jueves, 7 de marzo de 2019

Childhood Rhabdomyosarcoma Treatment (PDQ®) 1/2 —Health Professional Version - National Cancer Institute

Childhood Rhabdomyosarcoma Treatment (PDQ®)—Health Professional Version - National Cancer Institute



National Cancer Institute



Childhood Rhabdomyosarcoma Treatment (PDQ®)–Health Professional Version

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General Information About Childhood Rhabdomyosarcoma





Dramatic improvements in survival have been achieved for children and adolescents with cancer.[1] Between 1975 and 2010, childhood cancer mortality decreased by more than 50%.[1] For rhabdomyosarcoma, the 5-year survival rate increased over the same time, from 53% to 67% for children younger than 15 years and from 30% to 51% for adolescents aged 15 to 19 years.[1] Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)


Incidence

Childhood rhabdomyosarcoma is a soft tissue malignant tumor of mesenchymal origin. It accounts for approximately 3.5% of the cases of cancer among children aged 0 to 14 years and 2% of the cases among adolescents and young adults aged 15 to 19 years.[2,3] The incidence is 4.5 cases per 1 million children, and 50% of cases are seen in the first decade of life.[4]
Incidence may depend on the histologic subtype of rhabdomyosarcoma, as follows:
  • Embryonal: Patients with embryonal rhabdomyosarcoma are predominantly male (male to female ratio, 1.5). The peak incidence is in the 0- to 4-year age group at approximately 4 cases per 1 million children, with a lower rate in adolescents, approximately 1.5 cases per 1 million adolescents. This subtype constitutes 57% of patients in the Surveillance, Epidemiology, and End Results (SEER) database.[4]
  • Alveolar: The incidence of alveolar rhabdomyosarcoma does not vary by sex and is constant from ages 0 to 19 years at approximately 1 case per 1 million children and adolescents. This subtype constitutes 23% of patients in the SEER database.[4]
  • Other: Pleomorphic/anaplastic, mixed type, and spindle cell subtypes each constitute less than 2% of children with rhabdomyosarcoma.[4]
The following are the most common primary sites for rhabdomyosarcoma:[5,6]
  • Head and neck region (approximately 25%).
  • Genitourinary tract (approximately 22%).
  • Extremities (approximately 18%). Within extremity tumors, tumors of the hand and foot occur more often in older patients and have an alveolar histology.[7]
Other less common primary sites include the trunk, chest wall, perineal/anal region, and abdomen, including the retroperitoneum and biliary tract.[6]

Risk Factors

Most cases of rhabdomyosarcoma occur sporadically, with no recognized predisposing risk factor, with the exception of the following:[8]
  • Genetic conditions associated with rhabdomyosarcoma:
    • Li-Fraumeni cancer susceptibility syndrome (with germline TP53 mutations).[9-11]
    • Pleuropulmonary blastoma (with DICER1 mutations).[12,13]
    • Neurofibromatosis type I.[14,15]
    • Costello syndrome (with germline HRAS mutations).[16-19]
    • Beckwith-Wiedemann syndrome (with which Wilms tumor and hepatoblastoma are more commonly associated).[20,21]
    • Noonan syndrome.[19,22,23]
  • High birth weight and large size for gestational age are associated with an increased incidence of embryonal rhabdomyosarcoma.[24]

