERMS) subtypes. The majority of ARMS contain a PAX3-FOXO1 or PAX7-FOXO1 gene fusion, but about 20% do not. Intergroup Rhabdomyosarcoma Study stage-matched and group-matched ARMS typically behaves more aggressively than ERMS, but recent studies have shown that it is, in fact, the fusion status that drives the outcome for RMS. Gene expression microarray data indicate that several genes discriminate between fusion-positive and fusion-negative RMS with high specificity. Using tissue microarrays containing a series of both ARMS and ERMS, we identified a panel of 4 immunohistochemical markers-myogenin, AP2β, NOS-1, and HMGA2-which can be used as surrogate markers of fusion status in RMS. These antibodies provide an alternative to molecular methods for identification of fusion-positive RMS, particularly in cases in which there is scant or poor-quality material. In addition, these antibodies may be useful in fusion-negative ARMS as an indicator that a variant gene fusion may be present.

Related: Monoclonal Antibodies PAX7 gene

Kikuchi K, Hettmer S, Aslam MI, et al.
Cell-cycle dependent expression of a translocation-mediated fusion oncogene mediates checkpoint adaptation in rhabdomyosarcoma.
PLoS Genet. 2014; 10(1):e1004107 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.

Related: Rhabdomyosarcoma PAX3 gene

Zin A, Bertorelle R, Dall'Igna P, et al.
Epithelioid rhabdomyosarcoma: a clinicopathologic and molecular study.
Am J Surg Pathol. 2014; 38(2):273-8 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma and is mostly represented by the embryonal (ERMS) and alveolar (ARMS) histotypes. Whereas ERMS shows variable genetic alterations including TP53, RB1, and RAS mutations, ARMS carries a gene fusion between PAX3 or PAX7 and FOXO1. Epithelioid RMS is a morphologic variant of RMS recently described in adults. Five cases of epithelioid RMS were identified after histologic review of 85 cases of ARMS enrolled in Italian therapeutic protocols. Immunostaining analyses (muscle-specific actin, desmin, myogenin, AP-2β, EMA, cytokeratins, INI-1) and reverse transcription polymerase chain reaction assays to detect MyoD1, myogenin, and PAX3/7-FOXO1 transcripts were performed. In 4 cases DNA sequencing of TP53 was performed; and RB1 allelic imbalance and homozygous deletion were analyzed by quantitative real-time polymerase chain reaction. Histologically, epithelioid RMS displayed sheets of large cells without rhabdomyoblastic differentiation or anaplasia in 3 and prominent rhabdoid cells in 2; necrosis was evident in 4, often with a geographic pattern. Immunostainings for INI, desmin, myogenin (scattered cells in 4, diffuse in 1) were positive in all; EMA and MNF116 were positive in 2; AP-2β was negative. PAX3/7-FOXO1 transcripts were absent. In all cases RB1 was wild type, and a TP53 mutation at R273H codon was found in 1. All patients are in complete remission, with a median follow-up of 6 years. Epithelioid RMS may occur in children and is probably related to ERMS, as suggested by lack of fusion transcripts, weak staining for myogenin, negative AP-2β, evidence of TP53 mutation (although only in 1 case), and a favorable clinical course.

Related: Rhabdomyosarcoma

Sangiolo D, Mesiano G, Gammaitoni L, et al.
Cytokine-induced killer cells eradicate bone and soft-tissue sarcomas.
Cancer Res. 2014; 74(1):119-29 [PubMed] Related Publications
Unresectable metastatic bone sarcoma and soft-tissue sarcomas (STS) are incurable due to the inability to eradicate chemoresistant cancer stem-like cells (sCSC) that are likely responsible for relapses and drug resistance. In this study, we investigated the preclinical activity of patient-derived cytokine-induced killer (CIK) cells against autologous bone sarcoma and STS, including against putative sCSCs. Tumor killing was evaluated both in vitro and within an immunodeficient mouse model of autologous sarcoma. To identify putative sCSCs, autologous bone sarcoma and STS cells were engineered with a CSC detector vector encoding eGFP under the control of the human promoter for OCT4, a stem cell gene activated in putative sCSCs. Using CIK cells expanded from 21 patients, we found that CIK cells efficiently killed allogeneic and autologous sarcoma cells in vitro. Intravenous infusion of CIK cells delayed autologous tumor growth in immunodeficient mice. Further in vivo analyses established that CIK cells could infiltrate tumors and that tumor growth inhibition occurred without an enrichment of sCSCs relative to control-treated animals. These results provide preclinical proof-of-concept for an effective strategy to attack autologous sarcomas, including putative sCSCs, supporting the clinical development of CIK cells as a novel class of immunotherapy for use in settings of untreatable metastatic disease.

