Nonrhabdomyosarcoma Soft Tissue Sarcoma in Children: Developing New Treatments Based on a Better Understanding of Disease Biology

  • Stephen X. Skapek


Nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) are a large and very ­heterogeneous group of cancers in children. Although approximately 550 NRSTS diagnoses in the US each year represent only approximately 4% of cases of childhood cancer, NRSTS comprise nearly 60% of all soft tissue sarcomas in this age group [reviewed in Spunt et al. (2006)]. The incidence is bimodally distributed, with relatively high incidence in the first year of life and a second peak during later childhood and adolescence. While NRSTS is typically a sporadic disease, some types of NRSTS are associated with cancer susceptibility syndromes, such as the Li–Fraumeni familial cancer syndrome (associated with heritable p53 mutations) and neurofibromatosis type I (associated with heritable mutations in NF1 tumor suppressor genes) (Li et al. 1988; Malkin et al. 1990; Sorensen et al. 1986); with certain environmental exposures (therapeutic ionizing radiation and HHV8, HIV, or EBV virus infection); and with certain chemical carcinogens (Spunt et al. 2006).


Epidermal Growth Factor Receptor Anaplastic Lymphoma Kinase Synovial Sarcoma Malignant Peripheral Nerve Sheath Tumor Malignant Fibrous Histiocytoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abbott, J. J., Oliveira, A. M., and Nascimento, A. G. 2006. The prognostic significance of fibrosarcomatous transformation in dermatofibrosarcoma protuberans. Am. J. Surg. Pathol. 30:436–443.PubMedCrossRefGoogle Scholar
  2. Allander, S. V., Illei, P. B., Chen, Y., Antonescu, C. R., Bittner, M., Ladanyi, M., and Meltzer, P. S. 2002. Expression profiling of synovial sarcoma by cDNA microarrays: association of ERBB2, IGFBP2, and ELF3 with epithelial differentiation. Am. J. Pathol. 161:1587–1595.PubMedCrossRefGoogle Scholar
  3. Applebaum, H., Kieran, M. W., Cripe, T. P., Coffin, C. M., Collins, M. H., Kaipainen, A., Laforme, A., and Shamberger, R. C. 2005. The rationale for nonsteroidal anti-inflammatory drug therapy for inflammatory myofibroblastic tumors: a Children’s Oncology Group study. J. Pediatr. Surg. 40:999–1003.PubMedCrossRefGoogle Scholar
  4. Baird, K., Davis, S., Antonescu, C. R., Harper, U. L., Walker, R. L., Chen, Y., Glatfelter, A. A., Duray, P. H., and Meltzer, P. S. 2005. Gene expression profiling of human sarcomas: insights into sarcoma biology. Cancer Res. 65:9226–9235.PubMedCrossRefGoogle Scholar
  5. Bakkenist, C. J. and Kastan, M. B. 2004. Initiating cellular stress responses. Cell. 118:9–17.PubMedCrossRefGoogle Scholar
  6. Bauer, S., Duensing, A., Demetri, G. D., and Fletcher, J. A. 2007. KIT oncogenic signaling mechanisms in imatinib-resistant gastrointestinal stromal tumor: PI3-kinase/AKT is a crucial survival pathway. Oncogene. 26:7560–7568.PubMedCrossRefGoogle Scholar
  7. Bierie, B. and Moses, H. L. 2006. TGFβ: the molecular Jekyll and Hyde of cancer. Nat. Rev. Cancer. 6:506–520.PubMedCrossRefGoogle Scholar
  8. Birdsall, S., Osin, P., Lu, Y. -J., Fisher, C., and Shipley, J. 1999. Synovial sarcoma specific translocation associated with both epithelial and spindle components. Int. J. Cancer. 82:605–608.PubMedCrossRefGoogle Scholar
  9. Blay, J. Y., Le, C. A., Ray-Coquard, I., Bui, B., Duffaud, F., Delbaldo, C., Adenis, A., Viens, P., Rios, M., Bompas, E., Cupissol, D., Guillemet, C., Kerbrat, P., Fayette, J., Chabaud, S., Berthaud, P., and Perol, D. 2007. Prospective multicentric randomized phase III study of imatinib in patients with advanced gastrointestinal stromal tumors comparing interruption versus continuation of treatment beyond 1 year: the French Sarcoma Group. J. Clin. Oncol. 25:1107–1113.PubMedCrossRefGoogle Scholar