Prognostic Factors

Rhabdomyosarcoma is usually curable in most children with localized disease who receive combined-modality therapy, with more than 70% surviving 5 years after diagnosis.[5,6,25] Relapses are uncommon after 5 years of disease-free survival, with a 9% late-event rate at 10 years. Relapses, however, are more common in patients who have gross residual disease in unfavorable sites after initial surgery and in those who have metastatic disease at diagnosis.[26]
The prognosis for a child or adolescent with rhabdomyosarcoma is related to the following clinical and biological factors with proven or possible prognostic significance:
  • Age: Children aged 1 to 9 years have the best prognosis, while those younger and older fare less well. In recent Intergroup Rhabdomyosarcoma Study Group (IRSG) trials, 5-year failure-free survival (FFS) was 57% for patients younger than 1 year, 81% for patients aged 1 to 9 years, and 68% for patients older than 10 years. Five-year survival for these groups was 76%, 87%, and 76%, respectively.[27] Historical data show that adults fare less well than children (5-year overall survival [OS] rates, 27% ± 1.4% and 61% ± 1.4%, respectively; P < .0001).[28-31]
    • Infants: Infants may do poorly because their bone marrow is less tolerant of chemotherapy doses that older children can receive; thus, infants are relatively underdosed compared with older patients. In addition, infants younger than 1 year are less likely to receive radiation therapy for local control, because of bias and/or concern about the high incidence of late effects in this age group.[25,32,33] The 5-year FFS for infants was found to be 67%, compared with 81% in a matched group of older patients treated by the Children's Oncology Group (COG).[27] This inferior FFS was largely because of a relatively high rate of local failure.
    • Older children: In older children, vincristine and dactinomycin have upper dosage limits based on body surface area (BSA), and these patients may also require reduced vincristine doses because of neurotoxicity.[33,34]
    • Adolescents: A report from the AIEOP (Italian) Soft Tissue Sarcoma Committee suggests that adolescents may have more frequent unfavorable tumor characteristics, including alveolar histology, regional lymph node involvement, and metastatic disease at diagnosis, accounting for their poor prognosis. This study also found that 5-year OS and progression-free survival (PFS) rates were somewhat lower in adolescents than in children, but the differences among age groups younger than 1 year and aged 10 to 19 years at diagnosis were significantly worse than those in the group aged 1 to 9 years.[35]
  • Site of origin: Prognosis for childhood rhabdomyosarcoma varies according to the primary tumor site (refer to Table 1).
    Table 1. 5-Year Survival by Primary Site of Disease
    Primary SiteNumber of PatientsSurvival at 5 Years (%)
    aPatients treated on Intergroup Rhabdomyosarcoma Study III.[5]
    bPatients treated on Intergroup Rhabdomyosarcoma Studies I–IV.[36]
    Orbita10795
    Superficial head and neck (nonparameningeal)a10678
    Cranial parameningeala13474
    Genitourinary (excluding bladder/prostate)a15889
    Bladder/prostatea10481
    Extremitya15674
    Trunk, abdomen, perineum, etc.a14767
    Biliaryb2578
  • Tumor size: Children with smaller tumors (≤5 cm) have improved survival compared with children with larger tumors (>5 cm).[5] Both tumor volume and maximum tumor diameter are associated with outcome.[37][Level of evidence: 3iiA]
    A retrospective review of soft tissue sarcomas in children and adolescents suggests that the 5 cm cutoff used for adults with soft tissue sarcoma may not be ideal for smaller children, especially infants. The review identified an interaction between tumor diameter and BSA.[38] This was not confirmed by a COG study of patients with intermediate-risk rhabdomyosarcoma.[39] This relationship requires prospective study to determine the therapeutic implications of the observation.
  • Resectability: The extent of disease after the primary surgical procedure (i.e., the Surgical-pathologic Group, also called the Clinical Group) is also correlated with outcome.[5] In the IRS-III study, patients with localized, gross residual disease after initial surgery (Surgical-pathologic Group III) had a 5-year survival rate of approximately 70%, compared with a more than 90% 5-year survival rate for patients without residual tumor after surgery (Group I) and an approximately 80% 5-year survival rate for patients with microscopic residual tumor after surgery (Group II).[5,40]
    Resectability without functional impairment is related to initial size and site of the tumor, making the Grouping system less useful than a TNM system. Regardless, outcome is optimized with the use of multimodality therapy. All patients require chemotherapy and at least 85% also benefit from radiation therapy, with favorable outcome even for those patients with nonresectable disease. In IRS-IV, the Group III patients with localized unresectable disease who were treated with chemotherapy and radiation therapy had a 5-year FFS of about 75% and a local control rate of 87%.[41]
  • Histopathologic subtype: The alveolar subtype is more prevalent among patients with less favorable clinical features (e.g., younger than 1 year or older than 10 years, extremity primary tumors, and metastatic disease at diagnosis), and is generally associated with a worse outcome than in similar patients with embryonal rhabdomyosarcoma.
    • In the IRS-I and IRS-II studies, the alveolar subtype was associated with a less favorable outcome even in patients whose primary tumor was completely resected (Group I).[42]
    • A statistically significant difference in 5-year survival by histopathologic subtype (82% for embryonal rhabdomyosarcoma vs. 65% for alveolar rhabdomyosarcoma), was not noted when 1,258 IRS-III and IRS-IV patients with rhabdomyosarcoma were analyzed.[43]
    • In the IRS-III study, outcome for patients with Group I alveolar subtype tumors was similar to that for other patients with Group I tumors, but the alveolar patients received more intensive therapy.[5]
    • Patients with alveolar rhabdomyosarcoma who have regional lymph node involvement have significantly worse outcomes (5-year FFS, 43%) than patients who do not have regional lymph node involvement (5-year FFS, 73%).[44]
    Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).[45]
  • PAX3/PAX7-FOXO1: Occasionally, patients with histology consistent with alveolar rhabdomyosarcoma do not have one of the two gene fusions that are characteristic of the disease. Patients with translocation-negative alveolar rhabdomyosarcoma have outcomes similar to those for patients with embryonal rhabdomyosarcoma and do better than patients with fusion-positive alveolar rhabdomyosarcoma.[46-48] For example, in a study from the Soft Tissue Sarcoma Committee of the COG of 434 cases of intermediate-risk rhabdomyosarcoma, fusion-positive patients had a lower event-free survival (EFS) (PAX3, 54% and PAX7, 65%) than did those with embryonal rhabdomyosarcoma (EFS, 77%). Patients with fusion-negative alveolar rhabdomyosarcoma had outcomes similar to those for patients with embryonal rhabdomyosarcoma.[48] These studies also demonstrated that fusion status was a better predictor of outcome than was histology and will replace histology in COG studies going forward. Similar conclusions were reached in a retrospective study of three consecutive trials in the United Kingdom. The authors underscored the probable value of treating fusion-negative patients whose tumors have alveolar histology with therapy that is stage appropriate for embryonal histology tumors.[49][Level of evidence: 3iiA]
  • Metastases at diagnosis: Children with metastatic disease at diagnosis have the worst prognosis.
    The prognostic significance of metastatic disease is modified by the following:
    • Tumor histology (embryonal rhabdomyosarcoma is more favorable than alveolar). Only patients with alveolar histology and regional node disease have a worse prognosis provided that regional disease is treated with radiation therapy.[44]
    • Age at diagnosis (<10 years for children with embryonal rhabdomyosarcoma).
    • The site of metastatic disease. Patients with metastatic genitourinary (nonbladder, nonprostate) primary tumors have a more favorable outcome than do patients with metastatic disease from other primary sites.[50]
    • The number of metastatic sites.[51-54]
    The COG performed a retrospective review of patients enrolled on high-risk protocols for rhabdomyosarcoma. PAX fusion status correlated with clinical characteristics at diagnosis, including age, stage, histology, and extent of metastatic disease (Oberlin status). Among patients with metastatic disease, PAX-FOXO1 fusion status was not an independent predictor of outcome.[55][Level of evidence: 1iiDi]
  • Lymph node involvement at diagnosis: Lymph node involvement at diagnosis is associated with an inferior prognosis, and clinical and/or imaging evaluation is performed before treatment and preoperatively. Sentinel lymph node identification by appropriate methodology can aid in this evaluation. Suspicious nodes are sampled surgically with open biopsy preferred to needle aspiration, although this may occasionally be appropriate. Pathologic evaluation of clinically uninvolved nodes is site specific; in the United States, it is performed for extremity sites or for boys older than 10 years with paratesticular primaries.
    Data on the frequency of lymph node involvement in various sites is informative in clinical decision making. For example, up to 40% of patients with rhabdomyosarcoma in genitourinary sites have lymph node involvement, while patients with head and neck sites have a much lower likelihood (<10%). Patients with nongenitourinary pelvic sites (e.g. anus/perineum) have an intermediate frequency of lymph node involvement.[56]
    In the extremities and trunk, sentinel lymph node evaluation is a more accurate form of diagnosis than is random regional lymph node sampling. In clinically negative lymph nodes of the extremity or trunk, sentinel lymph node biopsy is the preferred form of node sampling by the COG. Technical considerations are obtained from surgical experts. Needle or open biopsy of clinically enlarged nodes is appropriate.[57-60]
    Adjuvant radiation therapy is administered to patients with lymph node involvement to enhance regional control.
  • Biological characteristics: Refer to the Molecular Characteristics of Rhabdomyosarcoma section of this summary for more information.
It is unlikely that response to induction chemotherapy, as judged by anatomic imaging, correlates with the likelihood of survival in patients with rhabdomyosarcoma, on the basis of the IRSG, COG, and International Society of Pediatric Oncology (SIOP) studies that found no association.[61]; [62][Level of evidence: 3iiDi]; [63][Level of evidence: 3iiiA] However, an Italian study did find that patient response correlated with likelihood of survival.[37][Level of evidence: 3iiA] In patients with embryonal rhabdomyosarcoma who had metastases only in the lungs, the Cooperative Weichteilsarkom Studiengruppe (CWS) assessed the relationship between complete response of the lung metastases at weeks 7 to 10 after chemotherapy and outcome in 53 patients.[64][Level of evidence: 3iiA] Five-year survival was 68% for 26 complete responders at weeks 7 to 10 versus 36% for 27 patients who achieved complete responses at later time points (P = .004).
Other studies have investigated response to induction therapy, showing benefit to response. These data are somewhat flawed because therapy is usually tailored on the basis of response and thus, the situation is not as clear as the COG data suggests.[65-70]
Response as judged by sequential functional imaging studies with fluorine F 18-fludeoxyglucose positron emission tomography (PET) may be an early indicator of outcome [71] and is under investigation by several pediatric cooperative groups. A retrospective analysis of 107 patients from a single institution examined PET scans performed at baseline, after induction chemotherapy, and after local therapy.[71] Standardized uptake value measured at baseline predicted PFS and OS, but not local control. A negative scan after induction chemotherapy correlated with statistically significantly better PFS. A positive scan after local therapy predicted worse PFS, OS, and local control.
Adult patients with rhabdomyosarcoma have a higher incidence of pleomorphic histology (19%) than do children (<2%). Adults also have a higher incidence of tumors in unfavorable sites than do children.[28]
Because treatment and prognosis depend, in part, on the histology and molecular genetics of the tumor, it is necessary that the tumor tissue be reviewed by pathologists and cytogeneticists/molecular geneticists with experience in the evaluation and diagnosis of tumors in children. Additionally, the diversity of primary sites, the distinctive surgical and radiation therapy treatments for each primary site, and the subsequent site-specific rehabilitation underscore the importance of treating children with rhabdomyosarcoma in medical centers with appropriate experience in all therapeutic modalities.


