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Soft Tissues: Rhabdomyosarcoma

Written1998-03Jérome Couturier
Department of Pathology, Institut Curie, Paris, France
Updated2009-01Jennifer Reichek, Frederic G Barr
Department of Pathology, Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA

(Note : for Links provided by Atlas : click)

Identity

Atlas_Id 5004
Phylum Soft Tissues::Rhabdomyosarcoma
WHO/OMS Classification Soft Tissues
Note Rhabdomyosarcoma (RMS) refers to a family of mesenchymal tumours related to the skeletal muscle lineage.

Classification

    The two main histopathologic subtypes of rhabdomyosarcoma are :
  • Embryonal rhabdomyosarcoma (ERMS)
  • Alveolar rhabdomyosarcoma (ARMS)
    		•

    Clinics and Pathology

    Embryonic origin RMS is postulated to be derived from mesodermal tissues.
    Epidemiology RMS is the most common pediatric soft tissue sarcoma, representing ~5% of all malignancies among children and adolescents. The annual incidence is 4-5 per million. ERMS accounts for 70-80% of all RMS, and usually occurs in young children (median age of 6.5 years). ARMS accounts for the remaining 20-30% of RMS, and more often occurs in older children and young adults (median age of 12 years).
    Clinics RMS often presents as a painless mass. In other cases, the tumor may be discovered from symptoms produced by compression of structures at the primary site, such as diplopia (double vision) caused by RMS in the orbital region. The two histopathologic subtypes tend to occur at different sites. ERMS often occurs in the head and neck region, genitourinary tract, and retroperitoneum whereas ARMS often occurs in the extremities. All types of RMS are treated with a combination of surgery, radiation therapy, and intensive chemotherapy.
    Pathology
  • In ERMS, the tumor cells range from small round cells to large elongated cells, and exhibit varying degrees of myogenic differentiation. There is often varying cell density with highly cellular areas alternating with low cellular areas in a loose myxoid stroma.
  • In ARMS, tumor cells are small with a round nucleus and scant cytoplasm. Aggregates of these tumors cells often become discohesive and produce spaces, reminiscent of lung alveoli.
  • An anaplastic RMS subset is recognized by large, lobated hyperchromatic nuclei and atypical mitoses. Anaplasia is more prevalent in ERMS and can be found as a focal or diffuse feature in the tumor.
  • The tumor cells of both subtypes of RMS variably express muscle specific proteins (such as desmin, myoglobin, muscle-specific actin, or the myogenic transcription factors MyoD and myogenin) that can be detected by immunohistochemistry.
    •  
    Histopathology of rhabdomyosarcoma subtypes. A. Embryonal subtype. B. Alveolar subtype. (hematoxylin-eosin, original magnification: 100X; courtesy of Dr. Linda Ernst)
    Prognosis Factors that influence the selection of therapy and the outcome of patients include primary site (orbit, superficial head and neck, biliary tree, vagina, and paratestis are considered favorable), size of primary tumor, extent of local spread, presence of nodal and distal metastases, and histologic subtype. Of the two histologic subtypes, ARMS has a poorer prognosis than ERMS.

    Genetics

    Note Most cases of RMS occur sporadically without an apparent genetic predisposition. However, a small subset of RMS is associated with the following known genetic syndromes:
  • Hereditary retinoblastoma syndrome (RB1)
  • Li-Fraumeni syndrome (TP53)
  • Neurofibromatosis type I (NF1)
  • Costello syndrome (HRAS)
  • Beckwith-Wiedemann syndrome (11p15 genes)
  • Nevoid basal cell carcinoma syndrome (PTCH)
  • Rubinstein-Taybi syndrome (CREBBP).

    • Cytogenetics

    Cytogenetics
    Morphological    		 Studies of cytogenetics and other acquired genetic changes in ERMS and ARMS have revealed significant genetic differences between these two subtypes.

  • Most ARMS cases are distinguished from ERMS and other solid tumors by the presence of one of two recurrent chromosomal translocations, which generate related fusion genes.
    - t(2;13)(q35;q14) generates PAX3 - FOXO1 in ~60% of ARMS cases
    - t(1;13)(p36;q14) generates PAX7 - FOXO1 in ~20% of ARMS cases

  • ERMS does not have recurrent structural chromosome rearrangements, but rather has frequent chromosome gains and losses. In addition, ERMS has a much higher frequency of loss of one of the two alleles of many chromosome 11 loci, particularly in the 11p15.5 region.

    • Bibliography

    Germline mutations in HRAS proto-oncogene cause Costello syndrome.
    Aoki Y, Niihori T, Kawame H, Kurosawa K, Ohashi H, Tanaka Y, Filocamo M, Kato K, Suzuki Y, Kure S, Matsubara Y.
    Nat Genet. 2005 Oct;37(10):1038-40. Epub 2005 Sep 18.
    PMID 16170316
     
    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
     
    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
     
    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 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
     
    Nevoid basal cell carcinoma syndrome.
    Gorlin RJ.
    Dermatol Clin. 1995 Jan;13(1):113-25. Review
    PMID 7712637
     
    Tumor predisposition in Costello syndrome.
    Gripp KW.
    Am J Med Genet C Semin Med Genet. 2005 Aug 15;137C(1):72-7. Review
    PMID 16010679
     
    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.
     