  10. Bonvini, P., Dalla Rosa, H., Vignes, H., and Rosolen, A. 2004. Ubiquitination and proteasomal degradation of nucleophosmin-anaplastic lymphoma kinase induced by 17-allylamino-demethoxygeldanamycin: role of the co-chaperone carboxyl heat shock protein 70-interacting protein. Cancer Res. 64:3256–3264.PubMedCrossRefGoogle Scholar
  11. Cichowski, K. and Jacks, T. 2001. NF1 tumor suppressor gene function: narrowing the GAP. Cell. 104:593–604.PubMedCrossRefGoogle Scholar
  12. Cichowski, K., Shih, T. S., Schmitt, E., Santiago, S., Reilly, K., McLaughlin, M. E., Bronson, R. T., and Jacks, T. 1999. Mouse models of tumor development in neurofibromatosis type 1. Science. 286:2172–2176.PubMedCrossRefGoogle Scholar
  13. Clark, J., Rocques, P. J., Crew, A. J., Gill, S., Shipley, J., Chan, A. M. L., Gusterson, B. A., and Cooper, C. S. 1994. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nat. Genet. 7:502–508.PubMedCrossRefGoogle Scholar
  14. Cypriano, M. S., Jenkins, J. J., Pappo, A. S., Rao, B. N., and Daw, N. C. 2004. Pediatric gastrointestinal stromal tumors and leiomyosarcoma. Cancer. 101:39–50.PubMedCrossRefGoogle Scholar
  15. Daw, N. C., Billups, C. A., Pappo, A. S., Jenkins, J. J., Mahmoud, H. H., Krasin, M. J., and Rao, B. N. 2003. Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children’s Research Hospital experience. Cancer. 97:2839–2847.PubMedCrossRefGoogle Scholar
  16. DeClue, J. E., Heffelfinger, S., Benvenuto, G., Ling, B., Li, S., Rui, W., Vass, W. C., Viskochil, D., and Ratner, N. 2000. Epidermal growth factor receptor expression in neurofibromatosis type 1-related tumors and NF1 animal models. J. Clin. Invest. 105:1233–1241.PubMedCrossRefGoogle Scholar
  17. Dehner, L. P. 2004. Inflammatory myofibroblastic tumor: the continued definition of one type of so-called inflammatory pseudotumor. Am. J. Surg. Pathol. 28:1652–1654.PubMedCrossRefGoogle Scholar
  18. Dilworth, J. T., Kraniak, J. M., Wojtkowiak, J. W., Gibbs, R. A., Borch, R. F., Tainsky, M. A., Reiners, Jr. J. J., and Mattingly, R. R. 2006. Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Biochem. Pharmacol. 72:1485–1492.PubMedCrossRefGoogle Scholar
  19. Dishop, M. K., Warner, B. W., Dehner, L. P., Kriss, V. M., Greenwood, M. F., Geil, J. D., and Moscow, J. A. 2003. Successful treatment of inflammatory myofibroblastic tumor with malignant transformation by surgical resection and chemotherapy. J. Pediatr. Hematol. Oncol. 25:153–158.PubMedCrossRefGoogle Scholar
  20. Donehower, L. A., Harvey, M., Slagle, B. L., McArthur, M. J., Montgomery, C. A., Jr., Butel, J. S., and Bradley, A. 1992. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 356:215–221.PubMedCrossRefGoogle Scholar
  21. Druker, B. J., Tamura, S., Buchdunger, E., Ohno, S., Segal, G. M., Fanning, S., Zimmermann, J., and Lydon, N. B. 1996. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat. Med. 2:561–566.PubMedCrossRefGoogle Scholar
  22. Duyster, J., Bai, R. Y., and Morris, S. W. 2001. Translocations involving anaplastic lymphoma kinase (ALK). Oncogene. 20:5623–5637.PubMedCrossRefGoogle Scholar
  23. Eguchi, M., Eguchi-Ishimae, M., Tojo, A., Morishita, K., Suzuki, K., Sato, Y., Kudoh, S., Tanaka, K., Setoyama, M., Nagamura, F., Asano, S., and Kamada, N. 1999. Fusion of ETV6 to neurotrophin-3 receptor TRKC in acute myeloid leukemia with t(12;15)(p13;q25). Blood. 93:1355–1363.PubMedGoogle Scholar
  24. Ferrari, A., Casanova, M., Collini, P., Meazza, C., Luksch, R., Massimino, M., Cefalo, G., Terenziani, M., Spreafico, F., Catania, S., Gandola, L., Gronchi, A., Mariani, L., and Fossati-Bellani, F. 2005. Adult-type soft tissue sarcomas in pediatric-age patients: experience at the Istituto Nazionale Tumori in Milan. J. Clin. Oncol. 23:4021–4030.PubMedCrossRefGoogle Scholar