References
  1. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  2. Gurney JG, Severson RK, Davis S, et al.: Incidence of cancer in children in the United States. Sex-, race-, and 1-year age-specific rates by histologic type. Cancer 75 (8): 2186-95, 1995. [PUBMED Abstract]
  3. Ries LA, Kosary CL, Hankey BF, et al., eds.: SEER Cancer Statistics Review, 1973-1996. Bethesda, Md: National Cancer Institute, 1999. Also available online. Last accessed January 29, 2019.
  4. Ognjanovic S, Linabery AM, Charbonneau B, et al.: Trends in childhood rhabdomyosarcoma incidence and survival in the United States, 1975-2005. Cancer 115 (18): 4218-26, 2009. [PUBMED Abstract]
  5. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PUBMED Abstract]
  6. Maurer HM, Gehan EA, Beltangady M, et al.: The Intergroup Rhabdomyosarcoma Study-II. Cancer 71 (5): 1904-22, 1993. [PUBMED Abstract]
  7. Casanova M, Meazza C, Favini F, et al.: Rhabdomyosarcoma of the extremities: a focus on tumors arising in the hand and foot. Pediatr Hematol Oncol 26 (5): 321-31, 2009 Jul-Aug. [PUBMED Abstract]
  8. Gurney JG, Young JL Jr, Roffers SD, et al.: Soft tissue sarcomas. In: Ries LA, Smith MA, Gurney JG, et al., eds.: Cancer incidence and survival among children and adolescents: United States SEER Program 1975-1995. Bethesda, Md: National Cancer Institute, SEER Program, 1999. NIH Pub.No. 99-4649, pp 111-123. Also available online. Last accessed January 29, 2019.
  9. Li FP, Fraumeni JF Jr: Rhabdomyosarcoma in children: epidemiologic study and identification of a familial cancer syndrome. J Natl Cancer Inst 43 (6): 1365-73, 1969. [PUBMED Abstract]
  10. Diller L, Sexsmith E, Gottlieb A, et al.: Germline p53 mutations are frequently detected in young children with rhabdomyosarcoma. J Clin Invest 95 (4): 1606-11, 1995. [PUBMED Abstract]
  11. Trahair T, Andrews L, Cohn RJ: Recognition of Li Fraumeni syndrome at diagnosis of a locally advanced extremity rhabdomyosarcoma. Pediatr Blood Cancer 48 (3): 345-8, 2007. [PUBMED Abstract]
  12. Dehner LP, Jarzembowski JA, Hill DA: Embryonal rhabdomyosarcoma of the uterine cervix: a report of 14 cases and a discussion of its unusual clinicopathological associations. Mod Pathol 25 (4): 602-14, 2012. [PUBMED Abstract]
  13. Doros L, Yang J, Dehner L, et al.: DICER1 mutations in embryonal rhabdomyosarcomas from children with and without familial PPB-tumor predisposition syndrome. Pediatr Blood Cancer 59 (3): 558-60, 2012. [PUBMED Abstract]
  14. Ferrari A, Bisogno G, Macaluso A, et al.: Soft-tissue sarcomas in children and adolescents with neurofibromatosis type 1. Cancer 109 (7): 1406-12, 2007. [PUBMED Abstract]
  15. Crucis A, Richer W, Brugières L, et al.: Rhabdomyosarcomas in children with neurofibromatosis type I: A national historical cohort. Pediatr Blood Cancer 62 (10): 1733-8, 2015. [PUBMED Abstract]
  16. Gripp KW, Lin AE, Stabley DL, et al.: HRAS mutation analysis in Costello syndrome: genotype and phenotype correlation. Am J Med Genet A 140 (1): 1-7, 2006. [PUBMED Abstract]
  17. Aoki Y, Niihori T, Kawame H, et al.: Germline mutations in HRAS proto-oncogene cause Costello syndrome. Nat Genet 37 (10): 1038-40, 2005. [PUBMED Abstract]
  18. Gripp KW: Tumor predisposition in Costello syndrome. Am J Med Genet C Semin Med Genet 137 (1): 72-7, 2005. [PUBMED Abstract]
  19. Kratz CP, Rapisuwon S, Reed H, et al.: Cancer in Noonan, Costello, cardiofaciocutaneous and LEOPARD syndromes. Am J Med Genet C Semin Med Genet 157 (2): 83-9, 2011. [PUBMED Abstract]
  20. Samuel DP, Tsokos M, DeBaun MR: Hemihypertrophy and a poorly differentiated embryonal rhabdomyosarcoma of the pelvis. Med Pediatr Oncol 32 (1): 38-43, 1999. [PUBMED Abstract]
  21. DeBaun MR, Tucker MA: Risk of cancer during the first four years of life in children from The Beckwith-Wiedemann Syndrome Registry. J Pediatr 132 (3 Pt 1): 398-400, 1998. [PUBMED Abstract]
  22. Moschovi M, Touliatou V, Vassiliki T, et al.: Rhabdomyosarcoma in a patient with Noonan syndrome phenotype and review of the literature. J Pediatr Hematol Oncol 29 (5): 341-4, 2007. [PUBMED Abstract]
  23. Hasle H: Malignant diseases in Noonan syndrome and related disorders. Horm Res 72 (Suppl 2): 8-14, 2009. [PUBMED Abstract]
  24. Ognjanovic S, Carozza SE, Chow EJ, et al.: Birth characteristics and the risk of childhood rhabdomyosarcoma based on histological subtype. Br J Cancer 102 (1): 227-31, 2010. [PUBMED Abstract]
  25. Crist WM, Anderson JR, Meza JL, et al.: Intergroup rhabdomyosarcoma study-IV: results for patients with nonmetastatic disease. J Clin Oncol 19 (12): 3091-102, 2001. [PUBMED Abstract]
  26. Sung L, Anderson JR, Donaldson SS, et al.: Late events occurring five years or more after successful therapy for childhood rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Eur J Cancer 40 (12): 1878-85, 2004. [PUBMED Abstract]
  27. Malempati S, Rodeberg DA, Donaldson SS, et al.: Rhabdomyosarcoma in infants younger than 1 year: a report from the Children's Oncology Group. Cancer 117 (15): 3493-501, 2011. [PUBMED Abstract]
  28. Sultan I, Qaddoumi I, Yaser S, et al.: Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27 (20): 3391-7, 2009. [PUBMED Abstract]
  29. Streby KA, Ruymann FB, Whiteside S, et al.: Rhabdomyosarcoma in adolescents and young adults: A 25-year review at Nationwide Children’s Hospital. J Adolesc Young Adult Oncol 1 (4): 164-167, 2012.
  30. Van Gaal JC, Van Der Graaf WT, Rikhof B, et al.: The impact of age on outcome of embryonal and alveolar rhabdomyosarcoma patients. A multicenter study. Anticancer Res 32 (10): 4485-97, 2012. [PUBMED Abstract]
  31. Dumont SN, Araujo DM, Munsell MF, et al.: Management and outcome of 239 adolescent and adult rhabdomyosarcoma patients. Cancer Med 2 (4): 553-63, 2013. [PUBMED Abstract]
  32. Ferrari A, Casanova M, Bisogno G, et al.: Rhabdomyosarcoma in infants younger than one year old: a report from the Italian Cooperative Group. Cancer 97 (10): 2597-604, 2003. [PUBMED Abstract]
  33. Joshi D, Anderson JR, Paidas C, et al.: Age is an independent prognostic factor in rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Pediatr Blood Cancer 42 (1): 64-73, 2004. [PUBMED Abstract]
  34. Gupta AA, Anderson JR, Pappo AS, et al.: Patterns of chemotherapy-induced toxicities in younger children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. Cancer 118 (4): 1130-7, 2012. [PUBMED Abstract]
  35. Bisogno G, Compostella A, Ferrari A, et al.: Rhabdomyosarcoma in adolescents: a report from the AIEOP Soft Tissue Sarcoma Committee. Cancer 118 (3): 821-7, 2012. [PUBMED Abstract]
  36. Spunt SL, Lobe TE, Pappo AS, et al.: Aggressive surgery is unwarranted for biliary tract rhabdomyosarcoma. J Pediatr Surg 35 (2): 309-16, 2000. [PUBMED Abstract]
  37. Ferrari A, Miceli R, Meazza C, et al.: Comparison of the prognostic value of assessing tumor diameter versus tumor volume at diagnosis or in response to initial chemotherapy in rhabdomyosarcoma. J Clin Oncol 28 (8): 1322-8, 2010. [PUBMED Abstract]
  38. Ferrari A, Miceli R, Meazza C, et al.: Soft tissue sarcomas of childhood and adolescence: the prognostic role of tumor size in relation to patient body size. J Clin Oncol 27 (3): 371-6, 2009. [PUBMED Abstract]
  39. Rodeberg DA, Stoner JA, Garcia-Henriquez N, et al.: Tumor volume and patient weight as predictors of outcome in children with intermediate risk rhabdomyosarcoma: a report from the Children's Oncology Group. Cancer 117 (11): 2541-50, 2011. [PUBMED Abstract]
  40. Smith LM, Anderson JR, Qualman SJ, et al.: Which patients with microscopic disease and rhabdomyosarcoma experience relapse after therapy? A report from the soft tissue sarcoma committee of the children's oncology group. J Clin Oncol 19 (20): 4058-64, 2001. [PUBMED Abstract]
  41. Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001. [PUBMED Abstract]
  42. Crist WM, Garnsey L, Beltangady MS, et al.: Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 8 (3): 443-52, 1990. [PUBMED Abstract]
  43. Meza JL, Anderson J, Pappo AS, et al.: Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol 24 (24): 3844-51, 2006. [PUBMED Abstract]
  44. Rodeberg DA, Garcia-Henriquez N, Lyden ER, et al.: Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 29 (10): 1304-11, 2011. [PUBMED Abstract]
  45. Qualman S, Lynch J, Bridge J, et al.: Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 113 (11): 3242-7, 2008. [PUBMED Abstract]
  46. Arnold MA, Anderson JR, Gastier-Foster JM, et al.: Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (4): 634-9, 2016. [PUBMED Abstract]
  47. 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 28 (13): 2151-8, 2010. [PUBMED Abstract]
  48. Skapek SX, Anderson J, Barr FG, et al.: PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr Blood Cancer 60 (9): 1411-7, 2013. [PUBMED Abstract]
  49. Selfe J, Olmos D, Al-Saadi R, et al.: Impact of fusion gene status versus histology on risk-stratification for rhabdomyosarcoma: Retrospective analyses of patients on UK trials. Pediatr Blood Cancer 64 (7): , 2017. [PUBMED Abstract]
  50. Koscielniak E, Rodary C, Flamant F, et al.: Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: a retrospective European multi-center analysis. Med Pediatr Oncol 20 (3): 209-14, 1992. [PUBMED Abstract]
  51. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [PUBMED Abstract]
  52. Bisogno G, Ferrari A, Prete A, et al.: Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma. Eur J Cancer 45 (17): 3035-41, 2009. [PUBMED Abstract]
  53. Dantonello TM, Winkler P, Boelling T, et al.: Embryonal rhabdomyosarcoma with metastases confined to the lungs: report from the CWS Study Group. Pediatr Blood Cancer 56 (5): 725-32, 2011. [PUBMED Abstract]
  54. Oberlin O, Rey A, Lyden E, et al.: Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups. J Clin Oncol 26 (14): 2384-9, 2008. [PUBMED Abstract]
  55. Rudzinski ER, Anderson JR, Chi YY, et al.: Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group. Pediatr Blood Cancer 64 (12): , 2017. [PUBMED Abstract]
  56. Lawrence W Jr, Hays DM, Heyn R, et al.: Lymphatic metastases with childhood rhabdomyosarcoma. A report from the Intergroup Rhabdomyosarcoma Study. Cancer 60 (4): 910-5, 1987. [PUBMED Abstract]
  57. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014. [PUBMED Abstract]
  58. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013. [PUBMED Abstract]
  59. Wright S, Armeson K, Hill EG, et al.: The role of sentinel lymph node biopsy in select sarcoma patients: a meta-analysis. Am J Surg 204 (4): 428-33, 2012. [PUBMED Abstract]
  60. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012. [PUBMED Abstract]
  61. Burke M, Anderson JR, Kao SC, et al.: Assessment of response to induction therapy and its influence on 5-year failure-free survival in group III rhabdomyosarcoma: the Intergroup Rhabdomyosarcoma Study-IV experience--a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. J Clin Oncol 25 (31): 4909-13, 2007. [PUBMED Abstract]
  62. Rosenberg AR, Anderson JR, Lyden E, et al.: Early response as assessed by anatomic imaging does not predict failure-free survival among patients with Group III rhabdomyosarcoma: a report from the Children's Oncology Group. Eur J Cancer 50 (4): 816-23, 2014. [PUBMED Abstract]
  63. Vaarwerk B, van der Lee JH, Breunis WB, et al.: Prognostic relevance of early radiologic response to induction chemotherapy in pediatric rhabdomyosarcoma: A report from the International Society of Pediatric Oncology Malignant Mesenchymal Tumor 95 study. Cancer 124 (5): 1016-1024, 2018. [PUBMED Abstract]
  64. Sparber-Sauer M, von Kalle T, Seitz G, et al.: The prognostic value of early radiographic response in children and adolescents with embryonal rhabdomyosarcoma stage IV, metastases confined to the lungs: A report from the Cooperative Weichteilsarkom Studiengruppe (CWS). Pediatr Blood Cancer 64 (10): , 2017. [PUBMED Abstract]
  65. Koscielniak E, Harms D, Henze G, et al.: Results of treatment for soft tissue sarcoma in childhood and adolescence: a final report of the German Cooperative Soft Tissue Sarcoma Study CWS-86. J Clin Oncol 17 (12): 3706-19, 1999. [PUBMED Abstract]
  66. Koscielniak E, Jürgens H, Winkler K, et al.: Treatment of soft tissue sarcoma in childhood and adolescence. A report of the German Cooperative Soft Tissue Sarcoma Study. Cancer 70 (10): 2557-67, 1992. [PUBMED Abstract]
  67. Dantonello TM, Int-Veen C, Harms D, et al.: Cooperative trial CWS-91 for localized soft tissue sarcoma in children, adolescents, and young adults. J Clin Oncol 27 (9): 1446-55, 2009. [PUBMED Abstract]
  68. Oberlin O, Rey A, Sanchez de Toledo J, et al.: Randomized comparison of intensified six-drug versus standard three-drug chemotherapy for high-risk nonmetastatic rhabdomyosarcoma and other chemotherapy-sensitive childhood soft tissue sarcomas: long-term results from the International Society of Pediatric Oncology MMT95 study. J Clin Oncol 30 (20): 2457-65, 2012. [PUBMED Abstract]
  69. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005. [PUBMED Abstract]
  70. Dantonello TM, Stark M, Timmermann B, et al.: Tumour volume reduction after neoadjuvant chemotherapy impacts outcome in localised embryonal rhabdomyosarcoma. Pediatr Blood Cancer 62 (1): 16-23, 2015. [PUBMED Abstract]
  71. Casey DL, Wexler LH, Fox JJ, et al.: Predicting outcome in patients with rhabdomyosarcoma: role of [(18)f]fluorodeoxyglucose positron emission tomography. Int J Radiat Oncol Biol Phys 90 (5): 1136-42, 2014. [PUBMED Abstract]