Related: Cytokines

Chen X, Stewart E, Shelat AA, et al.
Targeting oxidative stress in embryonal rhabdomyosarcoma.
Cancer Cell. 2013; 24(6):710-24 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic analysis shows that embryonal tumors have more structural and copy number variations than alveolar tumors. Mutations in the RAS/NF1 pathway are significantly associated with intermediate- and high-risk embryonal rhabdomyosarcomas (ERMS). In contrast, alveolar rhabdomyosarcomas (ARMS) have fewer genetic lesions overall and no known recurrently mutated cancer consensus genes. To identify therapeutics for ERMS, we developed and characterized orthotopic xenografts of tumors that were sequenced in our study. High-throughput screening of primary cultures derived from those xenografts identified oxidative stress as a pathway of therapeutic relevance for ERMS.

Zhang M, Truscott J, Davie J
Loss of MEF2D expression inhibits differentiation and contributes to oncogenesis in rhabdomyosarcoma cells.
Mol Cancer. 2013; 12(1):150 [PubMed] Article available free on PMC after 09/12/2014 Related Publications
BACKGROUND: Rhabdomyosarcoma (RMS) is a highly malignant pediatric cancer that is the most common form of soft tissue tumors in children. RMS cells have many features of skeletal muscle cells, yet do not differentiate. Thus, our studies have focused on the defects present in these cells that block myogenesis.
METHODS: Protein and RNA analysis identified the loss of MEF2D in RMS cells. MEF2D was expressed in RD and RH30 cells by transient transfection and selection of stable cell lines, respectively, to demonstrate the rescue of muscle differentiation observed. A combination of techniques such as proliferation assays, scratch assays and soft agar assays were used with RH30 cells expressing MEF2D to demonstrate the loss of oncogenic growth in vitro and xenograft assays were used to confirm the loss of tumor growth in vivo.
RESULTS: Here, we show that one member of the MEF2 family of proteins required for normal myogenesis, MEF2D, is largely absent in RMS cell lines representing both major subtypes of RMS as well as primary cells derived from an embryonal RMS model. We show that the down regulation of MEF2D is a major cause for the failure of RMS cells to differentiate. We find that MyoD and myogenin are bound with their dimerization partner, the E proteins, to the promoters of muscle specific genes in RMS cells. However, we cannot detect MEF2D binding at any promoter tested. We find that exogenous MEF2D expression can activate muscle specific luciferase constructs, up regulate p21 expression and increase muscle specific gene expression including the expression of myosin heavy chain, a marker for skeletal muscle differentiation. Restoring expression of MEF2D also inhibits proliferation, cell motility and anchorage independent growth in vitro. We have confirmed the inhibition of tumorigenicity by MEF2D in a tumor xenograft model, with a complete regression of tumor growth.
CONCLUSIONS: Our data indicate that the oncogenic properties of RMS cells can be partially attributed to the loss of MEF2D expression and that restoration of MEF2D may represent a useful therapeutic strategy to decrease tumorigenicity.

Related: Rhabdomyosarcoma

Senerchia AA, Ribeiro KB, Rodriguez-Galindo C
Trends in incidence of primary cutaneous malignancies in children, adolescents, and young adults: a population-based study.
Pediatr Blood Cancer. 2014; 61(2):211-6 [PubMed] Related Publications
BACKGROUND: Skin cancer incidence among young adults is rising; however, the epidemiological characteristics of primary cutaneous lymphomas and cutaneous soft tissue sarcomas (CSTS) in individuals <30 years old has not been investigated. We analyzed the incidence and time-trends of primary cutaneous malignancies in children and adolescents/young adults (AYA).
PROCEDURE: SEER-17 and -13 data were used to assess the descriptive epidemiology and time-trends in incidence of primary cutaneous malignancies in children and AYA. SEERStat and Joinpoint softwares were utilized to estimate annual percent changes (APC) in incidence.
RESULTS: In total, 7,814 cases (ASR = 25.66/1,000,000 habitants) of primary skin cancers in <30 years old were diagnosed in 2000-2008. Females had a higher incidence of melanoma (risk ratio (RR) = 1.95; P < 0.001) and a lower risk of developing CSTS (RR = 0.64, P < 0.001). Compared to whites, blacks have a lower incidence of melanoma (RR = 0.03, P < 0.001), and higher risk of CSTS (RR = 2.28, P < 0.001). Melanoma increased in females over a 15-year period (1992-2006) (APC = 2.5, 95%CI = 1.8; 3.2), and the incidence of cutaneous T-cell lymphomas increased over the period 1992-2008 (APC = 9.5, 95% CI = 6.7; 12.4). CSTS incidence decreased among males over the period 1992-1999 (APC = -21.4, 95% CI -27.2; -15.1), particularly due to a decrease in Kaposi sarcoma incidence (AAPC 1992-2008 = -13.6, 95% CI = -22.4;-3.8), although with a notable racial disparity (whites, AAPC = -15.2, 95% CI = -23.2;-6.4; blacks, AAPC = -10.6, 95% CI = -13.2;-7.9).
CONCLUSIONS: Non-melanoma skin cancer is very rare in children and AYA. We have shown variation in time-trends in incidence as well as in incidence patterns by race, sex, age, and histologic type, highlighting the importance of descriptive epidemiology to better understand the characteristics of these malignancies.