  25. Fletcher, C. D. 2006. The evolving classification of soft tissue tumours: an update based on the new WHO classification. Histopathology. 48:3–12.PubMedCrossRefGoogle Scholar
  26. Goldblum, J. R., Reith, J. D., and Weiss, S. W. 2000. Sarcomas arising in dermatofibrosarcoma protuberans: a reappraisal of biologic behavior in eighteen cases treated by wide local excision with extended clinical follow up. Am. J. Surg. Pathol. 24:1125–1130.PubMedCrossRefGoogle Scholar
  27. Granovsky, M. O., Mueller, B. U., Nicholson, H. S., Rosenberg, P. S., and Rabkin, C. S. 1998. Cancer in human immunodeficiency virus-infected children: a case series from the Children’s Cancer Group and the National Cancer Institute. J. Clin. Oncol. 16:1729–1735.PubMedGoogle Scholar
  28. Guillou, L., Benhattar, J., Bonichon, F., Gallagher, G., Terrier, P., Stauffer, E., Somerhausen, N. S., Michels, J. J., Jundt, G., Vince, D. R., Taylor, S., Genevay, M., Collin, F., Trassard, M., and Coindre, J. M. 2004. Histologic grade, but not SYT-SSX fusion type, is an important prognostic factor in patients with synovial sarcoma: a multicenter, retrospective analysis. J. Clin. Oncol. 22:4040–4050.PubMedCrossRefGoogle Scholar
  29. Haldar, M., Hancock, J. D., Coffin, C. M., Lessnick, S. L., and Capecchi, M. R. 2007. A conditional mouse model of synovial sarcoma: insights into a myogenic origin. Cancer Cell. 11:375–388.PubMedCrossRefGoogle Scholar
  30. Hanahan, D. and Weinberg R. A. 2000. The hallmarks of cancer. Cell. 100:57–70.PubMedCrossRefGoogle Scholar
  31. Helman, L. J. and Meltzer, P. 2003. Mechanisms of sarcoma development. Nat. Rev. Cancer. 3:685–694.PubMedCrossRefGoogle Scholar
  32. Hernando, E., Charytonowicz, E., Dudas, M. E., Menendez, S., Matushansky, I., Mills, J., Socci, N. D., Behrendt, N., Ma, L., Maki, R. G., Pandolfi, P. P., and Cordon-Cardo, C. 2007. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat. Med. 13:748–753.PubMedCrossRefGoogle Scholar
  33. Hirota, S., Isozaki, K., Moriyama, Y., Hashimoto, K., Nishida, T., Ishiguro, S., Kawano, K., Hanada, M., Kurata, A., Takeda, M., Muhammad, T. G., Matsuzawa, Y., Kanakura, Y., Shinomura, Y., and Kitamura, Y. 1998. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science. 279:577–580.PubMedCrossRefGoogle Scholar
  34. Irsan, I., Akisue, T., Hara, H., Fujimoto, T., Imabori, M., Doita, M., Kuroda, R., Fujioka, H., Kawamoto, T., Yamamoto, T., and Kurosaka, M. 2007. Imatinib mesylate inhibits tumorigenicity of malignant fibrous histiocytoma cells in vivo. Anticancer Res. 27:423–429.PubMedGoogle Scholar
  35. Ishida, M., Miyamoto, M., Naitoh, S., Tatsuda, D., Hasegawa, T., Nemoto, T., Yokozeki, H., Nishioka, K., Matsukage, A., Ohki, M., and Ohta, T. 2007. The SYT-SSX fusion protein down-regulates the cell proliferation regulator COM1 in t(x;18) synovial sarcoma. Mol.Cell Biol. 27:1348–1355.PubMedCrossRefGoogle Scholar
  36. Ito, T., Ouchida, M., Morimoto, Y., Yoshida, A., Jitsumori, Y., Ozaki, T., Sonobe, H., Inoue, H., and Shimizu, K. 2005. Significant growth suppression of synovial sarcomas by the histone deacetylase inhibitor FK228 in vitro and in vivo. Cancer Lett. 224:311–319.PubMedCrossRefGoogle Scholar
  37. Jacks, T., Remington, L., Williams, B. O., Schmitt, E. M., Halachmi, S., Bronson, R. T., and Weinberg, R. A. 1994a. Tumor spectrum analysis in p53-mutant mice. Curr. Biol. 4:1–7.PubMedCrossRefGoogle Scholar
  38. Jacks, T., Shih, T. S., Schmitt, E. M., Bronson, R. T., Bernards, A., and Weinberg, R. A. 1994b. Tumour predisposition in mice heterozygous for a targeted mutation in Nf1. Nat. Genet. 7:353–361.PubMedCrossRefGoogle Scholar
  39. Jin, W., Kim, B.-C., Tognon, C., Lee, H.-J., Patel, S., Lannon, C. L., Maris, J. M., Triche, T. J., Sorensen, P. H. B., and Kim, S.-J. 2005. The ETV6-NTRK3 chimeric tyrosine kinase suppresses TGF-b-signaling by inactivating the TGF-b type II receptor. Proc. Natl. Acad. Sci. 102:16239–16244.PubMedCrossRefGoogle Scholar
