Rhabdomyosarcoma and undifferentiated sarcoma in childhood and adolescence: Epidemiology, pathology, and molecular pathogenesis
- M Fatih Okcu, MD, MPH
M Fatih Okcu, MD, MPH
- Professor of Pediatrics
- Baylor College of Medicine
- John Hicks, MD, DDS, PhD
John Hicks, MD, DDS, PhD
- Department of Pathology
- Baylor College of Medicine
- Marc Horowitz, MD
Marc Horowitz, MD
- Baylor College of Medicine
- Section Editors
- Alberto S Pappo, MD
Alberto S Pappo, MD
- Section Editor — Pediatric Oncology
- Head of Solid Malignancies Program
- St. Jude Children's Research Hospital
- Thomas F DeLaney, MD
Thomas F DeLaney, MD
- Section Editor — Bone and Soft Tissue Tumors
- Professor of Radiation Oncology
- Harvard Medical School
Pediatric soft tissue sarcomas are a heterogeneous group of tumors that are presumed to arise from a primitive mesenchymal cell. These tumors can arise in many anatomic locations and can resemble fat, fibrous tissue, and muscle. Overall, these pediatric tumors are rare, accounting for about 7 percent of all childhood cancers; they have an estimated incidence of 11 per million .
This topic review will cover the epidemiology, pathology, and pathogenesis of two specific types of pediatric soft tissue sarcoma, rhabdomyosarcoma (RMS) and undifferentiated sarcoma (UDS). Clinical manifestations, the diagnostic evaluation, staging and risk-adapted therapy for RMS and UDS are discussed elsewhere, as are primary tumors of bone, and other soft tissue neoplasms arising in children as well as adults. (See appropriate topic reviews).
RMS is the most common soft tissue tumor of childhood, and responsible for approximately one-half of all soft tissue sarcomas in this age group [1,2]. However, they are rare, representing only 3 to 4 percent of pediatric cancers overall. Approximately 350 new cases are diagnosed in the US each year, and the annual incidence in children, adolescents, and young adults under the age of 20 is 4.3 cases per one million population .
Two-thirds of cases are diagnosed in children younger than six years of age, and there is a small male predominance (male to female ratio between 1.3 and 1.5). The incidence in African-American patients is higher than in whites, most notably in 15 to 19 year olds . The incidence appears to be lower in Asians when compared to predominantly Caucasian populations .
Although RMS can arise anywhere in the body, distinct patterns link primary site, histology, and age at diagnosis:
- Ries LAG, Harkins D, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2003, National Cancer Institute. Bethesda, MD. http://seer.cancer.gov/csr/1975_2003 (Accessed on June 10, 2011).
- Pastore G, Peris-Bonet R, Carli M, et al. Childhood soft tissue sarcomas incidence and survival in European children (1978-1997): report from the Automated Childhood Cancer Information System project. Eur J Cancer 2006; 42:2136.
- Stiller CA, McKinney PA, Bunch KJ, et al. Childhood cancer and ethnic group in Britain: a United Kingdom children's Cancer Study Group (UKCCSG) study. Br J Cancer 1991; 64:543.
- Grufferman S, Wang HH, DeLong ER, et al. Environmental factors in the etiology of rhabdomyosarcoma in childhood. J Natl Cancer Inst 1982; 68:107.
- Grufferman S, Gula M, Olshan A, et al. In utero X-ray exposure and risk of childhood rhabdomyosarcoma. Paediatr Perinatol Epidemiol 1991; 5:A6.
- Grufferman S, Schwartz AG, Ruymann FB, Maurer HM. Parents' use of cocaine and marijuana and increased risk of rhabdomyosarcoma in their children. Cancer Causes Control 1993; 4:217.
- Magnani C, Pastore G, Luzzatto L, et al. Risk factors for soft tissue sarcomas in childhood: a case-control study. Tumori 1989; 75:396.
- Hartley AL, Birch JM, McKinney PA, et al. The Inter-Regional Epidemiological Study of Childhood Cancer (IRESCC): case control study of children with bone and soft tissue sarcomas. Br J Cancer 1988; 58:838.
- Ognjanovic S, Carozza SE, Chow EJ, et al. Birth characteristics and the risk of childhood rhabdomyosarcoma based on histological subtype. Br J Cancer 2010; 102:227.
- 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; 134:431.
- Von Behren J, Spector LG, Mueller BA, et al. Birth order and risk of childhood cancer: a pooled analysis from five US States. Int J Cancer 2011; 128:2709.
- Li FP, Fraumeni JF Jr. Soft-tissue sarcomas, breast cancer, and other neoplasms. A familial syndrome? Ann Intern Med 1969; 71:747.
- Hartley AL, Birch JM, Marsden HB, et al. Neurofibromatosis in children with soft tissue sarcoma. Pediatr Hematol Oncol 1988; 5:7.
- DeBaun MR, Tucker MA. Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 1998; 132:398.
- Matsui I, Tanimura M, Kobayashi N, et al. Neurofibromatosis type 1 and childhood cancer. Cancer 1993; 72:2746.