Related: Haematological Malignancies & Realted Disorders Cutaneous T-cell lymphoma Melanoma Skin Cancer USA

Friedrich P, Ortiz R, Fuentes S, et al.
Barriers to effective treatment of pediatric solid tumors in middle-income countries: can we make sense of the spectrum of nonbiologic factors that influence outcomes?
Cancer. 2014; 120(1):112-25 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
BACKGROUND: The delivery of effective treatment for pediatric solid tumors poses a particular challenge to centers in middle-income countries (MICs) that already are vigorously addressing pediatric cancer. The objective of this study was to improve the current understanding of barriers to effective treatment of pediatric solid tumors in MICs.
METHODS: An ecologic model centered on pediatric sarcoma and expanded to country as the environment was used as a benchmark for studying the delivery of solid tumor care in MICs. Data on resources were gathered from 7 centers that were members of the Central American Association of Pediatric Hematologists and Oncologists (AHOPCA) using an infrastructure assessment tool. Pediatric sarcoma outcomes data were available, were retrieved from hospital-based cancer registries for 6 of the 7 centers, and were analyzed by country. Patients who were diagnosed from January 1, 2000 to December 31, 2009 with osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, and other soft tissue sarcomas were included in the analysis. To explore correlations between resources and outcomes, a pilot performance index was created.
RESULTS: The analyses identified specific deficits in human resources, communication, quality, and infrastructure. The treatment abandonment rate, the proportion of metastatic disease at diagnosis, the relapse rate, and the 4-year abandonment-sensitive overall survival (AOS) rate varied considerably by country, ranging from 1% to 38%, from 15% to 54%, from 24% to 52%, and from 21% to 51%, respectively. The treatment abandonment rate correlated inversely with health economic expenditure per capita (r = -0.86; P = .03) and life expectancy at birth (r = -0.93; P = .007). The 4-year AOS rate correlated inversely with the mortality rate among children aged <5 years (r = -0.80; P = 0.05) and correlated directly with the pilot performance index (r = 0.98; P = 0.005).
CONCLUSIONS: Initiatives to improve the effectiveness of treatment for pediatric solid tumors in MICs are warranted, particularly for pediatric sarcomas. Building capacity and infrastructure, improving supportive care and communication, and fostering comprehensive, multidisciplinary teams are identified as keystones in Central America. A measure that meaningfully describes performance in delivering pediatric cancer care is feasible and needed to advance comparative, prospective analysis of pediatric cancer care and to define resource clusters internationally.

Li SQ, Cheuk AT, Shern JF, et al.
Targeting wild-type and mutationally activated FGFR4 in rhabdomyosarcoma with the inhibitor ponatinib (AP24534).
PLoS One. 2013; 8(10):e76551 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
Rhabdomyosarcoma (RMS) is the most common childhood soft tissue sarcoma. Despite advances in modern therapy, patients with relapsed or metastatic disease have a very poor clinical prognosis. Fibroblast Growth Factor Receptor 4 (FGFR4) is a cell surface tyrosine kinase receptor that is involved in normal myogenesis and muscle regeneration, but not commonly expressed in differentiated muscle tissues. Amplification and mutational activation of FGFR4 has been reported in RMS and promotes tumor progression. Therefore, FGFR4 is a tractable therapeutic target for patients with RMS. In this study, we used a chimeric Ba/F3 TEL-FGFR4 construct to test five tyrosine kinase inhibitors reported to specifically inhibit FGFRs in the nanomolar range. We found ponatinib (AP24534) to be the most potent FGFR4 inhibitor with an IC50 in the nanomolar range. Ponatinib inhibited the growth of RMS cells expressing wild-type or mutated FGFR4 through increased apoptosis. Phosphorylation of wild-type and mutated FGFR4 as well as its downstream target STAT3 was also suppressed by ponatinib. Finally, ponatinib treatment inhibited tumor growth in a RMS mouse model expressing mutated FGFR4. Therefore, our data suggests that ponatinib is a potentially effective therapeutic agent for RMS tumors that are driven by a dysregulated FGFR4 signaling pathway.