  40. Jin, W., Yun, C., Hobbie, A., Martin, M. J., Sorensen, P. H., and Kim, S. J. 2007. Cellular transformation and activation of the phosphoinositide-3-kinase-Akt cascade by the ETV6-NTRK3 chimeric tyrosine kinase requires c-Src. Cancer Res. 67:3192–3200.PubMedCrossRefGoogle Scholar
  41. Joensuu, H. 2007. Second line therapies for the treatment of gastrointestinal stromal tumor. Curr. Opin. Oncol. 19:353–358.PubMedCrossRefGoogle Scholar
  42. Joensuu, H., Roberts, P. J., Sarlomo-Rikala, M., Andersson, L. C., Tervahartiala, P., Tuveson, D., Silberman, S., Capdeville, R., Dimitrijevic, S., Druker, B., and Demetri, G. D. 2001. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N. Engl. J. Med. 344:1052–1056.PubMedCrossRefGoogle Scholar
  43. Johannessen, C. M., Reczek, E. E., James, M. F., Brems, H., Legius, E., and Cichowski, K. 2005. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc. Natl. Acad. Sci. U.S.A. 102:8573–8578.PubMedCrossRefGoogle Scholar
  44. Joyner, D. E., Albritton, K. H., Bastar, J. D., and Randall, R. L. 2006. G3139 antisense oligonucleotide directed against antiapoptotic Bcl-2 enhances doxorubicin cytotoxicity in the FU-SY-1 synovial sarcoma cell line. J. Orthop. Res. 24:474–480.PubMedCrossRefGoogle Scholar
  45. Kamijo, T., Bodner, S., van de Kamp, E., Randle, D. H., and Sherr, C. J. 1999. Tumor spectrum in ARF-deficient mice. Cancer Res. 59:2217–2222.PubMedGoogle Scholar
  46. Kawai, A., Woodruff, J., Healey, J. H., Brennan, M. F., Antonescu, C. R., and Ladany, M. 1998. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N. Engl. J. Med. 338:153–160.PubMedCrossRefGoogle Scholar
  47. Knezevich, S. R., McFadden, D. E., Tao, W., Lim, J. F., and Sorensen, P. H. B. 1998. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat. Genet. 18:184–187.PubMedCrossRefGoogle Scholar
  48. Ladanyi, M. 2001. Fusions of the SYT and SSX genes in synovial sarcoma. Oncogene. 20:5755–5762.PubMedCrossRefGoogle Scholar
  49. Lee, Y. F., John, M., Edwards, S., Clark, J., Flohr, P., Maillard, K., Edema, M., Baker, L., Mangham, D. C., Grimer, R., Wooster, R., Thomas, J. M., Fisher, C., Judson, I., and Cooper, C. S. 2003. Molecular classification of synovial sarcomas, leiomyosarcomas and malignant fibrous histiocytomas by gene expression profiling. Br. J. Cancer. 88:510–515.PubMedCrossRefGoogle Scholar
  50. Li, F. P., Fraumeni, J. F., Jr., Mulvihill, J. J., Blattner, W. A., Dreyfus, M. G., Tucker, M. A., and Miller, R. W. 1988. A cancer family syndrome in 24 kindreds. Cancer Res. 48:5358–5362.PubMedGoogle Scholar
  51. Li, H., Velasco-Miguel, S., Vass, W. C., Parada, L. F., and DeClue, J. E. 2002. Epidermal growth factor receptor signaling pathways are associated with tumorigenesis in the Nf1:p53 mouse tumor model. Cancer Res. 62:4507–4513.PubMedGoogle Scholar
  52. Ling, B. C., Wu, J., Miller, S. J., Monk, K. R., Shamekh, R., Rizvi, T. A., DeCourten-Myers, G., Vogel, K. S., DeClue, J. E., and Ratner, N. 2005. Role for the epidermal growth factor receptor in neurofibromatosis-related peripheral nerve tumorigenesis. Cancer Cell. 7:65–75.PubMedCrossRefGoogle Scholar
  53. Liu, Y., Tseng, M., Perdreau, S. A., Rossi, F., Antonescu, C., Besmer, P., Fletcher, J. A., Duensing, S., and Duensing, A. 2007. Histone H2AX is a mediator of gastrointestinal stromal tumor cell apoptosis following treatment with imatinib mesylate. Cancer Res. 67:2685–2692.PubMedCrossRefGoogle Scholar
  54. Lopez-Guerrero, J. A., Navarro, S., Noguera, R., Carda, C., Farinas, S. C., Pellin, A., and Llombart-Bosch, A. 2005. Mutational analysis of the c-KIT AND PDGFRalpha in a series of molecularly well-characterized synovial sarcomas. Diagn. Mol. Pathol. 14:134–139.PubMedCrossRefGoogle Scholar