- Quezada E, Gripp KW. Costello syndrome and related disorders. Curr Opin Pediatr 2007; 19:636.
- Gripp KW, Scott CI Jr, Nicholson L, et al. Five additional Costello syndrome patients with rhabdomyosarcoma: proposal for a tumor screening protocol. Am J Med Genet 2002; 108:80.
- Smith AC, Squire JA, Thorner P, et al. Association of alveolar rhabdomyosarcoma with the Beckwith-Wiedemann syndrome. Pediatr Dev Pathol 2001; 4:550.
- Malkin D, Li FP, Strong LC, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science 1990; 250:1233.
- Moutou C, Le Bihan C, Chompret A, et al. Genetic transmission of susceptibility to cancer in families of children with soft tissue sarcomas. Cancer 1996; 78:1483.
- Diller L, Sexsmith E, Gottlieb A, et al. Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest 1995; 95:1606.
- Dagher R, Helman L. Rhabdomyosarcoma: an overview. Oncologist 1999; 4:34.
- Steenman M, Westerveld A, Mannens M. Genetics of Beckwith-Wiedemann syndrome-associated tumors: common genetic pathways. Genes Chromosomes Cancer 2000; 28:1.
- Costello JM. A new syndrome: mental subnormality and nasal papillomata. Aust Paediatr J 1977; 13:114.
- Franceschini P, Licata D, Di Cara G, et al. Bladder carcinoma in Costello syndrome: report on a patient born to consanguineous parents and review. Am J Med Genet 1999; 86:174.
- Feingold M. Costello syndrome and rhabdomyosarcoma. J Med Genet 1999; 36:582.
- Kerr B, Eden OB, Dandamudi R, et al. Costello syndrome: two cases with embryonal rhabdomyosarcoma. J Med Genet 1998; 35:1036.
- Aoki Y, Niihori T, Kawame H, et al. Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 2005; 37:1038.
- Sung L, Anderson JR, Arndt C, et al. Neurofibromatosis in children with Rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma study IV. J Pediatr 2004; 144:666.
- Ruymann FB, Maddux HR, Ragab A, et al. Congenital anomalies associated with rhabdomyosarcoma: an autopsy study of 115 cases. A report from the Intergroup Rhabdomyosarcoma Study Committee (representing the Children's Cancer Study Group, the Pediatric Oncology Group, the United Kingdom Children's Cancer Study Group, and the Pediatric Intergroup Statistical Center). Med Pediatr Oncol 1988; 16:33.
- Pohar-Marinsek Z. Difficulties in diagnosing small round cell tumours of childhood from fine needle aspiration cytology samples. Cytopathology 2008; 19:67.
- Qualman SJ, Bowen J, Parham DM, et al. Protocol for the examination of specimens from patients (children and young adults) with rhabdomyosarcoma. Arch Pathol Lab Med 2003; 127:1290.
- Qualman SJ, Coffin CM, Newton WA, et al. Intergroup Rhabdomyosarcoma Study: update for pathologists. Pediatr Dev Pathol 1998; 1:550.
- Wachtel M, Runge T, Leuschner I, et al. Subtype and prognostic classification of rhabdomyosarcoma by immunohistochemistry. J Clin Oncol 2006; 24:816.
- Dias P, Chen B, Dilday B, et al. Strong immunostaining for myogenin in rhabdomyosarcoma is significantly associated with tumors of the alveolar subclass. Am J Pathol 2000; 156:399.
- Heerema-McKenney A, Wijnaendts LC, Pulliam JF, et al. Diffuse myogenin expression by immunohistochemistry is an independent marker of poor survival in pediatric rhabdomyosarcoma: a tissue microarray study of 71 primary tumors including correlation with molecular phenotype. Am J Surg Pathol 2008; 32:1513.
- Halliday BE, Slagel DD, Elsheikh TE, Silverman JF. Diagnostic utility of MIC-2 immunocytochemical staining in the differential diagnosis of small blue cell tumors. Diagn Cytopathol 1998; 19:410.
- Bahrami A, Gown AM, Baird GS, et al. Aberrant expression of epithelial and neuroendocrine markers in alveolar rhabdomyosarcoma: a potentially serious diagnostic pitfall. Mod Pathol 2008; 21:795.
- Hicks J, Flaitz C. Rhabdomyosarcoma of the head and neck in children. Oral Oncol 2002; 38:450.
- Holsinger FC, Weeks BH, Hicks MJ, et al. Contemporary concepts in the management of pediatric rhabdomyosarcoma. Curr Opin Otolaryngol Head Neck Surg 2002; 10:91.
- Parham DM. Pathologic classification of rhabdomyosarcomas and correlations with molecular studies. Mod Pathol 2001; 14:506.
- Kodet R, Newton WA Jr, Hamoudi AB, et al. Childhood rhabdomyosarcoma with anaplastic (pleomorphic) features. A report of the Intergroup Rhabdomyosarcoma Study. Am J Surg Pathol 1993; 17:443.