Related: Apoptosis Rhabdomyosarcoma

Parham DM, Barr FG
Classification of rhabdomyosarcoma and its molecular basis.
Adv Anat Pathol. 2013; 20(6):387-97 [PubMed] Related Publications
Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, has traditionally been classified into embryonal rhabdomyosarcoma (ERMS) and alveolar rhabdomyosarcoma (ARMS) for pediatric oncology practice. This review outlines the historical development of classification of childhood RMS and the challenges that have been associated with it, particularly problems with the diagnosis of "solid variant" ARMS and its distinction from ERMS. In addition to differences in clinical presentation and outcome, a number of genetic features underpin separation of ERMS from ARMS. Genetic differences associated with RMS subclassification include the presence of reciprocal translocations and their associated fusions in ARMS, amplification of genes in ARMS and its fusion subsets, chromosomal losses and gains that mostly occur in ERMS, and allelic losses and mutations usually associated with ERMS. Chimeric proteins encoded in most ARMS from the fusion of PAX3 or PAX7 with FOXO1 are expressed, result in a distinct pattern of downstream protein expression, and appear to be the proximate cause of the bad outcome associated with this subtype. A sizeable minority of ARMS lacks these fusions and shares the clinical and biological features of ERMS. A battery of immunohistochemical tests may prove useful in separating ERMS from ARMS and fusion-positive ARMS from fusion-negative ARMS. Because of limitation of predicting outcome solely based on histologic classification, treatment protocols will begin to utilize fusion testing for stratification of affected patients into low-risk, intermediate-risk, and high-risk groups.

Related: PAX7 gene PAX3 gene

Thacker MM
Malignant soft tissue tumors in children.
Orthop Clin North Am. 2013; 44(4):657-67 [PubMed] Related Publications
Soft tissue masses are frequently seen in children. Although most are benign or reactive, soft tissue sarcomas (STS)-both rhabdomyosarcoma (most common) and non-rhabdo STS, do occur in the extremities. Appropriate evaluation of extremity soft tissue tumors often includes a biopsy as the clinical and imaging features may not be enough to establish a definitive diagnosis. Much needs to be done for improving the treatment of these rare but often devastating sarcomas. Given the small numbers of these cases seen at various centers, collaborative efforts should be made to further our understanding and improve the management of these challenging cases.

Related: Cancer Cytogenetics

Chu WP
Anterior mediastinal alveolar rhabdomyosarcoma in an infant: rare site for a common paediatric tumour.
Hong Kong Med J. 2013; 19(5):458-9 [PubMed] Related Publications
Rhabdomyosarcoma is a common paediatric soft tissue tumour. However, the anterior mediastinum is an extremely rare site for its occurrence. This report describes the imaging and histological findings of such a tumour in a 4-month-old boy.

Alcorn KM, Deans KJ, Congeni A, et al.
Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging.
J Pediatr Surg. 2013; 48(9):1903-6 [PubMed] Related Publications
BACKGROUND: The purpose of this study was to report our experience with sentinel lymph node biopsy (SLNB) for pediatric soft tissue sarcomas to add to the limited literature about its feasibility, utility, and concordance with pre-operative imaging, including CT and (18)F-FDG PET (PET) scanning.
METHODS: Medical records of patients with a sarcoma who underwent SLNB as part of their treatment for a soft tissue sarcoma at our institution from 2000 to 2011 were identified and reviewed.
RESULTS: Eight patients underwent SLNB for soft tissue sarcoma during the study period. Two patients had positive SLNBs; both of these patients had rhabdomyosarcoma. Three patients with pathologically enlarged lymph nodes on CT scan underwent PET functional imaging prior to SLNB. The PET suggested the presence of nodal disease in all three patients; however, only one of these patients had a positive SLNB.
CONCLUSIONS: Our series confirms that SLNB is feasible in pediatric sarcoma patients. Small numbers preclude definitive conclusions regarding the utility of SLNB compared with PET, however our data suggest functional imaging alone may not be sufficient to definitively determine lymph node status in these patients. Surgical lymph node sampling may still need to be performed to accurately identify nodal status in pediatric patients with soft tissue sarcoma.

Diaconescu S, Burlea M, Miron I, et al.
Childhood rhabdomyosarcoma. Anatomo-clinical and therapeutic study on 25 cases. Surgical implications.
Rom J Morphol Embryol. 2013; 54(3):531-7 [PubMed] Related Publications
UNLABELLED: Rhabdomyosarcomas (RMS) are the most frequent soft tissue sarcomas of childhood. Despite advances in knowledge about biological pathways of tumorigenesis, risk stratification and multimodal treatment, the immediate and long-term prognosis of these lesions in many countries with limited resources is still poor.
PATIENTS AND METHODS: Twenty-five histologically confirmed pediatric RMS were recorded during the period of study. Demography, clinical presentation, diagnostic means, pretreatment staging and post-surgical grouping, histological type, therapy and outcome were evaluated.
RESULTS: The mean age was 6.7 years; the group included 12 boys and 13 girls. Twelve lesions were localized in the genitourinary tract, eight in the trunk and extremities, two cases each in head and neck and retroperitoneum and one case in biliary tract. Primary surgical attempt was performed in 15 patients but only in nine of them underwent complete resection (three with free margins) other six cases achieving removal with residual disease. In 10 cases, solely biopsy was possible. Twenty-four patients received chemotherapy but only four cases performed radiation therapy. Overall survival rate was only 36% (nine cases).
CONCLUSIONS: As mean feature children from our series had late presentation with locally extended (bulky and node positive) lesions and unfavorable sites. Improved multimodal management of RMS in recent years will probably lead to better survival curves in an increasing number of cases and an outstanding outcome in children with locally advanced disease.