  55. Mahller, Y. Y., Vaikunth, S. S., Currier, M. A., Miller, S. J., Ripberger, M. C., Hsu, Y. -H., Mehrian-Shai, R., Collins, M. H., Crombleholme, T. M., Ratner, N., and Cripe, T. P. 2007. Oncolytic HSV and erlotinib inhibit tumor growth and angiogenesis in a novel malignant peripheral nerve sheath tumor xenograft model. Mol. Ther. 15:279–286.PubMedCrossRefGoogle Scholar
  56. Maire, G., Fraitag, S., Galmiche, L., Keslair, F., Ebran, N., Terrier-Lacombe, M. J., De, P. Y., and Pedeutour, F. 2007. A clinical, histologic, and molecular study of 9 cases of congenital dermatofibrosarcoma protuberans. Arch. Dermatol. 143:203–210.PubMedCrossRefGoogle Scholar
  57. Malkin, D., Li, F. P., Strong, L. C., Fraumeni, J. F., Jr., Nelson, C. E., Kim, D. H., Kassel, J., Gryka, M. A., Bischoff, F. A., Tainsky, M. A., and Friend, S. H. 1990. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 250:1233–1238.PubMedCrossRefGoogle Scholar
  58. Martin, M. J., Melnyk, N., Pollard, M., Bowden, M., Leong, H., Podor, T. J., Gleave, M., and Sorensen, P. H. 2006. The insulin-like growth factor I receptor is required for Akt activation and suppression of anoikis in cells transformed by the ETV6-NTRK3 chimeric tyrosine kinase. Mol. Cell Biol. 26:1754–1769.PubMedCrossRefGoogle Scholar
  59. Marzec, M., Kasprzycka, M., Ptasznik, A., Wlodarski, P., Zhang, Q., Odum, N., and Wasik, M. A. 2005. Inhibition of ALK enzymatic activity in T-cell lymphoma cells induces apoptosis and suppresses proliferation and STAT3 phosphorylation independently of Jak3. Lab. Invest. 85:1544–1554.PubMedGoogle Scholar
  60. Maser, R. S., Choudhury, B., Campbell, P. J., Feng, B., Wong, K. K., Protopopov, A., O’Neil, J., Gutierrez, A., Ivanova, E., Perna, I., Lin, E., Mani, V., Jiang, S., McNamara, K., Zaghlul, S., Edkins, S., Stevens, C., Brennan, C., Martin, E. S., Wiedemeyer, R., Kabbarah, O., Nogueira, C., Histen, G., Aster, J., Mansour, M., Duke, V., Foroni, L., Fielding, A. K., Goldstone, A. H., Rowe, J. M., Wang, Y. A., Look, A. T., Stratton, M. R., Chin, L., Futreal, P. A., and DePinho, R. A. 2007. Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers. Nature. 447:966–971.PubMedCrossRefGoogle Scholar
  61. Mattingly, R. R., Kraniak, J. M., Dilworth, J. T., Mathieu, P., Bealmear, B., Nowak, J. E., Benjamins, J. A., Tainsky, M. A., and Reiners, J. J., Jr. 2006. The mitogen-activated protein kinase/extracellular signal-regulated kinase kinase inhibitor PD184352 (CI-1040) selectively induces apoptosis in malignant Schwannoma cell lines. J. Pharmacol. Exp. Ther. 316:456–465.PubMedCrossRefGoogle Scholar
  62. McArthur, G. A. 2006. Dermatofibrosarcoma protuberans: a surgical disease with a molecular savior. Curr. Opin. Oncol. 18:341–346.PubMedCrossRefGoogle Scholar
  63. McArthur, G. A., Demetri, G. D., van Oosterom, A., Heinrich, M. C., Debiec-Rychter, M., Corless, C. L., Nikolova, Z., Dimitrijevic, S., and Fletcher, J. A. 2005. Molecular and clinical analysis of locally advanced dermatofibrosarcoma protuberans treated with imatinib: Imatinib Target Exploration Consortium study B2225. J. Clin. Oncol. 23:866–873.PubMedCrossRefGoogle Scholar
  64. Morris, S. W., Kirstein, M. N., Valentine, M. B., Dittmer, K. G., Shapiro, D. N., Saltman, D. L., and Look, A. T. 1994. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s lymphoma. Science. 263:1281–1284.PubMedCrossRefGoogle Scholar
  65. Nagayama, S., Katagiri, T., Tsunoda, T., Hosaka, T., Nakashima, Y., Araki, N., Kusuzaki, K., Nakayama, T., Tsuboyama, T., Nakamura, T., Imamura, M., Nakamura, Y., and Toguchida, J. 2002. Genome-wide analysis of gene expression in synovial sarcomas using a cDNA microarray. Cancer Res. 62:5859–5866.PubMedGoogle Scholar