- Hostein I, Andraud-Fregeville M, Guillou L, et al. Rhabdomyosarcoma: value of myogenin expression analysis and molecular testing in diagnosing the alveolar subtype: an analysis of 109 paraffin-embedded specimens. Cancer 2004; 101:2817.
- Shapiro DN, Sublett JE, Li B, et al. Fusion of PAX3 to a member of the forkhead family of transcription factors in human alveolar rhabdomyosarcoma. Cancer Res 1993; 53:5108.
- Galili N, Davis RJ, Fredericks WJ, et al. Fusion of a fork head domain gene to PAX3 in the solid tumour alveolar rhabdomyosarcoma. Nat Genet 1993; 5:230.
- Davis RJ, D'Cruz CM, Lovell MA, et al. Fusion of PAX7 to FKHR by the variant t(1;13)(p36;q14) translocation in alveolar rhabdomyosarcoma. Cancer Res 1994; 54:2869.
- Sorensen PH, Lynch JC, Qualman SJ, et al. PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children's oncology group. J Clin Oncol 2002; 20:2672.
- Kelly KM, Womer RB, Sorensen PH, et al. Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 1997; 15:1831.
- Scrable HJ, Witte DP, Lampkin BC, Cavenee WK. Chromosomal localization of the human rhabdomyosarcoma locus by mitotic recombination mapping. Nature 1987; 329:645.
- Scrable H, Witte D, Shimada H, et al. Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1989; 1:23.
- El-Badry OM, Minniti C, Kohn EC, et al. Insulin-like growth factor II acts as an autocrine growth and motility factor in human rhabdomyosarcoma tumors. Cell Growth Differ 1990; 1:325.
- Kalebic T, Tsokos M, Helman LJ. In vivo treatment with antibody against IGF-1 receptor suppresses growth of human rhabdomyosarcoma and down-regulates p34cdc2. Cancer Res 1994; 54:5531.
- Khan J, Bittner ML, Saal LH, et al. cDNA microarrays detect activation of a myogenic transcription program by the PAX3-FKHR fusion oncogene. Proc Natl Acad Sci U S A 1999; 96:13264.
- Zhan S, Shapiro DN, Helman LJ. Activation of an imprinted allele of the insulin-like growth factor II gene implicated in rhabdomyosarcoma. J Clin Invest 1994; 94:445.
- Gallego Melcón S, Sánchez de Toledo Codina J. Molecular biology of rhabdomyosarcoma. Clin Transl Oncol 2007; 9:415.
- Mercado GE, Barr FG. Fusions involving PAX and FOX genes in the molecular pathogenesis of alveolar rhabdomyosarcoma: recent advances. Curr Mol Med 2007; 7:47.
- Goldstein M, Meller I, Issakov J, Orr-Urtreger A. Novel genes implicated in embryonal, alveolar, and pleomorphic rhabdomyosarcoma: a cytogenetic and molecular analysis of primary tumors. Neoplasia 2006; 8:332.
- Anderson J, Gordon A, Pritchard-Jones K, Shipley J. Genes, chromosomes, and rhabdomyosarcoma. Genes Chromosomes Cancer 1999; 26:275.
- Parham DM, Qualman SJ, Teot L, et al. Correlation between histology and PAX/FKHR fusion status in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Am J Surg Pathol 2007; 31:895.
- Davicioni E, Anderson MJ, Finckenstein FG, et al. Molecular classification of rhabdomyosarcoma--genotypic and phenotypic determinants of diagnosis: a report from the Children's Oncology Group. Am J Pathol 2009; 174:550.
- Williamson D, Missiaglia E, de Reyniès A, et al. Fusion gene-negative alveolar rhabdomyosarcoma is clinically and molecularly indistinguishable from embryonal rhabdomyosarcoma. J Clin Oncol 2010; 28:2151.
- Davicioni E, Finckenstein FG, Shahbazian V, et al. Identification of a PAX-FKHR gene expression signature that defines molecular classes and determines the prognosis of alveolar rhabdomyosarcomas. Cancer Res 2006; 66:6936.
- Reichek JL, Duan F, Smith LM, et al. Genomic and clinical analysis of amplification of the 13q31 chromosomal region in alveolar rhabdomyosarcoma: a report from the Children's Oncology Group. Clin Cancer Res 2011; 17:1463.
- Missiaglia E, Williamson D, Chisholm J, et al. PAX3/FOXO1 fusion gene status is the key prognostic molecular marker in rhabdomyosarcoma and significantly improves current risk stratification. J Clin Oncol 2012; 30:1670.
- Risk factors
- Inherited syndromes
- Tissue diagnosis
- - Immunohistochemistry
- - Other adjunctive studies
- Histologic classification
- - Embryonal RMS
- - Botryoid variant
- - Alveolar RMS
- - Anaplastic RMS
- - Undifferentiated sarcoma
- MOLECULAR PATHOGENESIS AND MOLECULAR DIAGNOSTIC TESTING
- Alveolar RMS and chromosome translocations
- Embryonal type
- Other pathways
- Molecular classification
- INFORMATION FOR PATIENTS