Cellular Classification for Childhood Rhabdomyosarcoma



Histologic Subtypes

Rhabdomyosarcoma can be divided into several histologic subsets, as follows:[1,2]

Embryonal rhabdomyosarcoma

Embryonal rhabdomyosarcoma has the following three subtypes:
  • Embryonal.
  • Botryoid.
  • Spindle cell/sclerosing.
Embryonal-subtype rhabdomyosarcoma. The embryonal subtype is the most frequently observed subtype in children, accounting for approximately 60% to 70% of childhood rhabdomyosarcomas.[1] Tumors with embryonal histology typically arise in the head and neck region or in the genitourinary tract, although they may occur at any primary site.
Anaplasia has been observed in 13% of embryonal rhabdomyosarcoma cases, and its presence may adversely influence clinical outcome in patients with intermediate-risk embryonal rhabdomyosarcoma. However, anaplasia was not shown to be an independent prognostic variable in a multivariate analysis (P = .081).[3]
Botryoid-subtype rhabdomyosarcoma. Botryoid tumors represent about 10% of all rhabdomyosarcoma cases and are embryonal tumors that arise under the mucosal surface of body orifices such as the vagina, bladder, nasopharynx, and biliary tract. The World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone (4th edition) eliminated botryoid rhabdomyosarcoma, with these cases classified as typical embryonal rhabdomyosarcoma.[4]
A study of 2,192 children with rhabdomyosarcoma enrolled on clinical trials and diagnosed with embryonal histology (including botryoid and spindle cell variants) showed improved event-free survival (EFS) for patients with botryoid tumors (80%; 95% confidence interval [CI], 74%–84%) compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%–75%).[5] However, after adjusting for primary site, resection, and metastatic status, there was no difference in EFS by histologic subtype. This observation supports the elimination of the botryoid variant as a specific histologic subtype of rhabdomyosarcoma.
Spindle cell/sclerosing-subtype rhabdomyosarcoma. The 4th edition of the WHO Classification of Tumours of Soft Tissue and Bone added spindle cell/sclerosing rhabdomyosarcoma as a separate subtype of rhabdomyosarcoma.[4] The spindle cell variant of embryonal rhabdomyosarcoma is most frequently observed at the paratesticular site.[5,6]
A study of 2,192 children with rhabdomyosarcoma enrolled on clinical trials and diagnosed with embryonal histology (including botryoid and spindle cell variants) showed improved EFS for patients with spindle cell rhabdomyosarcoma (83%; 95% CI, 77%–87%) compared with typical embryonal rhabdomyosarcoma (73%; 95% CI, 71%–75%).[5] Patients with spindle cell rhabdomyosarcoma with parameningeal primary tumors (n = 18) were the exception to the overall favorable prognosis for this subtype; they had a 5-year EFS of 28% (compared with >70% EFS for parameningeal non-spindle cell embryonal rhabdomyosarcoma). As discussed in the Molecular Characteristics of Rhabdomyosarcomasection of this summary, the variable outcome by primary site for spindle cell rhabdomyosarcoma may reflect distinctive molecular subtypes with divergent prognostic significance within this histology.
In the WHO classification, sclerosing rhabdomyosarcoma is considered a variant pattern of spindle cell rhabdomyosarcoma, as descriptions note increasing degrees of hyalinization and matrix formation in spindle cell tumors. Sclerosing rhabdomyosarcoma is more common in adults, arises in the extremities and head and neck region, and has a more aggressive course. Recurrent MyoD1 mutations in sclerosing rhabdomyosarcoma were also identified.[7] Data on the outcome of sclerosing rhabdomyosarcoma in the pediatric population are limited, however. The largest previous study of sclerosing rhabdomyosarcoma in children had a follow-up of 0.01 to 3.58 years; of 13 patients, three relapsed and one died from the disease.[5]

