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Soft Tissues: Alveolar rhabdomyosarcoma

Written2009-01Frederic G Barr
Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

(Note : for Links provided by Atlas : click)


ICD-Topo C470-C476,C478-C479,C490-C496,C498-C499 CONNECTIVE & SOFT TISSUE
ICD-Morpho 8920/3 Alveolar rhabdomyosarcoma
Atlas_Id 5194
Phylum Soft Tissues::Alveolar rhabdomyosarcoma
WHO/OMS Classification Soft Tissues
Note Alveolar rhabdomyosarcoma (ARMS) refers to one subtype of the rhabdomyosarcoma family of soft tissue tumors. These are mesenchymal tumours related to the skeletal muscle lineage.


    ARMS is one of two subtypes of rhabdomyosarcoma. The other major subype is embryonal rhabdosarcoma (ERMS). Within the ARMS subtype, there is no further histopathologic subtyping of clinical significance. Genetic subtyping has identified PAX3-FKHR, PAX7-FKHR, and fusion-negative subsets of ARMS; the clinical significance of these subsets is still being actively investigated.

Clinics and Pathology

Embryonic origin ARMS tends to occur within skeletal muscle and is postulated to derive from precursor cells within the skeletal muscle. Therefore, the embryonic derivation of these tumors is presumed to be mesoderm, the same as that of skeletal muscle.
Epidemiology ARMS accounts for 20-30% of all RMS tumors. Therefore ARMS represents ~1% of all malignancies among children and adolescents, and has an annual incidence of ~1 per million. Many ARMS tumors occur in older children and young adults - this age association characterizes the more prevalent PAX3-FKHR-positive subset of ARMS. In contrast, PAX7-FKHR-positive ARMS as well as fusion-negative tumors tend to occur in younger children.
Clinics ARMS often occurs within skeletal muscle of the extremities but can also occur in other sites including the trunk and head and neck. This tumor often presents as a painless mass, but in other cases, may be discovered from symptoms produced by compression of structures at the primary site. A substantial fraction of patients with ARMS (25-30%) will have metastatic disease at the time of diagnosis. ARMS most frequently spreads to bone marrow, distal nodes, and bone. The standard treatment for ARMS is a combination of surgery, radiation, and intensive chemotherapy.
Pathology Tumor cells in ARMS are relatively small with scant cytoplasm. They have round regular nuclei with a monotonous chromatin pattern. The cells form aggregates interrupted by fibrovascular septae, and within these aggregates, areas of discohesion often form, resulting in spaces that resemble alveoli of the lung. In some ARMS cases, there are few fibrovascular septae, no alveoli-like spaces, and a predominant cellular small round cell population; the term solid variant applies to this situation.
In addition to general immunohistochemical markers to identify RMS, certain markers aid in the identification of ARMS. Immunostaining for myogenin and MyoD show different patterns between ARMS and ERMS, such that most cells within an ARMS tumor stain positive whereas fewer cells within an ERMS tumor stain positive. In addition, based on microarray studies that distinguish fusion-postive ARMS from fusion-negative ERMS, AP2β and p-cadherin were found to be specific markers for the fusion-positive ARMS subtype.
Histopathology of alveolar rhabdomyosarcoma (hematoxylin-eosin, original magnification: 100X; courtesy of Dr. Linda Ernst).
Prognosis Patients with ARMS tumors have a poorer outcome than patients with ERMS tumors. The 4-year failure free survival rates for patients with localized and metastastic ARMS are 65% and 15%, respectively. Other risk factors that influence outcome of ARMS include primary site, size of primary tumor, extent of local spread, and the presence of nodal and distal metastases.
In an analysis of patients from the IRS-IV study, patients with localized PAX3-FKHR and PAX7-FKHR-positive ARMS had comparable outcomes. In contrast, among patients presenting with metastatic disease, those with PAX3-FKHR-positive tumors had a significantly poorer outcome than those with PAX7-FKHR-positive tumors (4-year overall survival rate of 8% compared to 75%, p=0.0015).


Note Most cases of ARMS occur sporadically without an apparent genetic predisposition.