Related: Rhabdomyosarcoma

Zhang WL, Zhang Y, Huang DS, et al.
Clinical character of pediatric head and neck rhabdomysarcomas: a 7-year retrospective study.
Asian Pac J Cancer Prev. 2013; 14(7):4089-93 [PubMed] Related Publications
OBJECTIVE: The rhabdomysarcoma (RMS) is most common soft tissue carcinoma in children, mostly found in the head and neck with high degree of malignancy. The current study aimed to summarize clinical data and evaluate treatment outcome of cases in a single hospital.
METHODS: Forty-one (24 male, 17 female) children with newly diagnosed RMS in Beijing Tong Ren Hospital were enrolled between November, 2004 and May, 2011. The. Students' t and Chi tests were then performed on retrospectively reviewed clinical data, followed by survival analysis based on the Kaplan Meier method using SPSS 17.0 software.
RESULTS: Of all cases, 32 were treated by common chemotherapy, and 3 cases with stage III RMS received high-dose chemotherapy and auto-peripheral blood stem cell transplantation (APBSCT). Side-effects in the former were: I grade for 62.5% (20/32), II grade for 28.1% (9/32), III grade account for 9.275% (3/32). Side-effects of 3 cases with APBSCT: 2 were I grade, 1 was III grade. The median follow-up time of 41 RMS cases was 41 months. Four cases were lost to follow-up, 7 cases recurred, and 5 cases died of cerebral metastasis, witha total survival rate was 86.5% (32/37). CR rate was 67.6% (25/37), PR was 18.9% (7/37).
CONCLUSION: Multidiscipline treatment including chemotherapy, radiotherapy, surgery and auto-PBSCT is highly recommended for pediatric patients with head and neck RMS.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Rhabdomyosarcoma

Hishiki T, Saito T, Mitsunaga T, et al.
Optimal surgical treatment and urological outcomes in boys with pelvic and urogenital rhabdomyosarcomas and soft tissue sarcomas.
Pediatr Surg Int. 2013; 29(10):1077-82 [PubMed] Related Publications
BACKGROUND: Soft tissue sarcomas (STS) of pelvic origin in boys often involve the urogenital organs. The optimal extensiveness of radical surgery has long been an issue of discussion, since exenterative surgeries result in severe urogenital adverse effects. We conducted a retrospective review of patients with pelvic STS treated in two regional center hospitals and assessed the radicality of surgery and the functional outcome of the bladder.
PATIENTS: Medical records and surgical reports of nine cases (embryonal rhabdomyosarcoma 6, malignant triton tumor 2, suspected rhabdomyosarcoma 1) treated within 1997-2012 were reviewed. Site of origin was prostate in seven, retroperitoneal in two. Average follow-up period was 96 months.
TREATMENT AND OUTCOME: All cases were subjected to neoadjuvant chemotherapy. Response was PR in four, SD in two, and PD in two. Radical surgery resulted in gross total resection in eight, and partial resection in one. Three underwent cystoprostatectomy, two cases underwent prostatectomy, and bladder-preserving tumor resection was carried out in four cases. At the last follow-up, three retained a functional bladder. Two required augmentation cystoplasty with intestinal conduits.
CONCLUSIONS: The majority of the on-going clinical trials recommend conservative surgery for bladder/prostate rhabdomyosarcoma, and to preserve the bladder function particularly in chemosensitive tumors. Some other groups, however, advocate the importance of radical surgery to prevent local relapse. These reports include heterogenous group of patients in the cohort, and therefore it is difficult to draw a conclusion of which approach truly contributes to the survival of the patients better. Future studies should evaluate bladder and sexual function objectively to establish reliable evidence regarding the benefit and adverse effects of different surgical approaches. These data would be informative to optimize the treatment balance for children with pelvic rhabdomyosarcomas.

Related: Rhabdomyosarcoma

Schoot RA, McHugh K, van Rijn RR, et al.
Response assessment in pediatric rhabdomyosarcoma: can response evaluation criteria in solid tumors replace three-dimensional volume assessments?
Radiology. 2013; 269(3):870-8 [PubMed] Related Publications
PURPOSE: To investigate (a) interobserver variability for three-dimensional (3D) (based on European Pediatric Soft-Tissue Sarcoma Study Group [EpSSG] guidelines) and one-dimensional (1D) (based on Response Evaluation Criteria in Solid Tumors [RECIST]) response assessments, (b) intermethod variability between EpSSG guidelines and RECIST, and (c) clinically relevant consequences of interobserver and intermethod variability in pediatric patients with rhabdomyosarcoma.
MATERIALS AND METHODS: The study was approved by the Academic Medical Center Ethics Committee and the Great Ormond Street Hospital Ethics Committee; both committees waived the requirement for informed consent because of the retrospective nature of the study. Data were analyzed from 124 consecutive male and female children and young adults (age range, 1-18 years) with rhabdomyosarcoma at two institutions (1999-2009) with relevant imaging studies. Tumors were measured by two radiologists (1D and 3D measurements) at diagnosis and after induction chemotherapy. Interobserver variability was analyzed by using three different tests, and the intermethod variation was calculated.
RESULTS: Sixty-four eligible patients were included (median age, 4.6 years). Agreement between observers for EpSSG guidelines and RECIST was moderate (κ = 0.565 and 0.592, respectively); interobserver variation led to different potential treatment decisions in nine (14%) and 11 (17%) of the 64 patients, respectively. Comparison of EpSSG guidelines and RECIST resulted in 13 discrepant response classifications (20%), which were equally distributed (under- and overestimation of response) and led to consequences for treatment choice in five patients (8%).
CONCLUSION: EpSSG guidelines and RECIST are not interchangeable; neither technique demonstrated superiority in this study. These findings should be taken into account in future study protocol design. Online supplemental material is available for this article.

