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© 1999 American Society for Clinical Oncology
Soft Tissue Sarcoma: Apples, Oranges, and Passion FruitDana-Farber Cancer Institute and Children's Hospital, Boston, MA EACH YEAR IN THE United States, 850 to 900 children and adolescents less than 20 years of age are diagnosed with soft tissue sarcoma. Approximately 350 of these patients have rhabdomyosarcoma.1 The rest have one of several distinct pathologic entities: synovial sarcoma, malignant peripheral nerve sheath tumor, the Ewing family of tumors (Ewing's sarcoma and peripheral primitive neuroectodermal tumor), and alveolar soft part sarcoma to name just a few. Adult soft tissue sarcomas have a similar diversity of classifications. Traditionally, investigators have separated rhabdomyosarcoma from the other soft tissue sarcomas because of the high response rate of this tumor to chemotherapy. The tumors left behind have thus been termed the nonrhabdomyosarcoma soft tissue sarcomas, a term with enough difficulty in pronunciation that the abbreviation NRSTS has become quite common. The German Cooperative Soft Tissue Sarcoma Group has taken the different tact of lumping rhabdomyosarcoma with three other entities with relatively high response rates to chemotherapy2: the Ewing family of tumors, synovial sarcoma, and undifferentiated sarcoma. As can be seen by their report in this issue,2 the incidence of rhabdomyosarcoma in childhood swamped the other diagnoses; only 23% of the patient entries had one of the three other entities. Their results with rhabdomyosarcoma were split out so that they could compare them with outcomes from other cooperative groups, such as the North American Intergroup Rhabdomyosarcoma Group. Spunt et al3 from St Jude Children's Research Hospital took a more traditional approach and grouped all of the NRSTS patients seen over a 27-year period at their institution to evaluate prognostic factors in this relatively rare group of entities. Their findings were similar to many adult and fewer pediatric studies of NRSTS; for instance, size and high histologic grade predicted for distant recurrence.4,5 Why are the lumpers winning in soft tissue sarcoma? Traditionally, pathologists had difficulty separating these tumors, with poor interobserver consistency. More sophisticated histologic staining began to solve that problem some time ago. More importantly, we now can separate many of the NRSTSs by distinct chromosomal translocations associated with specific tumors. Synovial sarcomas virtually always have a translocation between chromosomes X and 18, fusing either the SSX-1 or SSX-2 gene (on X) with the SYT gene on 18.6-8 The Ewing family of tumors has translocations placing an ETS-like oncogene (most commonly FLI-1 on chromosome 11) with the EWS gene on chromosome 22.9 Alveolar rhabdomyosarcoma (one of the two most common histologic subtypes, along with embryonal) is highly associated with translocations that place parts of either PAX7 (on chromosome 1) or PAX3 (on chromosome 2) next to FKHR on chromosome 13.10 Other tumors (malignant peripheral nerve sheath tumors, liposarcomas, myxoid chondrosarcoma, clear-cell sarcoma, and alveolar soft part sarcoma) also have characteristic translocations.11-15 Admittedly, some NRSTS subtypes have been more difficult to classify by cytogenetics; for instance, investigators were unable to find a characteristic chromosomal change in 48 patients with pleomorphic soft tissue sarcomas.16 If it is easier to tell the tumors apart, why do we still lump? The relative rarity of these entities makes tumor-specific studies impossible, even in large cooperative groups. Every study has grouped many of the NRSTSs into one monolith, frequently only separating them by histologic grade of the tumor. There is no reason to believe that, with rare exception, such as infantile fibrosarcoma, pediatric and adolescent patients have a different natural history than adults with NRSTS. Important clinical and biologic questions will only be answered by further cooperation, necessitating an intergroup process. To that end, as the Journal of Clinical Oncology goes to press, a sarcoma intergroup meeting is planned to occur in conjunction with the American College of Surgeons Oncology Group on November 12, 1999. Included on the agenda are ideas and proposals for new agents for phase II studies, proposals for phase III studies of specific diseaseentities, and correlate biologic studies. The possibility now exists to finally understand the biology and treatment of each of these separate but related diseases. REFERENCES 1. Gurney JG, Young JL Jr, Roffers SD, et al: Soft tissue sarcomas, in Ries LAG, Smith MA, Gurney JG, et al (eds): Cancer Incidence and Survival Among Children and Adolescents: United States SEER Program 1975-1995, National Cancer Institute, SEER Program (NIH Pub No. I 99-4649). Bethesda, MD, National Cancer Institute, 1999, pp 111-124
2.
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 Oncol17:3706-3719, 1999
3.
Spunt SL, Poquette CA, Hurt YS, et al: Prognostic factors for children and adolescents with surgically resected nonrhabdomyosarcoma soft tissue sarcoma: An analysis of 121 patients treated at St Jude Children's Research Hospital. J Clin Oncol17:3697-3705, 1999
4.
Pisters PW, Leung DH, Woodruff J, et al: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol14:1679-1689, 1996 5. Marcus KC, Grier HE, Shamberger RC, et al: Childhood soft tissue sarcoma: A 20-year experience. J Pediatr131:603-607, 1997[Medline] 6. Sreekantaiah C, Ladanyi M, Rodriguez E, et al: Chromosomal aberrations in soft tissue tumors: Relevance to diagnosis, classification, and molecular mechanisms. Am J Pathol144:1121-1134, 1994[Abstract]
7.
de Leeuw B, Balemans M, Olde Weghuis D, et al: Identification of two alternative fusion genes, SYT-SSX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial sarcomas. Hum Mol Genet4:1097-1099, 1995
8.
Kawal A, Woodruff J, Healey JH, et al: SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med338:153-160, 1998
9.
Delattre O, Zucman J, Melot T, et al: The Ewing family of tumors: A subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med331:294-299, 1994 10. Barr FG: Molecular genetics and pathogenesis of rhabdomyosarcoma. J Pediatr Hematol Oncol19:483-491, 1997[Medline]
11.
Lothe RA, Karhu R, Mandahl N, et al: Gain of 17q24-qter detected by comparative genomic hybridization in malignant tumors from patients with von Recklinghausen's neurofibromatosis. Cancer Res56:4778-4781, 1996 12. Jhanwar SC, Chen Q, Li FPet al: Cytogenetic analysis of soft tissue sarcomas: Recurrent chromosome abnormalities in malignant peripheral nerve sheath tumors (MPNST). Cancer Genet Cytogenet78:138-144, 1994[Medline] 13. Crozat A, Aman P, Mandahl N, et al: Fusion of CHOP to a novel RNA-binding protein in human myxoid liposarcoma. Nature363:640-644, 1993[Medline] 14. Sciot R, Dal Cin P, De Vos R, et al: Alveolar soft-part sarcoma: Evidence for its myogenic origin and for the involvement of 17q25. Histopathology23:439-444, 1993[Medline] 15. Zucman J, Delattre O, Desmaze C, et al: EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet4:341-345, 1993[Medline] 16. Mertens F, Fletcher CDM, Dal Cin P, et al: Cytogenetic analysis of 46 pleomorphic soft tissue sarcomas and correlation with morphologic and clinical features: A report of the CHAMP study group. Genes Chromosom Cancer22:16-25, 1998[Medline]
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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