Most ARMS cases contain one of two recurrent chromosomal translocations: t(2;13)(q35;q14) or t(1;13)(p36;q14). Reciprocal balanced translocations are often present for the 2;13 translocation. The 1;13 is sometimes visible as a balanced translocation, and other times is associated with a subsequent amplification event.
Additional cytogenetic changes in ARMS include:
  • Amplification events involving 12q13-15, 2p24, 1p36, 13q14, 2q34-qter, 13q31 (as determined by comparative genomic hybridization studies).
  • Numerical chromosome gains, such as chromosomes 2, 12, and 20.
  • Examples of 2;13 translocation from ARMS tumors. G-banding (above) - Courtesy G. Reza Hafez, Eric B.Johnson, and Sara Morrison-Delap, Cytogenetics at the Waisman Center ; R- banding (below) - Courtesy Jean-Luc Lai.
    Diagram of t(2;13)(q35;q14) and t(1;13)(p36;q14) chromosomal translocations.

    Genes involved and Proteins

    Gene NameFOXO1 (Forkhead box O1)
    Location 13q14.11
    Protein Transcription factor.

    Gene NamePAX3 (paired box gene 3 (Waardenburg syndrome 1))
    Location 2q36.1
    Protein Transcription factor.

    Gene NamePAX7 (paired box 7)
    Location 1p36.13
    Protein Transcription factor.

    Result of the chromosomal anomaly

    Hybrid Gene
    Comparison of wild-type and fusion products associated with the 2;13 and 1;13 translocations. The paired box, octapeptide, homeobox and fork head domain are indicated as open boxes, and transcriptional domains (DNA binding domain, DBD; transcriptional activiation domain) are shown as solid bars. The vertical dash line indicates the translocation fusion point.
    Description The 2;13 and 1;13 translocations rearrange the PAX3 or PAX7 gene on chromosome 2 or 1 and the FOXO1 gene on chromosome 13 to generate a PAX3-FOXO1 or PAX7-FOXO1 fusion gene.
    Among ARMS tumors, ~60% are PAX3-FOXO1-positive, ~20% are PAX7-FOXO1-positive, and ~20% are fusion-negative.
    The PAX7-FKHR fusion is often amplified in tumors (70% of PAX7-FKHR-positive cases) whereas the PAX3-FKHR gene fusion is much less frequently amplified in tumors (5% of PAX3-FKHR-positive cases). Gene amplification appears to be one mechanism to increase the expression level of the gene fusion in ARMS tumor cells.
    Fusion Protein
    Description These fusion genes encode fusion transcription factors with a PAX3 or PAX7 DNA binding domain and FOXO1 transactivation domain.
    Expression Localisation Nuclear.
    Oncogenesis Transcription dysregulation.