Alveolar rhabdomyosarcoma

Approximately 30% of children with rhabdomyosarcoma have the alveolar subtype when histology alone is used to determine subtype.[8] An increased frequency of this subtype is noted in adolescents and in patients with primary sites involving the extremities, trunk, and perineum/perianal region.[1] Eighty percent of patients with alveolar histology will have one of two gene fusions, PAX3 on chromosome 2 or PAX7 on chromosome 1, with FOXO1 gene on chromosome 13.[9-11] Patients without a fusion have outcomes that are similar to those for patients with embryonal rhabdomyosarcoma.[12-14]
The current trial for intermediate-risk patients from the Soft Tissue Sarcoma Committee of the Children's Oncology Group (ARST1431 [NCT02567435]) and all future trials will use fusion status rather than histology to determine eligibility; fusion-negative patients with alveolar histology will undergo the same treatments as patients with embryonal histology.

Pleomorphic (anaplastic) rhabdomyosarcoma

Pleomorphic rhabdomyosarcoma occurs predominantly in adults aged 30 to 50 years and is rarely seen in children.[15] In adults, pleomorphic rhabdomyosarcoma is associated with a worse prognosis. In children, the term anaplastic is preferred.[16]

Molecular Characteristics of Rhabdomyosarcoma

The embryonal and alveolar histologies have distinctive molecular characteristics that have been used for diagnostic confirmation, and may be useful for assigning risk group, determining therapy, and monitoring residual disease during treatment.[9,17-20]
  1. Embryonal histology: Embryonal tumors often show loss of heterozygosity at 11p15 and gains on chromosome 8.[10,21,22] Embryonal tumors have a higher background mutation rate and higher single-nucleotide variant rate than do alveolar tumors, and the number of somatic mutations increases with older age at diagnosis.[23,24] Genes with recurring mutations include those in the RAS pathway (e.g., NRAS, KRAS, HRAS, and NF1), which together are observed in approximately one-third of cases. Other genes with recurring mutations include FGFR4, PIK3CA, CTNNB1, FBXW7, and BCOR, all of which are present in fewer than 10% of cases.[23,24]
    Embryonal histology with anaplasia: Anaplasia has been reported in a minority of children with rhabdomyosarcoma, primarily arising in children with the embryonal subtype who are younger than 10 years.[3,16] Rhabdomyosarcoma with nonalveolar, anaplastic morphology may be a presenting feature for children with Li-Fraumeni syndrome and germline TP53 mutations.[25] Among eight consecutively presenting children with rhabdomyosarcoma and TP53 germline mutations, all showed anaplastic morphology. Among an additional seven children with anaplastic rhabdomyosarcoma and unknown TP53 germline mutation status, three of the seven children had functionally relevant TP53 germline mutations. The median age at diagnosis of the 11 children with TP53 germline mutation status was 40 months (range, 19–67 months).
  2. Alveolar histology: About 70% to 80% of alveolar tumors are characterized by translocations between the FOXO1 gene on chromosome 13 and either the PAX3 gene on chromosome 2 (t(2;13)(q35;q14)) or the PAX7 gene on chromosome 1 (t(1;13)(p36;q14)).[9-11] Other rare fusions include PAX3-NCOA1 and PAX3-INO80D.[23] Translocations involving the PAX3 gene occur in approximately 59% of alveolar rhabdomyosarcoma cases, while the PAX7 gene appears to be involved in about 19% of cases.[9] Patients with solid-variant alveolar histology have a lower incidence of PAX-FOXO1 gene fusions than do patients showing classical alveolar histology.[26] For the diagnosis of alveolar rhabdomyosarcoma, FOXO1 gene rearrangement may be detected with good sensitivity and specificity using either fluorescence in situhybridization or reverse transcription–polymerase chain reaction.[27]
    The alveolar histology that is associated with the PAX7 gene in patients with or without metastatic disease appears to occur at a younger age and may be associated with longer event-free survival rates than those associated with PAX3 gene rearrangements.[28-33] Patients with alveolar histology and the PAX3 gene are older and have a higher incidence of invasive tumor (T2). Around 22% of cases showing alveolar histology have no detectable PAX gene translocation.[20,26] In addition to FOXO1 rearrangements, alveolar tumors are characterized by a lower mutational burden than are fusion-negative tumors, with fewer genes having recurring mutations.[23,24] BCOR and PIK3CA mutations and amplification of MYCN, MIR17HG, and CDK4 have also been described.
  3. Spindle cell/sclerosing histology: Spindle cell/sclerosing rhabdomyosarcoma has been proposed as a separate entity in the World Health Organization Classification of Tumours of Soft Tissue and Bone.[34] For congenital/infantile spindle cell rhabdomyosarcoma, a study reported that 10 of 11 patients showed recurrent fusion genes. Most of these cases had truncal primary tumors, and no paratesticular tumors were found. Novel VGLL2 rearrangements were observed in seven patients (63%), including VGLL2-CITED2 fusion in four patients and VGLL2-NCOA2 in two patients.[35] Three patients (27%) harbored different NCOA2 gene fusions, including TEAD1-NCOA2in two patients and SRF-NCOA2 in one patient. All fusion-positive congenital/infantile spindle cell rhabdomyosarcoma patients with available long-term follow-up were alive and well, and no patients developed distant metastases.[35] Further study is needed to better define the prevalence and prognostic significance of these gene rearrangements in young children with spindle cell rhabdomyosarcoma.
    In older children and adults with spindle cell/sclerosing rhabdomyosarcoma, a specific MYOD1 mutation (p.L122R) has been observed in a large proportion of patients.[7,35-37] Activating PIK3CA mutations were common in MYOD1-mutated cases (4 of 10); when they were present, they were associated with sclerosing histology.[35] The presence of the MYOD1 mutation is associated with an increased risk of treatment failure.[7,35,36] In one study that included nine children aged 1 year or older with spindle cell/sclerosing histology and MYOD1 mutations, seven had a fatal outcome despite aggressive multimodality treatment.[35]
These findings highlight the important differences between embryonal and alveolar tumors. Data demonstrate that PAX-FOX01 fusion-positive alveolar tumors are biologically and clinically different from fusion-negative alveolar tumors and embryonal tumors.[13,14,20,38,39] In a study of Intergroup Rhabdomyosarcoma Study Group cases, which captured an entire cohort from a single prospective clinical trial, the outcome for patients with translocation-negative alveolar rhabdomyosarcoma was better than that observed for translocation-positive cases. The outcome was similar to that seen in patients with embryonal rhabdomyosarcoma and demonstrated that fusion status is a critical factor for risk stratification in pediatric rhabdomyosarcoma.