Related: Rhabdomyosarcoma

Krishnan J, Hathiramani V, Hastak M, Redkar RG
Myxoid lipoblastoma.
Indian Pediatr. 2013; 50(6):603-5 [PubMed] Related Publications
A rapidly growing soft tissue mass in the axilla of an infant raises the suspicion of a lipoblastoma or a liposarcoma. Excisional/incisional biopsy is vital in confirming the diagnosis and hence avoiding aggressive extirpation. This case report highlights the role of histopathology and immunohistochemistry as the gold standard in differentiating a lipoblastoma from a liposarcoma. In some cases where the histopathology is inconclusive, genetic rearrangement of the PLAG1 (pleomorphic adenoma gene 1) oncogene on chromosome 8q12 helps in confirming the diagnosis of lipoblastoma.

Guo Y, Xie D, Yan J, et al.
Primary pulmonary rhabdomyosarcoma with brain metastases in a child: a case report with medico-legal implications.
J Forensic Leg Med. 2013; 20(6):720-3 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is a rare type of soft tissue sarcoma that mainly affects children. RMS in childhood commonly occurs in the head and neck, followed by the genitourinary tract. Primary pulmonary rhabdomyosarcoma (PPR) is extremely rare. We report a 31-month-old girl who had PPR with brain metastasis. The girl with wheezing and cough of 3 weeks and vomiting of 1 day was referred to a county hospital. At 9:00 a.m., a chest X-ray showed an abnormal shadow on a chest radiogram. Four hours later, in the process of computed tomography (CT) scan her condition deteriorated dramatically, while resuscitation efforts were unsuccessful. CT showed a solid mass in the right middle lung lobe. Subsequent autopsy revealed a large tumour located in the right middle lung lobe. Surprisingly, a mass of haematoma appearance was found in the left occipital lobe. Histological and immunohistochemical investigations of the masses established the diagnosis of PPR with brain metastasis. Herniation of brain, caused by the brain metastasis, was ascertained as the cause of death. The morphological and pathological findings are presented; the difficulty to diagnose PPR and the medico-legal implications are discussed.

Related: Lung Cancer Rhabdomyosarcoma

Fanzani A, Monti E, Donato R, Sorci G
Muscular dystrophies share pathogenetic mechanisms with muscle sarcomas.
Trends Mol Med. 2013; 19(9):546-54 [PubMed] Related Publications
Several lines of recent evidence have opened a new debate on the mechanisms underlying the genesis of rhabdomyosarcoma, a pediatric soft tissue tumor with a widespread expression of muscle-specific markers. In particular, it is increasingly evident that the loss of skeletal muscle integrity observed in some mouse models of muscular dystrophy can favor rhabdomyosarcoma formation. This is especially true in old age. Here, we review these experimental findings and focus on the main molecular and cellular events that can dictate the tumorigenic process in dystrophic muscle, such as the loss of structural or regulatory proteins with tumor suppressor activity, the impaired DNA damage response due to oxidative stress, the chronic inflammation and the conflicting signals arising within the degenerated muscle niche.

Related: Rhabdomyosarcoma

Duan S, Zhang X, Wang G, et al.
Primary giant congenital infantile fibrosarcoma of the left forearm.
Chir Main. 2013; 32(4):265-7 [PubMed] Related Publications
Infantile fibrosarcoma is a rare soft tissue tumor in the infant, and only a few cases have been reported as congenital. We report a case of congenital infantile fibrosarcoma of the left forearm at birth. An amputation was performed because the tumor was relapsed soon after surgical removal, and associated with anabrosis and bleeding.

Tarik E, Lamiae R, Abdelouahed A, et al.
Unusual case of congenital/infantile fibrosarcoma in a new born.
Afr J Paediatr Surg. 2013 Apr-Jun; 10(2):185-7 [PubMed] Related Publications
Congenital infantile fibrosarcoma (CIFS) is a rare mesenchymal tumor that is primarily developed in the soft tissue of distal extremities and occasionally in unusual locations such as the lung and retroperitoneum. It occurs mainly in children below the age of 5 years. About 200 cases have been reported in the literature so far, very few of them in new-borns. The prognosis of this tumor is relatively good compared to adult forms. We report an unusual case of CIFS occurring in new-born mimicking an hemangioma and causing hemorrhage in the neonatal period. The tumor is located in the left arm and axilla and associated with a hand malformation. A shoulder amputation is performed after chemotherapy failure. The infant is now two-years old with no recurrence.