    Rearrangement of the PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma.
    Barr FG, Galili N, Holick J, Biegel JA, Rovera G, Emanuel BS.
    Nat Genet. 1993 Feb;3(2):113-7.
    PMID 8098985
    In vivo amplification of the PAX3-FKHR and PAX7-FKHR fusion genes in alveolar rhabdomyosarcoma.
    Barr FG, Nauta LE, Davis RJ, Schafer BW, Nycum LM, Biegel JA.
    Hum Mol Genet. 1996 Jan;5(1):15-21.
    PMID 8789435
    Gene fusions involving PAX and FOX family members in alveolar rhabdomyosarcoma.
    Barr FG.
    Oncogene. 2001 Sep 10;20(40):5736-46. Review
    PMID 11607823
    Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV.
    Breneman JC, Lyden E, Pappo AS, Link MP, Anderson JR, Parham DM, Qualman SJ, Wharam MD, Donaldson SS, Maurer HM, Meyer WH, Baker KS, Paidas CN, Crist WM.
    J Clin Oncol. 2003 Jan 1;21(1):78-84.
    PMID 12506174
    Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes.
    Bridge JA, Liu J, Qualman SJ, Suijkerbuijk R, Wenger G, Zhang J, Wan X, Baker KS, Sorensen P, Barr FG.
    Genes Chromosomes Cancer. 2002 Mar;33(3):310-21.
    PMID 11807989
    Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease.
    Crist WM, Anderson JR, Meza JL, Fryer C, Raney RB, Ruymann FB, Breneman J, Qualman SJ, Wiener E, Wharam M, Lobe T, Webber B, Maurer HM, Donaldson SS.
    J Clin Oncol. 2001 Jun 15;19(12):3091-102.
    PMID 11408506
    Fusion genes resulting from alternative chromosomal translocations are overexpressed by gene-specific mechanisms in alveolar rhabdomyosarcoma.
    Davis RJ, Barr FG.
    Proc Natl Acad Sci U S A. 1997 Jul 22;94(15):8047-51.
    PMID 9223312
    Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma.
    Davis RJ, D'Cruz CM, Lovell MA, Biegel JA, Barr FG.
    Cancer Res. 1994 Jun 1;54(11):2869-72.
    PMID 8187070
    Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma.
    Galili N, Davis RJ, Fredericks WJ, Mukhopadhyay S, Rauscher FJ 3rd, Emanuel BS, Rovera G, Barr FG.
    Nat Genet. 1993 Nov;5(3):230-5.
    PMID 8275086
    A novel and consistent amplicon at 13q31 associated with alveolar rhabdomyosarcoma.
    Gordon AT, Brinkschmidt C, Anderson J, Coleman N, Dockhorn-Dworniczak B, Pritchard-Jones K, Shipley J.
    Genes Chromosomes Cancer. 2000 Jun;28(2):220-6.
    PMID 10825007
    Soft Tissue Sarcomas.
    Gurney JG, Young JL, Roffers SD, Smith MA, Bunin GR.
    In L. A. Ries, M. A. Smith, J. G. Gurney, M. Linet, T. Tamra, J. L. Young, and G. R. Bunin (ed.), Cancer Incidence and Survival among Children and Adolescents: United States SEER Program 1975-1995. NIH Pub. No. 99-4649, Bethesda, MD. 1999; p. 111-124.
    Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma.
    Kelly KM, Womer RB, Sorensen PH, Xiong QB, Barr FG.
    J Clin Oncol. 1997 May;15(5):1831-6.
    PMID 9164192
    Rhabdomyosarcomas in adults and children: an update.
    Parham DM, Ellison DA.
    Arch Pathol Lab Med. 2006 Oct;130(10):1454-65.
    PMID 17090187
    Myogenin and MyoD1 expression in paediatric rhabdomyosarcomas.
    Sebire NJ, Malone M.
    J Clin Pathol. 2003 Jun;56(6):412-6. Review
    PMID 12783965
    PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group.
    Sorensen PH, Lynch JC, Qualman SJ, Tirabosco R, Lim JF, Maurer HM, Bridge JA, Crist WM, Triche TJ, Barr FG.
    J Clin Oncol. 2002 Jun 1;20(11):2672-9.
    PMID 12039929
    Consistent chromosomal translocation in alveolar rhabdomyosarcoma.
    Turc-Carel C, Lizard-Nacol S, Justrabo E, Favrot M, Philip T, Tabone E.
    Cancer Genet Cytogenet. 1986 Jan 15;19(3-4):361-2.
    PMID 3943053
    Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry.
    Wachtel M, Runge T, Leuschner I, Stegmaier S, Koscielniak E, Treuner J, Odermatt B, Behnke S, Niggli FK, Schafer BW.
    J Clin Oncol. 2006 Feb 10;24(5):816-22. Epub 2006 Jan 3.
    PMID 16391296
    Chromosomal analysis of sixteen human rhabdomyosarcomas.
    Wang-Wuu S, Soukup S, Ballard E, Gotwals B, Lampkin B.
    Cancer Res. 1988 Feb 15;48(4):983-7.
    PMID 3338090
    Gains, losses, and amplification of genomic material in rhabdomyosarcoma analyzed by comparative genomic hybridization.
    Weber-Hall S, Anderson J, McManus A, Abe S, Nojima T, Pinkerton R, Pritchard-Jones K, Shipley J.
    Cancer Res. 1996 Jul 15;56(14):3220-4.
    PMID 8764111
    Rhabdomyosarcoma and the undifferentiated sarcomas.
    Wexler LH, Meyer WH, Helman LJ.
    In P. A. Pizzo and D. G. Poplack (ed.), Principles and Practice of Pediatric Oncology, 2006. Fifth ed. Lippincott Williams & Wilkins, Philadelphia; p. 971-1001.


