Myogenin is a Specific Marker for Rhabdomyosarcoma: An Immunohistochemical Study in Paraffin-Embedded Tissues

Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda Maryland, USA.
Modern Pathology (Impact Factor: 6.19). 10/2000; 13(9):988-93. DOI: 10.1038/modpathol.3880179
Source: PubMed


Myogenin belongs to a group of myogenic regulatory proteins whose expression determines commitment and differentiation of primitive mesenchymal cells into skeletal muscle. The expression of myogenin has been demonstrated to be extremely specific for rhabdomyoblastic differentiation, which makes it a useful marker in the differential diagnosis of rhabdomyosarcomas (RMS) from other malignant small round cell tumors of childhood. Commercially available antibodies capable of detecting myogenin in routinely processed formalin-fixed paraffin-embedded (FFPE) tissue are now available. In this study, we evaluated myogenin expression using the monoclonal myf-4 antibody (Novocastra Labs) on FFPE in a large number of pediatric tumors in order to define the clinical utility of this marker. A total of 119 tumors were studied. These included 48 alveolar RMS (ARMS), 20 embryonal RMS (ERMS), one spindle cell RMS, 16 Ewing's sarcomas (ES), six nephroblastomas, two ectomesenchymomas, seven precursor hematopoietic neoplasms, five olfactory neuroblastomas, three neuroblastomas, six desmoplastic small round cell tumors, and five rhabdoid tumors. Distinct nuclear staining for myogenin was noted in all 69 RMS. Notably, the number of positive tumor cells differed between the ARMS and ERMS. In ARMS, the majority of tumor cells (75 to 100%) were positive, in contrast to ERMS, in which the positivity ranged from rare + to 25% in all but three tumors. Additionally, myogenin positivity was seen in two of two ectomesenchymomas and in two nephroblastomas with myogenous differentiation. All other tumors were clearly negative. Our results indicate that staining for myogenin is an extremely reliable and specific marker for rhabdomyoblastic differentiation. It gives consistent and easily interpretable results in routinely fixed tissues.