Glade Bender JL, Lee A, Reid JM, et al.
Phase I pharmacokinetic and pharmacodynamic study of pazopanib in children with soft tissue sarcoma and other refractory solid tumors: a children's oncology group phase I consortium report.
J Clin Oncol. 2013; 31(24):3034-43 [PubMed] Article available free on PMC after 20/08/2014 Related Publications
PURPOSE: Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors.
PATIENTS AND METHODS: Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD.
RESULTS: Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41).
CONCLUSION: Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Related: Angiogenesis Inhibitors Cancer Prevention and Risk Reduction Children's Cancer Web: Home Page Pazopanib (Votrient)

Orbach D, Brennan B, Casanova M, et al.
Paediatric and adolescent alveolar soft part sarcoma: A joint series from European cooperative groups.
Pediatr Blood Cancer. 2013; 60(11):1826-32 [PubMed] Related Publications
BACKGROUND: Alveolar soft part sarcomas (ASPS) are generally chemo- and radio-resistant mesenchymal tumours, with no standardized treatment guidelines. We describe the clinical behaviour of paediatric ASPS and compare these features to previously reported adult series.
PATIENTS AND METHODS: The clinical data of 51 children and adolescents with ASPS, prospectively enrolled in or treated according to seven European Paediatric trials were analysed.
RESULTS: Median age was 13 years [range: 2-21]. Primary sites included mostly limbs (63%). IRS post-surgical staging was: IRS-I (complete resection) 35%, II (microscopic residual disease) 20%, III (gross residual disease) 18% and IV (metastases) 27%. Only 3 of the 18 evaluable patients (17%) obtained a response to conventional chemotherapy. After a median follow-up of 126 months (range: 9-240), 14/18 patients with IRS-I tumour, 10/10 IRS-II, 7/9 IRS-III and 2/14 IRS-IV were alive in remission. Sunitinib treatment achieved two very good partial responses in four patients. Ten-year overall survival (OS) and event free survival (EFS) was 78.0 ± 7% and 62.8 ± 7% respectively. Stage IV, size >5 cm and T2 tumours had a poorer outcome, but only IRS staging was an independent prognostic factor.
CONCLUSIONS: ASPS is a very rare tumour frequently arising in adolescents and in the extremities, and chemo resistant. Local surgical control is critical. ASPS is a poorly chemo sensitive tumour. For IRS-III/IV tumours, delayed radical local therapies including surgery are essential. Metastatic patients had a poor prognosis but targeted therapies showed promising results.

Lupo PJ, Zhou R, Skapek SX, et al.
Allergies, atopy, immune-related factors and childhood rhabdomyosarcoma: a report from the Children's Oncology Group.
Int J Cancer. 2014; 134(2):431-6 [PubMed] Article available free on PMC after 15/01/2015 Related Publications
Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malignancies; however, to our knowledge, there have been no assessments of atopy and childhood RMS. Therefore, we explored this association in a case-control study of 322 childhood RMS cases and 322 pair-matched controls. Cases were enrolled in a trial run by the Intergroup Rhabdomyosarcoma Study Group. Controls were matched to cases on race, sex and age. The following atopic conditions were assessed: allergies, asthma, eczema and hives; in addition, we examined other immune-related factors: birth order, day-care attendance and breastfeeding. Conditional logistic-regression models were used to calculate an odds ratio (OR) and 95% confidence interval (CI) for each exposure, adjusted for age, race, sex, household income and parental education. As the two most common histologic types of RMS are embryonal (n=215) and alveolar (n=66), we evaluated effect heterogeneity of these exposures. Allergies (OR=0.60, 95% CI: 0.41-0.87), hives (OR = 0.61, 95% CI: 0.38-0.97), day-care attendance (OR=0.48, 95% CI: 0.32-0.71) and breastfeeding for ≥ 12 months (OR=0.36, 95% CI: 0.18-0.70) were inversely associated with childhood RMS. These exposures did not display significant effect heterogeneity between histologic types (p>0.52 for all exposures). This is the first study indicating that atopic exposures may be protective against childhood RMS, suggesting additional studies are needed to evaluate the immune system's role in the development of this tumor.