    This paper should be referenced as such :
    Barr, FG
    Soft tissue tumors: Alveolar rhabdomyosarcoma
    Atlas Genet Cytogenet Oncol Haematol. 2009;13(12):981-985.
    Free journal version : [ pdf ]   [ DOI ]
    On line version :

    Other genes implicated (Data extracted from papers in the Atlas) [ 13 ]


    Translocations implicated (Data extracted from papers in the Atlas)

     t(1;13)(p36;q14) PAX7/FOXO1
     t(2;13)(q35;q14) PAX3/FOXO1
     t(2;2)(p23;q36) PAX3/NCOA1
     t(2;8)(q36;q13) PAX3/NCOA2
     t(8;13)(p11;q14) FOXO1/FGFR1
     t(X;2)(q13;q36) PAX3/FOXO4

    External links

    Mitelman database t(1;13)(p36;q14) [CaseList]     t(1;13)(p36;q14) [Transloc - MCList]   PAX7/FOXO1 Fusion - MCList]
    COSMIC[ PAX7 ]   [ FOXO1 ]
    Mitelman database t(2;13)(q35;q14) [CaseList]     t(2;13)(q35;q14) [Transloc - MCList]   PAX3/FOXO1 Fusion - MCList]
    COSMIC[ PAX3 ]   [ FOXO1 ]
    Mitelman database t(2;2)(p23;q36) [CaseList]     t(2;2)(p23;q36) [Transloc - MCList]   PAX3/NCOA1 Fusion - MCList]
    COSMIC[ PAX3 ]   [ NCOA1 ]
    Mitelman database t(2;8)(q36;q13) [CaseList]     t(2;8)(q36;q13) [Transloc - MCList]   PAX3/NCOA2 Fusion - MCList]
    COSMIC[ PAX3 ]   [ NCOA2 ]
    Mitelman database t(8;13)(p11;q14) [CaseList]     t(8;13)(p11;q14) [Transloc - MCList]   FOXO1/FGFR1 Fusion - MCList]
    COSMIC[ FOXO1 ]   [ FGFR1 ]
    Mitelman database t(X;2)(q13;q36) [CaseList]     t(X;2)(q13;q36) [Transloc - MCList]   PAX3/FOXO4 Fusion - MCList]
    COSMIC[ PAX3 ]   [ FOXO4 ]
    arrayMap Topo ( C47,C49) arrayMap ((UZH-SIB Zurich)   [auto + random 100 samples .. if exist ]   [tabulated segments]
    Mitelman databasePAX3/FOXO1[MCList]    PAX3 (2q36.1) FOXO1 (13q14.11)   
    Mitelman databasePAX3/FOXO1[MCList]    PAX3 (2q36.1) FOXO1 (13q14.11)   t(1;13)(p36;q14)
    Mitelman databasePAX3/FOXO4[MCList]    PAX3 (2q36.1) FOXO4 (Xq13.1)   t(X;2)(q13;q36)
    COSMIC_fusionPAX3 (2q36.1) NCOA1 (2p23.3)    [fusion1042] [fusion1043] [fusion289] [fusion290]
    Mitelman databasePAX3/NCOA1[MCList]    PAX3 (2q36.1) NCOA1 (2p23.3)   t(2;2)(p23;q36)
    TICdbPAX3/NCOA1    PAX3 (2q36.1) NCOA1 (2p23.3)
    COSMIC_fusionPAX3 (2q36.1) NCOA2 (8q13.3)    [fusion1040] [fusion1041]
    Mitelman databasePAX3/NCOA2[MCList]    PAX3 (2q36.1) NCOA2 (8q13.3)   t(2;8)(q36;q13)
    TICdbPAX3/NCOA2    PAX3 (2q36.1) NCOA2 (8q13.3)
    COSMIC_fusionPAX7 (1p36.13) FOXO1 (13q14.11)    [fusion287] [fusion288] [fusion344]
    Mitelman databasePAX7/FOXO1[MCList]    PAX7 (1p36.13) FOXO1 (13q14.11)   
    Mitelman databasePAX7/FOXO1[MCList]    PAX7 (1p36.13) FOXO1 (13q14.11)   t(1;13)(p36;q14)
    Disease databaseSoft Tissues: Alveolar rhabdomyosarcoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed

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