References
  1. Parham DM, Ellison DA: Rhabdomyosarcomas in adults and children: an update. Arch Pathol Lab Med 130 (10): 1454-65, 2006. [PUBMED Abstract]
  2. Newton WA Jr, Gehan EA, Webber BL, et al.: Classification of rhabdomyosarcomas and related sarcomas. Pathologic aspects and proposal for a new classification--an Intergroup Rhabdomyosarcoma Study. Cancer 76 (6): 1073-85, 1995. [PUBMED Abstract]
  3. Qualman S, Lynch J, Bridge J, et al.: Prevalence and clinical impact of anaplasia in childhood rhabdomyosarcoma : a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group. Cancer 113 (11): 3242-7, 2008. [PUBMED Abstract]
  4. Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013.
  5. Rudzinski ER, Anderson JR, Hawkins DS, et al.: The World Health Organization Classification of Skeletal Muscle Tumors in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group. Arch Pathol Lab Med 139 (10): 1281-7, 2015. [PUBMED Abstract]
  6. Leuschner I: Spindle cell rhabdomyosarcoma: histologic variant of embryonal rhabdomyosarcoma with association to favorable prognosis. Curr Top Pathol 89: 261-72, 1995. [PUBMED Abstract]
  7. Agaram NP, Chen CL, Zhang L, et al.: Recurrent MYOD1 mutations in pediatric and adult sclerosing and spindle cell rhabdomyosarcomas: evidence for a common pathogenesis. Genes Chromosomes Cancer 53 (9): 779-87, 2014. [PUBMED Abstract]
  8. Meza JL, Anderson J, Pappo AS, et al.: Analysis of prognostic factors in patients with nonmetastatic rhabdomyosarcoma treated on intergroup rhabdomyosarcoma studies III and IV: the Children's Oncology Group. J Clin Oncol 24 (24): 3844-51, 2006. [PUBMED Abstract]
  9. Barr FG, Smith LM, Lynch JC, et al.: Examination of gene fusion status in archival samples of alveolar rhabdomyosarcoma entered on the Intergroup Rhabdomyosarcoma Study-III trial: a report from the Children's Oncology Group. J Mol Diagn 8 (2): 202-8, 2006. [PUBMED Abstract]
  10. Merlino G, Helman LJ: Rhabdomyosarcoma--working out the pathways. Oncogene 18 (38): 5340-8, 1999. [PUBMED Abstract]
  11. Dumont SN, Lazar AJ, Bridge JA, et al.: PAX3/7-FOXO1 fusion status in older rhabdomyosarcoma patient population by fluorescent in situ hybridization. J Cancer Res Clin Oncol 138 (2): 213-20, 2012. [PUBMED Abstract]
  12. Arnold MA, Anderson JR, Gastier-Foster JM, et al.: Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group. Pediatr Blood Cancer 63 (4): 634-9, 2016. [PUBMED Abstract]
  13. 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 28 (13): 2151-8, 2010. [PUBMED Abstract]
  14. Skapek SX, Anderson J, Barr FG, et al.: PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report. Pediatr Blood Cancer 60 (9): 1411-7, 2013. [PUBMED Abstract]
  15. Sultan I, Qaddoumi I, Yaser S, et al.: Comparing adult and pediatric rhabdomyosarcoma in the surveillance, epidemiology and end results program, 1973 to 2005: an analysis of 2,600 patients. J Clin Oncol 27 (20): 3391-7, 2009. [PUBMED Abstract]
  16. 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 17 (5): 443-53, 1993. [PUBMED Abstract]
  17. Kelly KM, Womer RB, Barr FG: Minimal disease detection in patients with alveolar rhabdomyosarcoma using a reverse transcriptase-polymerase chain reaction method. Cancer 78 (6): 1320-7, 1996. [PUBMED Abstract]
  18. Edwards RH, Chatten J, Xiong QB, et al.: Detection of gene fusions in rhabdomyosarcoma by reverse transcriptase-polymerase chain reaction assay of archival samples. Diagn Mol Pathol 6 (2): 91-7, 1997. [PUBMED Abstract]
  19. Sartori F, Alaggio R, Zanazzo G, et al.: Results of a prospective minimal disseminated disease study in human rhabdomyosarcoma using three different molecular markers. Cancer 106 (8): 1766-75, 2006. [PUBMED Abstract]
  20. 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 174 (2): 550-64, 2009. [PUBMED Abstract]
  21. Koufos A, Hansen MF, Copeland NG, et al.: Loss of heterozygosity in three embryonal tumours suggests a common pathogenetic mechanism. Nature 316 (6026): 330-4, 1985 Jul 25-31. [PUBMED Abstract]
  22. Scrable H, Witte D, Shimada H, et al.: Molecular differential pathology of rhabdomyosarcoma. Genes Chromosomes Cancer 1 (1): 23-35, 1989. [PUBMED Abstract]
  23. Shern JF, Chen L, Chmielecki J, et al.: Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors. Cancer Discov 4 (2): 216-31, 2014. [PUBMED Abstract]
  24. Chen X, Stewart E, Shelat AA, et al.: Targeting oxidative stress in embryonal rhabdomyosarcoma. Cancer Cell 24 (6): 710-24, 2013. [PUBMED Abstract]
  25. Hettmer S, Archer NM, Somers GR, et al.: Anaplastic rhabdomyosarcoma in TP53 germline mutation carriers. Cancer 120 (7): 1068-75, 2014. [PUBMED Abstract]
  26. 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 31 (6): 895-901, 2007. [PUBMED Abstract]
  27. Thway K, Wang J, Wren D, et al.: The comparative utility of fluorescence in situ hybridization and reverse transcription-polymerase chain reaction in the diagnosis of alveolar rhabdomyosarcoma. Virchows Arch 467 (2): 217-24, 2015. [PUBMED Abstract]
  28. 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 20 (11): 2672-9, 2002. [PUBMED Abstract]
  29. Krsková L, Mrhalová M, Sumerauer D, et al.: Rhabdomyosarcoma: molecular diagnostics of patients classified by morphology and immunohistochemistry with emphasis on bone marrow and purged peripheral blood progenitor cells involvement. Virchows Arch 448 (4): 449-58, 2006. [PUBMED Abstract]
  30. Kelly KM, Womer RB, Sorensen PH, et al.: Common and variant gene fusions predict distinct clinical phenotypes in rhabdomyosarcoma. J Clin Oncol 15 (5): 1831-6, 1997. [PUBMED Abstract]
  31. Barr FG, Qualman SJ, Macris MH, et al.: Genetic heterogeneity in the alveolar rhabdomyosarcoma subset without typical gene fusions. Cancer Res 62 (16): 4704-10, 2002. [PUBMED Abstract]
  32. 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 30 (14): 1670-7, 2012. [PUBMED Abstract]
  33. Duan F, Smith LM, Gustafson DM, et al.: Genomic and clinical analysis of fusion gene amplification in rhabdomyosarcoma: a report from the Children's Oncology Group. Genes Chromosomes Cancer 51 (7): 662-74, 2012. [PUBMED Abstract]
  34. Nascimento AF, Barr FG: Spindle cell/sclerosing rhabdomyosarcoma. In: Fletcher CDM, Bridge JA, Hogendoorn P, et al., eds.: WHO Classification of Tumours of Soft Tissue and Bone. 4th ed. Lyon, France: IARC Press, 2013, pp 134-5.
  35. Alaggio R, Zhang L, Sung YS, et al.: A Molecular Study of Pediatric Spindle and Sclerosing Rhabdomyosarcoma: Identification of Novel and Recurrent VGLL2-related Fusions in Infantile Cases. Am J Surg Pathol 40 (2): 224-35, 2016. [PUBMED Abstract]
  36. Kohsaka S, Shukla N, Ameur N, et al.: A recurrent neomorphic mutation in MYOD1 defines a clinically aggressive subset of embryonal rhabdomyosarcoma associated with PI3K-AKT pathway mutations. Nat Genet 46 (6): 595-600, 2014. [PUBMED Abstract]
  37. Szuhai K, de Jong D, Leung WY, et al.: Transactivating mutation of the MYOD1 gene is a frequent event in adult spindle cell rhabdomyosarcoma. J Pathol 232 (3): 300-7, 2014. [PUBMED Abstract]
  38. Davicioni E, Anderson JR, Buckley JD, et al.: Gene expression profiling for survival prediction in pediatric rhabdomyosarcomas: a report from the children's oncology group. J Clin Oncol 28 (7): 1240-6, 2010. [PUBMED Abstract]
  39. 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 66 (14): 6936-46, 2006. [PUBMED Abstract]

