Classification of Rhabdomyosarcoma and Its Molecular Basis

*Department of Pathology, University of Oklahoma Health Science Center, Oklahoma City, OK †Laboratory of Pathology, National Cancer Institute, Bethesda, MD.
Advances in anatomic pathology (Impact Factor: 3.23). 11/2013; 20(6):387-397. DOI: 10.1097/PAP.0b013e3182a92d0d
Source: PubMed


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.

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    • "Rhabdomyosarcoma (RMS) is the most common pediatric softtissue sarcoma, accounting for 50% of all neoplasias. It is one of the 10 most frequent childhood/adolescent tumors, with an incidence of 4–5 cases per million per year [1] [2] [3]. RMS may occur anywhere in the body but it is often found in the head and neck region or the genitourinary tract [4]. "
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    ABSTRACT: The treatment of rhabdomyosarcoma (RMS) is challenging, and the prognosis remains especially poor for high-grade RMS with metastasis. The conventional treatment of RMS is based on multi-agent chemotherapy combined with resection and radiotherapy, which are often marked by low success rate. Alternative therapeutic options include the combination of standard treatments with immunotherapy. We generated a microtubule-associated protein (MAP)-based fully human cytolytic fusion protein (hCFP) targeting the fetal acetylcholine receptor, which is expressed on RMS cells. We were able to express and purify functional scFv35-MAP from Escherichia coli cells. Moreover, we found that scFv35-MAP is rapidly internalized by target cells after binding its receptor, and exhibits specific cytotoxicity towards FL-OH1 and RD cells in vitro. We also confirmed that scFv35-MAP induces apoptosis in FL-OH1 and RD cells. The in vivo potential of scFv35-MAP will need to be considered in further studies. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 04/2015; 365(2). DOI:10.1016/j.canlet.2015.04.004 · 5.62 Impact Factor
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    • "Rhabdomyosarcoma (RMS) is a primarily pediatric malignancy which accounts for 50% of all soft tissue sarcomas and is therefore one of the ten most common forms of neoplasia among children and adolescents [1]. RMS can be subdivided into embryonal (eRMS), alveolar (aRMS) and pleomorphic (pRMS) subtypes, the first of which accounts for 70% of all cases and is characterized by several mutations that cause both, gain and loss of function phenotypes [2]. "
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    ABSTRACT: The treatment of rhabdomyosarcoma (RMS) remains challenging, with metastatic and alveolar RMS offering a particularly poor prognosis. Therefore, the identification and evaluation of novel antigens, which are suitable targets for immunotherapy, is one attractive possibility to improve the treatment of this disease. Here we show that chondroitin sulfate proteoglycan 4 (CSPG4) is expressed on RMS cell lines and RMS patient material. We evaluated the immunotoxin (IT) αMCSP-ETA', which specifically recognizes CSPG4 on the RMS cell lines RD, FL-OH1, TE-671 and Rh30. It is internalized rapidly, induces apoptosis and thus kills RMS cells selectively. We also demonstrate the specific binding of this IT to RMS primary tumor material from three different patients.
    Cancer Letters 07/2014; 352(2). DOI:10.1016/j.canlet.2014.07.006 · 5.62 Impact Factor
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    • "In cancer, there is mounting evidence that pCav-1 occurrence often predicts unfavorable outcome by supporting anchorage-independent cell growth, migration, invasiveness and multidrug resistance [11]–[15]. Rhabdomyosarcoma (RMS) is a pediatric soft-tissue cancer [16]–[20] that arises from various muscle and non-muscle progenitors characterized by interrupted myogenesis [21]–[28]. The current classification includes two major histological variants, known as embryonal (ERMS) and alveolar (ARMS), with the former characterized by a complex genomic aetiogenesis [16], [17] and the latter by the prevalent expression of chimeric transcription factors generated by the fusion of the paired box 3 or 7 with forkhead box O1 (Pax3-Foxo1 or Pax7-Foxo1) as a result of specific chromosomal translocations [29], [30]. "
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    ABSTRACT: Caveolin-1 (Cav-1) can ambiguously behave as either tumor suppressor or oncogene depending on its phosphorylation state and the type of cancer. In this study we show that Cav-1 was phosphorylated on tyrosine 14 (pCav-1) by Src-kinase family members in various human cell lines and primary mouse cultures of rhabdomyosarcoma (RMS), the most frequent soft-tissue sarcoma affecting childhood. Cav-1 overexpression in the human embryonal RD or alveolar RH30 cells yielded increased pCav-1 levels and reinforced the phosphorylation state of either ERK or AKT kinase, respectively, in turn enhancing in vitro cell proliferation, migration, invasiveness and chemoresistance. In contrast, reducing the pCav-1 levels by administration of a Src-kinase inhibitor or through targeted Cav-1 silencing counteracted the malignant in vitro phenotype of RMS cells. Consistent with these results, xenotransplantation of Cav-1 overexpressing RD cells into nude mice resulted in substantial tumor growth in comparison to control cells. Taken together, these data point to pCav-1 as an important and therapeutically valuable target for overcoming the progression and multidrug resistance of RMS.
    PLoS ONE 01/2014; 9(1):e84618. DOI:10.1371/journal.pone.0084618 · 3.23 Impact Factor
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