  66. Nakayama, R., Nemoto, T., Takahashi, H., Ohta, T., Kawai, A., Seki, K., Yoshida, T., Toyama, Y., Ichikawa, H., and Hasegawa, T. 2007. Gene expression analysis of soft tissue sarcomas: characterization and reclassification of malignant fibrous histiocytoma. Mod. Pathol. 20:749–759.PubMedCrossRefGoogle Scholar
  67. Nielsen, T. O., Hsu, F. D., O’Connell, J. X., Gilks, C. B., Sorensen, P. H., Linn, S., West, R. B., Liu, C. L., Botstein, D., Brown, P. O., and Van de, R. M. 2003. Tissue microarray validation of epidermal growth factor receptor and SALL2 in synovial sarcoma with comparison to tumors of similar histology. Am. J. Pathol. 163:1449–1456.PubMedCrossRefGoogle Scholar
  68. Nilsson, B., Sjolund, K., Meis-Kindblom, J. M., Bumming, P., Nilsson, O., Andersson, J., and Ahlman, H. 2007. Adjuvant imatinib treatmetn improves recurrence-free survival in patients with high-risk gastrointestinal stromal tumors (GIST). Br. J. Cancer. 96:1656–1658.PubMedCrossRefGoogle Scholar
  69. Nilsson, G., Skytting, B., Xie, Y., Brodin, B., Perfekt, R., Mandahl, N., Lundeberg, J., Uhlen, M., and Larsson, O. 1999. The SYT-SSX1 variant of synovial sarcoma is associated with a high rate of tumor cell proliferation and poor clinical outcome. Cancer Res. 59:3180–3184.PubMedGoogle Scholar
  70. Nuciforo, P. G., Pellegrini, C., Fasani, R., Maggioni, M., Coggi, G., Parafioriti, A., and Bosari, S. 2003. Molecular and immunohistochemical analysis of HER2/neu oncogene in synovial sarcoma. Hum. Pathol. 34:639–645.PubMedCrossRefGoogle Scholar
  71. Pappo, A. S., Rao, B. N., Jenkins, J. J., Merchant, T., Poquette, C. A., Cain, A., and Pratt, C. B. 1999. Metastatic nonrhabdomyosarcomatous soft-tissue sarcomas in children and adolescents: the St. Jude Children’s Research Hospital experience. Med. Pediatr. Oncol. 33:76–82.PubMedCrossRefGoogle Scholar
  72. Parham, D. M., Webber, B. L., Jenkins, J. J., III, Cantor, A. B., and Maurer, H. M. 1995. Nonrhabdomyosarcomatous soft tissue sarcomas of childhood: formulation of a simplified system for grading. Mod. Pathol. 8:705–710.PubMedGoogle Scholar
  73. Prakash, S., Sarran, L., Socci, N., DeMatteo, R. P., Eisenstat, J., Greco, A. M., Maki, R. G., Wexler, L. H., LaQuaglia, M. P., Besmer, P., and Antonescu, C. R. 2005. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic, molecular, and genomic study of 15 cases and review of the literature. J. Pediatr. Hematol. Oncol. 27:179–187.PubMedCrossRefGoogle Scholar
  74. Pratt, C. B., Maurer, H. M., Gieser, P., Salzberg, A., Rao, B. N., Parham, D., Thomas, P. R. M., Marcus, R. B., Cantor, A., Pick, T., Green, D., Neff, J., and Jenkins, J. J. 1998. Treatment of unresectable or metastatic pediatric soft tissue sarcomas with surgery, irradiation, and chemotherapy: a Pediatric Oncology Group study. Med. Pediatr. Oncol. 30:201–209.PubMedCrossRefGoogle Scholar
  75. Pratt, C. B., Pappo, A. S., Gieser, P., Jenkins, J. J., Salzbergdagger, A., Neff, J., Rao, B., Green, D., Thomas, P., Marcus, R., Parham, D., and Maurer, H. 1999. Role of adjuvant chemotherapy in the treatment of surgically resected pediatric nonrhabdomyosarcomatous soft tissue sarcomas: a Pediatric Oncology Group Study. J. Clin. Oncol. 17:1219.PubMedGoogle Scholar
  76. Pretto, D., Barco, R., Rivera, J., Neel, N., Gustavson, M. D., and Eid, J. E. 2006. The synovial sarcoma translocation protein SYT-SSX2 recruits beta-catenin to the nucleus and associates with it in an active complex. Oncogene. 25:3661–3669.PubMedCrossRefGoogle Scholar
  77. Price, V. W., Fletcher, J. A., Zielenska, M., Cole, W., Viero, S., Manson, D. E., Stuart, M., and Pappo, A. S. 2005. Imatinib mesylate: an attractive alternative in young children with large, surgically challenging dermatofibrosarcoma protuberans. Pediatr. Blood Cancer. 44:511–515.PubMedCrossRefGoogle Scholar