Stage Information for Childhood Rhabdomyosarcoma



Staging Evaluation

Before a biopsy of a suspected tumor mass is performed, imaging studies of the mass and baseline laboratory studies should be obtained. After the patient is diagnosed with rhabdomyosarcoma, an extensive evaluation to determine the extent of the disease should be performed before instituting therapy. This evaluation typically includes the following:
  • Chest x-ray.
  • Computed tomography (CT) scan of the chest.
  • CT scan of the abdomen and pelvis (for lower extremity or genitourinary primary tumors).
  • Magnetic resonance imaging (MRI) of the base of the skull and brain (for parameningeal primary tumors).
  • Regional lymph node evaluation.
    Cross-sectional imaging (CT or MRI scan) of regional lymph nodes should be obtained. Abnormal-appearing lymph nodes should be biopsied when possible. Many studies have demonstrated that sentinel lymph node biopsies can be safely performed in children with rhabdomyosarcoma, and tumor-positive biopsies alter the treatment plan.[1-5] Positron emission tomography (PET) with fluorine F 18-fludeoxyglucose scans can identify areas of possible metastatic disease not seen by other imaging modalities.[6-8] The efficacy of these imaging studies for identifying involved lymph nodes or other sites of disease is important for staging, and PET imaging is recommended on current Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG-STS) treatment protocols.
    Pathologic evaluation of regional nodes is currently required for all COG-STS study participants with extremity primary rhabdomyosarcoma and boys aged 10 years and older with paratesticular rhabdomyosarcoma, because microscopic tumor is often documented even when the nodes are not enlarged. (Refer to the Regional and in-transit lymph nodes section of this summary for more information.)
  • Bilateral bone marrow aspirates and biopsies for selected patients.
  • Bone scan for selected patients.
A retrospective study of 1,687 children with rhabdomyosarcoma enrolled in Intergroup studies from 1991 to 2004 suggests that about one-third of patients (those with localized negative regional lymph nodes, noninvasive embryonal tumors, and Group I alveolar tumors) can have limited staging procedures that eliminate bone marrow and bone scan examinations at diagnosis.[9]

Staging Process

Staging of rhabdomyosarcoma is complex. The process includes the following steps:
  1. Assigning a Stage: Determined by primary site, tumor size (widest dimension), and presence or absence of regional lymph node and/or distant metastases.
  2. Assigning a Group: Determined by status of the initial surgical resection/biopsy, with pathologic assessment of the tumor margin and of lymph node involvement, before the initiation of therapy.
  3. Assigning a Risk Group: Determined by Stage, Group, and histology.
Prognosis for children with rhabdomyosarcoma depends predominantly on the primary site, tumor size, Group, and histologic subtype. Favorable prognostic groups were identified in previous Intergroup Rhabdomyosarcoma Study Group (IRSG) studies, and treatment plans were designed on the basis of patient assignment to different treatment Groups according to prognosis.
Several years ago, the IRSG merged with the National Wilms Tumor Study Group and two large cooperative pediatric cancer treatment groups to form the COG. New protocols for children with soft tissue sarcoma are developed by the COG-STS.

Assignment of Stage

Current COG-STS protocols for rhabdomyosarcoma use the TNM-based pretreatment staging system that incorporates the primary tumor site, presence or absence of tumor invasion of surrounding tissues, tumor size, regional lymph node status, and the presence or absence of metastases. This staging system is described in Table 3 below.[10,11]
Terms defining the TNM criteria are described in Table 2.
Table 2. Definition of Terms
TermDefinition
Favorable siteOrbit; nonparameningeal head and neck; genitourinary tract other than kidney, bladder, and prostate; biliary tract.
Unfavorable siteAny site other than favorable.
T1Tumor confined to organ or tissue of origin (noninvasive).
T2Tumor extension beyond the organ or tissue of origin (invasive).
aTumor ≤5 cm in maximum dimension.
bTumor >5 cm in maximum dimension.
N0No clinical regional lymph node involvement.
N1Clinical regional lymph node involvement.
NXRegional lymph nodes not examined; no information.
M0No metastatic disease.
M1Metastatic disease.
Table 3. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Pretreatment Staging System
StageSites of Primary TumorT StageaTumor SizeRegional Lymph NodesaDistant Metastasisa
aRefer to Table 2 for the definitions of the TNM criteria.
1Favorable sitesT1 or T2Any sizeN0 or N1 or NXM0
2Unfavorable sitesT1 or T2a, ≤5 cmN0 or NXM0
3Unfavorable sitesT1 or T2a, ≤5 cmN1M0
b, >5 cmN0 or N1 or NX
4Any siteT1 or T2Any sizeN0 or N1 or NXM1

Assignment of Group

The IRS-I, IRS-II, and IRS-III studies prescribed treatment plans based on the Surgical-pathologic Group system. In this system, Groups are defined by the extent of disease and by the completeness or extent of initial surgical resection after pathologic review of the tumor specimen(s). The definitions for these Groups are shown in Table 4 below.[12,13]
Table 4. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Surgical-pathologic Group System
GroupIncidenceDefinition
IApproximately 13%Localized tumor, completely removed with microscopically clear margins and no regional lymph node involvement.
IIApproximately 20%Localized tumor, completely removed with: (a) microscopic residual disease; (b) regional disease with involved, grossly removed regional lymph nodes; or (c) regional disease with involved nodes, grossly removed but with microscopic residual and/or histologic involvement of the most distal node from the primary tumor.
IIIApproximately 48%Localized tumor, incompletely removed with gross, residual disease after: (a) biopsy only or (b) subtotal resection.
IVApproximately 18%Distant metastases present at diagnosis. This category includes: (a) radiographically identified evidence of tumor spread or (b) positive tumor cells in cerebral spinal fluid, pleural or peritoneal fluids, or implants in these regions.

Assignment of Risk Group

After patients are categorized by Stage and Surgical-pathologic Group, a Risk Group is assigned. This takes into account Stage, Group, and histology. Patients are classified for protocol purposes as having a low risk, intermediate risk, or high risk of disease recurrence.[14,15] Treatment assignment is based on Risk Group, as shown in Table 5.
Table 5. Soft Tissue Sarcoma Committee of the Children's Oncology Group: Rhabdomyosarcoma Risk Group Classification
Risk GroupHistologyStageGroup
Low riskEmbryonal1I, II, III
Embryonal2, 3I, II
Intermediate riskEmbryonal2, 3III
Alveolar1, 2, 3I, II, III
High riskEmbryonal or Alveolar4IV