    Second primary rhabdomyosarcomas in patients with bilateral retinoblastoma: a clinicopathologic and immunohistochemical study.
    Hasegawa T, Matsuno Y, Niki T, Hirohashi S, Shimoda T, Takayama J, Watanabe C, Kaneko A, Sano T, Sato M, Suzuki J.
    Am J Surg Pathol. 1998 Nov;22(11):1351-60.
    PMID 9808127
     
    Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome?
    Li FP, Fraumeni JF Jr.
    Ann Intern Med. 1969 Oct;71(4):747-52.
    PMID 5360287
     
    Molecular genetics of Wiedemann-Beckwith syndrome.
    Li M, Squire JA, Weksberg R.
    Am J Med Genet. 1998 Oct 2;79(4):253-9.
    PMID 9781904
     
    Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms.
    Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al.
    Science. 1990 Nov 30;250(4985):1233-8.
    PMID 1978757
     
    Rhabdomyosarcoma complicating multiple neurofibromatosis.
    McKeen EA, Bodurtha J, Meadows AT, Douglass EC, Mulvihill JJ.
    J Pediatr. 1978 Dec;93(6):992-3.
    PMID 102756
     
    Tumors in Rubinstein-Taybi syndrome.
    Miller RW, Rubinstein JH.
    Am J Med Genet. 1995 Mar 13;56(1):112-5.
    PMID 7747773
     
    Rhabdomyosarcomas in adults and children: an update.
    Parham DM, Ellison DA.
    Arch Pathol Lab Med. 2006 Oct;130(10):1454-65.
    PMID 17090187
     
    Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP.
    Petrij F, Giles RH, Dauwerse HG, Saris JJ, Hennekam RC, Masuno M, Tommerup N, van Ommen GJ, Goodman RH, Peters DJ, et al.
    Nature. 1995 Jul 27;376(6538):348-51.
    PMID 7630403
     
    Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.
    Qualman S, Lynch J, Bridge J, Parham D, Teot L, Meyer W, Pappo A.
    Cancer. 2008 Dec 1;113(11):3242-7.
    PMID 18985676
     
    Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping.
    Scrable HJ, Witte DP, Lampkin BC, Cavenee WK.
    Nature. 1987 Oct 15-21;329(6140):645-7.
    PMID 3657988
     
    Myogenin and MyoD1 expression in paediatric rhabdomyosarcomas.
    Sebire NJ, Malone M.
    J Clin Pathol. 2003 Jun;56(6):412-6. Review
    PMID 12783965
     
    Neurofibromatosis in children with Rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma study IV.
    Sung L, Anderson JR, Arndt C, Raney RB, Meyer WH, Pappo AS.
    J Pediatr. 2004 May;144(5):666-8.
    PMID 15127010
     
    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
     
    Allelotype of pediatric rhabdomyosarcoma.
    Visser M, Sijmons C, Bras J, Arceci RJ, Godfried M, Valentijn LJ, Voute PA, Baas F.
    Oncogene. 1997 Sep;15(11):1309-14.
    PMID 9315099
     
    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
     
    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.
     
    Molecular pathogenesis of rhabdomyosarcoma.
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    PMID 12170781
     

    Citation

    This paper should be referenced as such :
    Reichek J, Barr FG
    Soft Tissues: Rhabdomyosarcom
    Atlas Genet Cytogenet Oncol Haematol. in press
    On line version : http://AtlasGeneticsOncology.org/Tumors/rhabID5004.html
    History of this paper:
    Reichek, J ; Barr, FG. Soft tissue tumors: Rhabdomyosarcoma. Atlas Genet Cytogenet Oncol Haematol. 2009;13(12):989-991.
    http://documents.irevues.inist.fr/bitstream/handle/2042/44652/01-2009-rhab5004.pdf

    Other genes implicated (Data extracted from papers in the Atlas) [ 33 ]

    Genes FOXO3 FOXO4 BUB1B CBFA2T3 DYRK1B EWSR1 FBXO31 FGFR1 FGFR4 FHL2
    FOXF1 GPC5 HGF IGF1R IGFBP6 ITGA9 KCNH1 LOX MAD1L1 MEN1
    MIR183 MIR200C MIR26A1 MME NCOA1 MYCN PIWIL2 PTCH2 SIRT1 SIX1
    SRSF3 TWIST1 YBX1

    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(4;22)(q35;q12) EWSR1/DUX4
     t(6;8)(p21;q13) SRF/NCOA2
     t(8;11)(q13;p15) TEAD1/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(4;22)(q35;q12) [CaseList]     t(4;22)(q35;q12) [Transloc - MCList]   EWSR1/DUX4 Fusion - MCList]
    COSMIC[ EWSR1 ]   [ DUX4 ]
    Mitelman database t(6;8)(p21;q13) [CaseList]     t(6;8)(p21;q13) [Transloc - MCList]   SRF/NCOA2 Fusion - MCList]
    COSMIC[ SRF ]   [ NCOA2 ]
    Mitelman database t(8;11)(q13;p15) [CaseList]     t(8;11)(q13;p15) [Transloc - MCList]   TEAD1/NCOA2 Fusion - MCList]
    COSMIC[ TEAD1 ]   [ 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 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)
    Mitelman databaseSRF/NCOA2[MCList]    SRF (6p21.1) NCOA2 (8q13.3)   t(6;8)(p21;q13)
    Mitelman databaseTEAD1/NCOA2[MCList]    TEAD1 (11p15.3) NCOA2 (8q13.3)   t(8;11)(q13;p15)
     
    Disease databaseSoft Tissues: Rhabdomyosarcoma
    REVIEW articlesautomatic search in PubMed
    Last year articlesautomatic search in PubMed


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