  78. Rubin, B. P., Chen, C. J., Morgan, T. W., Xiao, S., Grier, H. E., Kozakewich, H. P., Perez-Atayde, A. R., and Fletcher, J. A. 1998. Congenital mesoblastic nephroma t(12;15) is associated with ETV6-NTRK3 gene fusion: cytogenetic and molecular relationship to congenital (infantile) fibrosarcoma. Am. J. Pathol. 153:1451–1458.PubMedCrossRefGoogle Scholar
  79. Rubin, B. P., Heinrich, M. C., and Corless, C. L. 2007. Gastrointestinal stromal tumour. Lancet. 369:1731–1741.PubMedCrossRefGoogle Scholar
  80. Rubin, B. P., Schuetze, S. M., Eary, J. F., Norwood, T. H., Mirza, S., Conrad, E. U., and Bruckner, J. D. 2002. Molecular targeting of platelet-derived growth factor B by imatinib mesylate in a patient with metastatic dermatofibrosarcoma protuberans. J. Clin. Oncol. 20:3586–3591.PubMedCrossRefGoogle Scholar
  81. Saito, T., Nagai, M., and Ladanyi, M. 2006. SYT-SSX1 and SYT-SSX2 interfere with repression of E-cadherin by snail and slug: a potential mechanism for aberrant mesenchymal to epithelial transition in human synovial sarcoma. Cancer Res. 66:6919–6927.PubMedCrossRefGoogle Scholar
  82. Sandberg, A. A. 2005. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: leiomyosarcoma. Cancer Genet. Cytogenet. 161:1–19.PubMedCrossRefGoogle Scholar
  83. Segal, N. H., Pavlidis, P., Antonescu, C. R., Maki, R. G., Noble, W. S., DeSantis, D., Woodruff, J. M., Lewis, J. J., Brennan, M. F., Houghton, A. N., and Cordon-Cardo, C. 2003. Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am. J. Pathol. 163:691–700.PubMedCrossRefGoogle Scholar
  84. Sharpless, N. E., Ferguson, D. O., O’Hagan, R. C. O., Castrillon, D. H., Lee, C., Farazi, P. A., Alson, S., Fleming, J., Morton, C. C., Frank, K., Chin, L., Alt, F. W., and DePinho, R. A. 2001. Impaired nonhomologous end-joining provokes soft tissue sarcomas harboring chromosomal translocations, amplifications, and deletions. Mol. Cell. 8:1187–1196.PubMedCrossRefGoogle Scholar
  85. Sjoblom, T., Shimizu, A., O’Brien, K. P., Pietras, K., Dal, C. P., Buchdunger, E., Dumanski, J. P., Ostman, A., and Heldin, C. H. 2001. Growth inhibition of dermatofibrosarcoma protuberans tumors by the platelet-derived growth factor receptor antagonist STI571 through induction of apoptosis. Cancer Res. 61:5778–5783.PubMedGoogle Scholar
  86. Skapek, S. X. and Chui, C. H. 2000. Cytogenetics and the biological basis of sarcomas. Curr. Opin. Oncol. 12:315–322.PubMedCrossRefGoogle Scholar
  87. Smithey, B. E., Pappo, A. S., and Hill, D. A. 2002. C-kit expression in pediatric solid tumors: a comparative immunohistochemical study. Am. J. Surg. Pathol. 26:486–492.PubMedCrossRefGoogle Scholar
  88. Sommer, G., Agosti, V., Ehlers, I., Rossi, F., Corbacioglu, S., Farkas, J., Moore, M., Manova, K., Antonescu, C. R., and Besmer, P. 2003. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc. Natl. Acad. Sci. U.S.A. 100:6706–6711.PubMedCrossRefGoogle Scholar
  89. Sorensen, S. A., Mulvihill, J. J., and Nielsen, A. 1986. Long-term follow-up of von Recklinghausen neurofibromatosis: survival and malignant neoplasms. N. Engl. J. Med. 314:1010–1015.PubMedCrossRefGoogle Scholar
  90. Spunt, S. L., Hill, D. A., Motosue, A. M., Billups, C. A., Cain, A. M., Rao, B. N., Pratt, C. B., Merchant, T. E., and Pappo, A. S. 2002. Clinical features and outcome of initially unresected nonmetastatic pediatric nonrhabdomyosarcoma soft tissue sarcoma. J. Clin. Oncol. 20:3225–3235.PubMedCrossRefGoogle Scholar
  91. Spunt, S. L., Poquette, C. A., Hurt, Y. S., Cain, A. M., Rao, B. N., Merchant, T. E., Jenkins, J. J., Santana, V. M., Pratt, C. B., and Pappo, A. S. 1999. 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. Oncol. 17:3697–3705.PubMedGoogle Scholar
  92. Spunt, S., Wolden, S., Schofield, D., and Skapek, S. 2006. Non-Rhabdomyosarcoma Soft Tissue Sarcomas. In Pediatric Bone and Soft Tissue Sarcomas, pp. 133–162. New York/Berlin/Heidelberg: Springer.CrossRefGoogle Scholar