Related: Rhabdomyosarcoma

Keller C, Guttridge DC
Mechanisms of impaired differentiation in rhabdomyosarcoma.
FEBS J. 2013; 280(17):4323-34 [PubMed] Related Publications
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood, with presumed skeletal muscle origins, because of its myogenic phenotype. RMS is composed of two main subtypes, embryonal RMS (eRMS) and alveolar RMS (aRMS). Whereas eRMS histologically resembles embryonic skeletal muscle, the aRMS subtype is more aggressive and has a poorer prognosis. In addition, whereas the genetic profile of eRMS is not well established, aRMS is commonly associated with distinct chromosome translocations that fuse domains of the transcription factors Pax3 and Pax7 to the forkhead family member FOXO1A. Both eRMS and aRMS tumor cells express myogenic markers such as MyoD, but their ability to complete differentiation is impaired. How this impairment occurs is the subject of this review, which will focus on several themes, including signaling pathways that converge on Pax-forkhead gene targets, alterations in MyoD function, epigenetic modifications of myogenic promoters, and microRNAs whose expression patterns in RMS alter key regulatory circuits to help maintain tumor cells in an opportunistically less differentiated state.

Related: Rhabdomyosarcoma

Novák J, Vinklárek J, Bienertová-Vašků J, Slabý O
MicroRNAs involved in skeletal muscle development and their roles in rhabdomyosarcoma pathogenesis.
Pediatr Blood Cancer. 2013; 60(11):1739-46 [PubMed] Related Publications
MicroRNAs (miRs) are small non-coding RNAs known to fulfill various functions in tissue development, function, and pathogenesis of various diseases, including cancer. Rhabdomyosarcoma (RMS) represents the most common soft tissue tumor in the pediatric population. miRs have been shown to play important roles in RMS pathogenesis and some of the studies suggest their potential as diagnostic, prognostic, and even therapeutic tools facilitating better management of this disease. This review summarizes current information about the role of miRs in the development of normal skeletal muscle and their deregulation in RMS.

Related: Rhabdomyosarcoma

Goswamy J, Aggarwal R, Bruce IA, Rothera MP
Kasabach-Merritt syndrome in a child with upper airway compromise and spontaneous periorbital bruising.
Ear Nose Throat J. 2013; 92(6):E16 [PubMed] Related Publications
A hemangioma that rapidly increases in size has the potential to trap platelets and cause a consumptive coagulopathy. We describe the case of an 18-week-old boy who was brought to a local emergency department with ecchymosis on his nasal bridge and medial epicanthi, as well as a subconjunctival hemorrhage. He was noted to be anemic and thrombocytopenic. Packed red blood cells and platelets were transfused. However, despite hematologic correction, the ecchymosis and petechiae worsened, and a mass became evident in the right posterior triangle of the patient's neck. Computed tomography demonstrated a lobular soft-tissue-density mass in the right posterior triangle that extended to the level of the skull base. Histologic analysis of a biopsy specimen revealed that the lesion was a giant kaposiform hemangioma. The patient was diagnosed with Kasabach-Merritt syndrome, and prednisolone was commenced as a first-line treatment. However, the mass continued to grow, resulting in inspiratory stridor. Magnetic resonance imaging revealed encroachment into the thecal sac and compression of the spinal cord. The lesion was embolized, and vincristine therapy was commenced. Following a second embolization, the size of the lesion decreased and no further blood products were required. The hemangioma was deemed to be unresectable. The successful treatment in this case was dependent on the maintenance of hemostasis, the initial medical treatment with a corticosteroid, repeat embolization, and longer-term control with vincristine.

Related: Head and Neck Cancers Head and Neck Cancers - Molecular Biology Kaposi Sarcoma Vincristine

Dang ND, Dang PT, Samuelian J, Paulino AC
Lymph node management in patients with paratesticular rhabdomyosarcoma: a population-based analysis.
Cancer. 2013; 119(17):3228-33 [PubMed] Related Publications
BACKGROUND: Paratesticular rhabdomyosarcoma (PTRMS) is the most common primary solid tumor arising from the mesenchymal tissue of the testis. Traditionally, retroperitoneal lymph node dissection is not recommended for children aged <10 years because of the morbidity of the procedure and low risk of retroperitoneal lymph node involvement. In the current study, the authors analyzed the patient and tumor characteristics of PTRMS as well as survival outcomes associated with lymph node dissection status.
METHODS: A total of 255 cases of PTRMS were identified from the patient data reported by the Surveillance, Epidemiology, and End Results (SEER) program of the National Cancer Institute from 1973 through 2009.
RESULTS: Among 173 patients aged ≥ 10 years, lymph node dissection was found to improve the 5-year overall survival (OS) rate from 64% to 86% (P  <  0.01). Conversely, patients aged <10 years fared extremely well regardless of lymph node dissection status; the 5-year OS rate was 100% and 97%, respectively, for patients who did versus those who did not undergo lymph node dissection (P  = .37). The yield of positive lymph nodes was approximately ≥  20% when <  11 lymph nodes were removed. The incidence of lymph node involvement was also higher in older patients compared with younger patients (40% vs 8%). Radiotherapy improved the OS rate in patients with lymph node involvement (5-year OS rate: 90% with vs 36% without radiation; P < .0001).
CONCLUSIONS: Lymph node dissection is recommended in patients aged ≥10 years. Radiotherapy is beneficial in patients with lymph node-positive disease.

Related: Rhabdomyosarcoma Testicular Cancer

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