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    • "The expression level of EGFR (Epidermal Growth Factor Receptor) and Fbn2 (Fibrillin-2) as specific markers for eRMS [16,17] were also paradoxically increased in Pax3:Foxo1a,p53,Rb1 tumors. Furthermore, Pax3:Foxo1a,p53,Rb1 tumors also had increased expression of Myogenin, a marker for alveolar and embryonic rhabdomyoblastic differentiation [18], compared with Pax3:Foxo1a,p53 tumors. These results suggested that Rb1 inactivation in the context of Pax3:Foxo1a activation and p53 inactivation may mix the molecular phenotype of tumors for a state neither consistent purely with aRMS or with eRMS. "
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    ABSTRACT: Alveolar rhabdomyosarcoma (aRMS) is a myogenic childhood sarcoma frequently associated with a translocation-mediated fusion gene, Pax3:Foxo1a. We investigated the complementary role of Rb1 loss in aRMS tumor initiation and progression using conditional mouse models. Rb1 loss was not a necessary and sufficient mutational event for rhabdomyosarcomagenesis, nor a strong cooperative initiating mutation. Instead, Rb1 loss was a modifier of progression and increased anaplasia and pleomorphism. Whereas Pax3:Foxo1a expression was unaltered, biomarkers of aRMS versus embryonal rhabdomyosarcoma were both increased, questioning whether these diagnostic markers are reliable in the context of Rb1 loss. Genome-wide gene expression in Pax3:Foxo1a,Rb1 tumors more closely approximated aRMS than embryonal rhabdomyosarcoma. Intrinsic loss of pRb function in aRMS was evidenced by insensitivity to a Cdk4/6 inhibitor regardless of whether Rb1 was intact or null. This loss of function could be attributed to low baseline Rb1, pRb and phospho-pRb expression in aRMS tumors for which the Rb1 locus was intact. Pax3:Foxo1a RNA interference did not increase pRb or improve Cdk inhibitor sensitivity. Human aRMS shared the feature of low and/or heterogeneous tumor cell pRb expression. Rb1 loss from an already low pRb baseline is a significant disease modifier, raising the possibility that some cases of pleomorphic rhabdomyosarcoma may in fact be Pax3:Foxo1a-expressing aRMS with Rb1 or pRb loss of function.
    Skeletal Muscle 11/2013; 3(1):27. DOI:10.1186/2044-5040-3-27
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    • "Excess blocking serum was removed and slides were incubated overnight at 4°C with primary antibodies (1∶250 anti-sarcomeric actin, mouse monoclonal IgM, Sigma; 1∶500 anti-smooth muscle actin, mouse monoclonal IgG2a, Sigma, St. Louis, MO; 1∶500 anti-myogenin, mouse monoclonal IgG1, BD Pharmingen, San Diego, CA) diluted in blocking serum. Myogenin was found to be the best marker for RSC immunohistochemistry [47]. Secondary antibodies were Alexa-conjugated fluorochromes 1∶500 IgM-546, 1∶1000 IgG2a-488, 1∶500 IgG1-647 (Molecular Probes, Carlsbad, CA). "
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    ABSTRACT: Rhabdomyosarcomas (RSCs) are skeletal muscle neoplasms found in humans and domestic mammals. The A/J inbred strain developed a high frequency (between 70-80%) of adult pleomorphic type (APT) RSC at >20 months of age while BALB/cByJ also develop RSC but less frequently. These neoplasms invaded skeletal muscle surrounding either the axial or proximal appendicular skeleton and were characterized by pleomorphic cells with abundant eosinophilic cytoplasm, multiple nuclei, and cross striations. The diagnosis was confirmed by detection of alpha-sarcomeric actin and myogenin in the neoplastic cells using immunocytochemistry. The A/J strain, but not the related BALB/c substrains, is also characterised by a progressive muscular dystrophy homologous to limb-girdle muscular dystrophy type 2B. The association between the development of RSC in similar muscle groups to those most severely affected by the progressive muscular dystrophy suggested that these neoplasms developed from abnormal regeneration of the skeletal muscle exacerbated by the dysferlin mutation. Transcriptome analyses of RSCs revealed marked downregulation of genes in muscular development and function signaling networks. Non-synonymous coding SNPs were found in Myl1, Abra, Sgca, Ttn, and Kcnj12 suggesting these may be important in the pathogenesis of RSC. These studies suggest that A strains of mice can be useful models for dissecting the molecular genetic basis for development, progression, and ultimately for testing novel anticancer therapeutic agents dealing with rhabdomyosarcoma.
    PLoS ONE 08/2011; 6(8):e23498. DOI:10.1371/journal.pone.0023498 · 3.23 Impact Factor
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    • "Immunohistochemistry is the first line supplemental methodology and is sufficient for diagnosis in many cases of small round cell tumors. For example, myogenin and myoD1 are specific and sensitive for the diagnosis of rhabdomyosarcoma [1] and lymphoid markers such as CD20, CD3, CD30 and CD45 are very useful in the diagnosis of lymphoma. However, many other markers, although helpful, are not so specific and require interpretation in the context of an immunohistochemical panel. "
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    ABSTRACT: The group of small blue round cell tumors encompasses a heterogeneous group of neoplasms characterized by primitive appearing round cells with few distinguishing histologic features. We report the case of a small blue round cell tumor with an EWS gene rearrangement detected by fluorescent in situ hybridization (FISH) analysis that mimicked Ewing sarcoma, but with unusual histology and immunohistochemical features. Multi-color karyotyping identified the presence of a t(2;22)(q34;q12) that was initially expected to represent a variant EWSR1-FEV translocation. After an extensive workup, the lesion is considered to represent a clear cell sarcoma harboring an EWSR1-CREB1 fusion transcript. This case appears to represent a rare variant of clear cell sarcoma arising in peripheral soft tissues with unusual histology and unique immunophenotype. In this circumstance, FISH for all EWSR1 translocation partners or RT- PCR for a spectrum of possible transcript variants is critically important for diagnosis, since cytogenetic analysis or clinical FISH assay using only commercial EWSR1 probes will be misleading.
    Molecular Cytogenetics 07/2010; 3(1):12. DOI:10.1186/1755-8166-3-12 · 2.14 Impact Factor
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