References
  1. Kayton ML, Delgado R, Busam K, et al.: Experience with 31 sentinel lymph node biopsies for sarcomas and carcinomas in pediatric patients. Cancer 112 (9): 2052-9, 2008. [PUBMED Abstract]
  2. Dall'Igna P, De Corti F, Alaggio R, et al.: Sentinel node biopsy in pediatric patients: the experience in a single institution. Eur J Pediatr Surg 24 (6): 482-7, 2014. [PUBMED Abstract]
  3. Alcorn KM, Deans KJ, Congeni A, et al.: Sentinel lymph node biopsy in pediatric soft tissue sarcoma patients: utility and concordance with imaging. J Pediatr Surg 48 (9): 1903-6, 2013. [PUBMED Abstract]
  4. Wright S, Armeson K, Hill EG, et al.: The role of sentinel lymph node biopsy in select sarcoma patients: a meta-analysis. Am J Surg 204 (4): 428-33, 2012. [PUBMED Abstract]
  5. Parida L, Morrisson GT, Shammas A, et al.: Role of lymphoscintigraphy and sentinel lymph node biopsy in the management of pediatric melanoma and sarcoma. Pediatr Surg Int 28 (6): 571-8, 2012. [PUBMED Abstract]
  6. Völker T, Denecke T, Steffen I, et al.: Positron emission tomography for staging of pediatric sarcoma patients: results of a prospective multicenter trial. J Clin Oncol 25 (34): 5435-41, 2007. [PUBMED Abstract]
  7. Tateishi U, Hosono A, Makimoto A, et al.: Comparative study of FDG PET/CT and conventional imaging in the staging of rhabdomyosarcoma. Ann Nucl Med 23 (2): 155-61, 2009. [PUBMED Abstract]
  8. Federico SM, Spunt SL, Krasin MJ, et al.: Comparison of PET-CT and conventional imaging in staging pediatric rhabdomyosarcoma. Pediatr Blood Cancer 60 (7): 1128-34, 2013. [PUBMED Abstract]
  9. Weiss AR, Lyden ER, Anderson JR, et al.: Histologic and clinical characteristics can guide staging evaluations for children and adolescents with rhabdomyosarcoma: a report from the Children's Oncology Group Soft Tissue Sarcoma Committee. J Clin Oncol 31 (26): 3226-32, 2013. [PUBMED Abstract]
  10. Lawrence W Jr, Gehan EA, Hays DM, et al.: Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II). J Clin Oncol 5 (1): 46-54, 1987. [PUBMED Abstract]
  11. Lawrence W Jr, Anderson JR, Gehan EA, et al.: Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the Intergroup Rhabdomyosarcoma Study Group. Children's Cancer Study Group. Pediatric Oncology Group. Cancer 80 (6): 1165-70, 1997. [PUBMED Abstract]
  12. Crist WM, Garnsey L, Beltangady MS, et al.: Prognosis in children with rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma studies I and II. Intergroup Rhabdomyosarcoma Committee. J Clin Oncol 8 (3): 443-52, 1990. [PUBMED Abstract]
  13. Crist W, Gehan EA, Ragab AH, et al.: The Third Intergroup Rhabdomyosarcoma Study. J Clin Oncol 13 (3): 610-30, 1995. [PUBMED Abstract]
  14. Raney RB, Anderson JR, Barr FG, et al.: Rhabdomyosarcoma and undifferentiated sarcoma in the first two decades of life: a selective review of intergroup rhabdomyosarcoma study group experience and rationale for Intergroup Rhabdomyosarcoma Study V. J Pediatr Hematol Oncol 23 (4): 215-20, 2001. [PUBMED Abstract]
  15. Breneman JC, Lyden E, Pappo AS, et al.: Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma--a report from the Intergroup Rhabdomyosarcoma Study IV. J Clin Oncol 21 (1): 78-84, 2003. [PUBMED Abstract]

Treatment Option Overview for Childhood Rhabdomyosarcoma



Multimodality Therapy

All children with rhabdomyosarcoma require multimodality therapy with systemic chemotherapy, in conjunction with either surgery, radiation therapy (RT), or both modalities to maximize local tumor control.[1-3] Surgical resection is performed before chemotherapy if it will not result in disfigurement, functional compromise, or organ dysfunction. If this is not possible, only an initial biopsy is performed.
Most patients (about 50%) have Group III (gross residual) disease; the remaining patients have Group I (about 15%), Group II (about 20%), and Group IV (about 15%) disease.[4] After initial chemotherapy, Group III patients receive definitive RT for control of the primary tumor. Some patients with initially unresected tumors may undergo delayed primary excision to remove residual tumor before the initiation of RT. This is appropriate only if the delayed excision is deemed feasible with acceptable functional/cosmetic outcome and if a grossly complete resection is anticipated. If a delayed primary excision results in complete resection or microscopic residual disease, a modest reduction in RT could be utilized. RT is given to clinically suspicious lymph nodes (detected by palpation or imaging) unless the suspicious lymph nodes are biopsied and shown to be free of rhabdomyosarcoma. RT is also administered to lymph node basins where a sentinel lymph node biopsy has identified microscopic disease.[5]
The discussion of treatment options for children with rhabdomyosarcoma is divided into the following separate sections:
  • Surgery (local control management).
  • RT (local control management).
  • Chemotherapy.
Rhabdomyosarcoma treatment options used by the Children's Oncology Group (COG) and by groups in Europe (as exemplified by trials from the Soft Tissue Sarcoma Committee of the COG [COG-STS], the Intergroup Rhabdomyosarcoma Study Group [IRSG], and the International Society of Pediatric Oncology Malignant Mesenchymal Tumor [MMT] Group) differ in management and overall treatment philosophy, as noted below:[2]
  • The primary COG-STS objective has been to employ local therapy soon after the initial operation or biopsy (except in patients with metastatic disease), using RT for patients with residual disease. Event-free survival (EFS) is the target endpoint, attempting to avoid relapse and subsequent salvage therapy.[3]
  • In the MMT trials, the main objective has been to reduce the use of local therapies using initial front-line chemotherapy followed by second-line therapy in the presence of poor response. Subsequent surgical resection is preferred over RT, which is used only after incomplete resection, documented regional lymph node involvement, or a poor clinical response to initial chemotherapy. This approach is designed to avoid major surgical procedures and long-term damaging effects from RT.
The MMT Group approach led to an overall survival (OS) rate of 71% in the European MMT89 study, compared with an OS rate of 84% in the IRS-IV study. Similarly, EFS rates at 5 years were 57% in the MMT89 study versus 78% in the IRS-IV study. Differences in outcome were most striking for patients with extremity and head and neck nonparameningeal tumors. Failure-free survival was lower for patients with bladder/prostate primary tumors who did not receive RT as part of their initial treatment, but there was no difference in OS between the two strategies for these patients.[6] The overall impression is that survival for most patient subsets is superior with the use of early local therapy, including RT. In the MMT trials, some patients have been spared aggressive local therapy, which may reduce the potential for morbidities associated with such therapy.[1-3]

Special Considerations for the Treatment of Children With Cancer

Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975.[7] Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the following individuals to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
  • Primary care physician.
  • Pediatric surgeon.
  • Radiation oncologist.
  • Pediatric oncologist and hematologist.
  • Pediatric radiologist.
  • Rehabilitation specialist.
  • Pediatric nurse specialist.
  • Social workers.
  • Psychologist.
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics.[8] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.


References
  1. Donaldson SS, Meza J, Breneman JC, et al.: Results from the IRS-IV randomized trial of hyperfractionated radiotherapy in children with rhabdomyosarcoma--a report from the IRSG. Int J Radiat Oncol Biol Phys 51 (3): 718-28, 2001. [PUBMED Abstract]
  2. Stevens MC, Rey A, Bouvet N, et al.: Treatment of nonmetastatic rhabdomyosarcoma in childhood and adolescence: third study of the International Society of Paediatric Oncology--SIOP Malignant Mesenchymal Tumor 89. J Clin Oncol 23 (12): 2618-28, 2005. [PUBMED Abstract]
  3. Donaldson SS, Anderson JR: Rhabdomyosarcoma: many similarities, a few philosophical differences. J Clin Oncol 23 (12): 2586-7, 2005. [PUBMED Abstract]
  4. Wexler LH, Skapek SX, Helman LJ: Rhabdomyosarcoma. In: Pizzo PA, Poplack DG, eds.: Principles and Practice of Pediatric Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams and Wilkins, 2015, pp 798-826.
  5. Wolden SL, Lyden ER, Arndt CA, et al.: Local Control for Intermediate-Risk Rhabdomyosarcoma: Results From D9803 According to Histology, Group, Site, and Size: A Report From the Children's Oncology Group. Int J Radiat Oncol Biol Phys 93 (5): 1071-6, 2015. [PUBMED Abstract]
  6. Rodeberg DA, Anderson JR, Arndt CA, et al.: Comparison of outcomes based on treatment algorithms for rhabdomyosarcoma of the bladder/prostate: combined results from the Children's Oncology Group, German Cooperative Soft Tissue Sarcoma Study, Italian Cooperative Group, and International Society of Pediatric Oncology Malignant Mesenchymal Tumors Committee. Int J Cancer 128 (5): 1232-9, 2011. [PUBMED Abstract]
  7. Smith MA, Altekruse SF, Adamson PC, et al.: Declining childhood and adolescent cancer mortality. Cancer 120 (16): 2497-506, 2014. [PUBMED Abstract]
  8. Corrigan JJ, Feig SA; American Academy of Pediatrics: Guidelines for pediatric cancer centers. Pediatrics 113 (6): 1833-5, 2004. [PUBMED Abstract]



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