  93. Storlazzi, C. T., Mertens, F., Mandahl, N., Gisselsson, D., Isaksson, M., Gustafson, P., Domanski, H. A., and Panagopoulos, I. 2003. A novel fusion gene, SS18L1/SSX1, in synovial sarcoma. Genes Chromosomes Cancer. 37:195–200.PubMedCrossRefGoogle Scholar
  94. Strizzi, L., Bianco, C., Hirota, M., Watanabe, K., Mancino, M., Hamada, S., Raafat, A., Lawson, S., Ebert, A. D., D’Antonio, A., Losito, S., Normanno, N., and Salomon, D. S. 2007. Development of leiomyosarcoma of the uterus in MMTV-CR-1 transgenic mice. J. Pathol. 211:36–44.PubMedCrossRefGoogle Scholar
  95. Subramaniam, M. M., Noguera, R., Piqueras, M., Navarro, S., Lopez-Guerrero, J. A., and Llombart-Bosch, A. 2006. p16INK4A (CDKN2A) gene deletion is a frequent genetic event in synovial sarcomas. Am. J. Clin. Pathol. 126:866–874.PubMedCrossRefGoogle Scholar
  96. Sun, Y., Gao, D., Liu, Y., Huang, J., Lessnick, S., and Tanaka, S. 2006. IGF2 is critical for tumorigenesis by synovial sarcoma oncoprotein SYT-SSX1. Oncogene. 25:1042–1052.PubMedCrossRefGoogle Scholar
  97. Tamborini, E., Bonadiman, L., Greco, A., Gronchi, A., Riva, C., Bertulli, R., Casali, P. G., Pierotti, M. A., and Pilotti, S. 2004. Expression of ligand-activated KIT and platelet-derived growth factor receptor beta tyrosine kinase receptors in synovial sarcoma. Clin. Cancer Res. 10:938–943.PubMedCrossRefGoogle Scholar
  98. Tognon, C., Garnett, M., Kenward, E., Kay, R., Morrison, K., and Sorensen, P. H. 2001. The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation. Cancer Res. 61:8909–8916.PubMedGoogle Scholar
  99. Tognon, C., Knezevich, S. R., Huntsman, D., Roskelley, C. D., Melnyk, N., Mathers, J. A., Becker, L., Carneiro, F., MacPherson, N., Horsman, D., Poremba, C., and Sorensen, P. H. 2002. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2:367–376.PubMedCrossRefGoogle Scholar
  100. Turc-Carel, C., Dal, C. P., Limon, J., Rao, U., Li, F. P., Corson, J. M., Zimmerman, R., Parry, D. M., Cowan, J. M., and Sandberg, A. A. 1987. Involvement of chromosome X in primary cytogenetic change in human neoplasia: nonrandom translocation in synovial sarcoma. Proc. Natl. Acad. Sci. U.S.A. 84:1981–1985.PubMedCrossRefGoogle Scholar
  101. Vogel, K. S., Klesse, L. J., Velasco-Miguel, S., Meyers, K., Rushing, E. J., and Parada, L. F. 1999. Mouse tumor model for neurofibromatosis type 1. Science. 286:2176–2179.PubMedCrossRefGoogle Scholar
  102. Wai, D. H., Knezevich, S. R., Lucas, T., Jansen, B., Kay, R. J., and Sorensen, P. H. 2000. The ETV6-NTRK3 gene fusion encodes a chimeric protein tyrosine kinase that transforms NIH3T3 cells. Oncogene. 19:906–915.PubMedCrossRefGoogle Scholar
  103. Webber, B. L. and Parham, D. M. 1996. Soft Tissue Tumors Other Than Rhabdomyosarcoma and Peripheral Neuroepithelioma. In Pediatric Neoplasia – Morphology and Biology, pp. 205–257. Little Rock, AR/Philadelphia, NY: Lippincott-Raven Publishers.Google Scholar
  104. Xie, Y., Skytting, B., Nilsson, G., Brodin, B., and Larsson, O. 1999. Expression of insulin-like growth factor-1 receptor in synovial sarocma: association with an aggressive phenotype. Cancer Res. 59:3588–3591.PubMedGoogle Scholar
  105. Xie, Y., Skytting, B., Nilsson, G., Gasbarri, A., Haslam, K., Bartolazzi, B., Mandahl, N., and Larsson, O. 2002. SYT-SSX is critical for Cyclin D1 expression in synovial sarcoma cells: A gain of function of the t(X;18)(p11.2;q11.2) translocation. Cancer. Res. 62:3861–3867.PubMedGoogle Scholar
  106. Zhu, Y., Ghosh, P., Charnay, P., Burns, D. K., and Parada, L. F. 2002. Neurofibromas in NF1: Schwann cell origin and role of tumor microenvironment. Science. 296:920–922.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  1. 1.Pediatric Hematology/OncologyThe University of Chicago Comer Children’s HospitalChicagoUSA

Personalised recommendations