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Molecular Pathology of Bone and Soft Tissue Neoplasms and Potential Targets for Novel Therapy

  • Evita B. Henderson-Jackson
  • Anthony Conley
  • Marilyn M. BuiEmail author
Chapter
  • 2.5k Downloads
Part of the Cancer Growth and Progression book series (CAGP, volume 16)

Abstract

Bone and soft tissue tumors encompass a rare but a heterogenous group of mesenchymal neoplasms ranging from benign to malignant. Frequently, the diagnosis of many bone and soft tissue tumors prove to be difficult due to the enormous variety of histologic subtypes, with some of them (especially the tumors of spindle cell morphology) presenting with similar clinical, microscopic, immunohistochemical, and/or radiographic characteristics. With continuous and more advanced understanding of the cytogenetic and molecular genetics of bone and soft tissue tumors, it is hopeful that, eventually, classifying bone and soft tissue tumor types can be based on molecular pathology rather than by traditional histogenesis. More importantly, the forecast for the prognosis or prediction to therapy can also be benefited from molecular pathology. Chapter 13 will review the most current molecular testing of bone and soft tissue tumors and the biomarkers that have the potential for targeted therapy with focus on the recent developments from the past 5 years.

Keywords

Cytogenetic Molecular pathology Diagnostic, bone tumor (neoplasm) Soft tissue tumor (neoplasm) Genetic Prognosis Prediction Biomarkers Targeted therapy 

Abbreviations

ASPS

Alveolar soft part sarcoma

DFSP

Dermatofibrosarcoma protuberans

FISH

Fluorescent in situ hybridization

GIST

Gastrointestinal stromal tumor

HMO

Hereditary multiple osteochondromas

HSP

Heat-shock protein

IGF1R

Insulin-like growth factor 1 receptor

NTRK3

Neurotrophin 3 receptor gene

PDGFRA

Platelet-derived growth factor receptor alpha

PIK3CA

Phosphotidylinosital-3 kinase catalytic alpha polypeptide

PNET

Primitive neuroectodermal tumor

PPARγ

Peroxisome proliferator-activated receptor-gamma

PVNS

Pigmented villonodular synovitis

RT-PCR

Reverse transcription-polymerase chain reaction

SNP

Single nucleotide polymorphism

VEGFR

Vascular endothelial growth factor receptor

WDLPS/ALT

Well-differentiated liposarcoma/atypical lipomatous tumor

References

  1. 1.
    Fletcher C, Uni K, Mertens F (eds) (2002) Pathology and genetics of tumours of soft tissue and bone, vol 5, World Health Organization classification of tumours. IARC Press, LyonGoogle Scholar
  2. 2.
    Igbokwe A, Lopez-Terrada D (2011) Molecular testing of solid tumors. Arch Pathol Lab Med 135:67–82PubMedGoogle Scholar
  3. 3.
    Bridge J, Cushman-Vokoun A (2011) Molecular diagnostics of soft tissue tumors. Arch Pathol Lab Med 135:588–601PubMedGoogle Scholar
  4. 4.
    Ordonez J, Osuna D, Garcia-Dominguez D, Amaral A, Otero-Motta A, Mackintosh C, Sevillano M, Barbado M, Hernandez T, Alva E (2010) The clinical relevance of molecular genetics in soft tissue sarcomas. Adv Anat Pathol 17:162–181PubMedGoogle Scholar
  5. 5.
    Taylor B, Barretina J, Maki R, Antonescu C, Singer S, Ladanyi M (2011) Advances in sarcoma genomics and new therapeutic targets. Nat Rev 11:541–557Google Scholar
  6. 6.
    Sandberg A, Bridge J (2000) Updates on cytogenetics and molecular genetics of bone and soft tissue tumors: Ewing sarcoma and peripheral primitive neuroectodermal tumors. Cancer Genet Cytogenet 123(1):1–26PubMedGoogle Scholar
  7. 7.
    Sorensen P, Lessnick S, Lopez-Terrada D, Liu X, Triche TJ, Denny CT (1994) A second Ewing’s sarcoma translocation, t(21;22), fuses the EWS gene to another ETS family transcription factor, ERG. Nat Genet 6(2):146–151PubMedGoogle Scholar
  8. 8.
    Parham D (2001) Pathologic classification of rhabdomyosarcomas and correlations with molecular studies. Mod Pathol 14(5):506–514PubMedGoogle Scholar
  9. 9.
    Douglass E, Shapiro D, Valentine M (1993) Alveolar rhabdomyosarcoma with the t(2;13): cytogenetic findings and clinicopathologic correlations. Med Pediatr Oncol 21(2):83–87PubMedGoogle Scholar
  10. 10.
    Wachtel M, Dettling M, Koscielniak E (2004) Gene expression signatures identify rhabdomyosarcoma subtypes and detect a novel t(2;2)(q35;p23) translocation fusing PAX3 to NCOA1. Cancer Res 64(16):5539–5545PubMedGoogle Scholar
  11. 11.
    Barr F, Galili N, Holick J, Biegel J, Rovera G, Emanuel B (1993) Rearrangement of PAX3 paired box gene in the paediatric solid tumour alveolar rhabdomyosarcoma. Nat Genet 3(2):113–117PubMedGoogle Scholar
  12. 12.
    Sorensen P, Lynch J, Qualman S (2002) PAX3-FKHR and PAX7-FKHR gene fusions are prognostic indicators in alveolar rhabdomyosarcoma: a report from the children’s oncology group. J Clin Oncol 20:2672–2679PubMedGoogle Scholar
  13. 13.
    Bridge J, Liu J, Qualman S (2002) Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer 33(3):310–321PubMedGoogle Scholar
  14. 14.
    Ladanyi M, Gerald W (1996) Specificity of the EWS/WT1 gene fusion for desmoplastic small round cell tumor. J Pathol 180(4):462PubMedGoogle Scholar
  15. 15.
    Antonescu C, Argani P, Erlandson R (1998) Skeletal and extraskeletal myxoid chondrosarcoma: a comparative clinicopathologic, ultrastructural, and molecular study. Cancer 83:1504–1521PubMedGoogle Scholar
  16. 16.
    Panagopoulos I, Mertens F, Isaksson M (2002) Molecular genetic characterization of the EWS/CHN and RBP56/CHN fusion genes in extraskeletal myxoid chondrosarcoma. Genes Chromosomes Cancer 35:340–352PubMedGoogle Scholar
  17. 17.
    Tanas M, Goldblum J (2009) Fluorescence in-situ hybridization in the diagnosis of soft tissue neoplasms: a review. Adv Anat Pathol 16:383–391PubMedGoogle Scholar
  18. 18.
    Enzinger F, Weiss S (2001) Soft tissue tumors, 4th edn. Mosby, St. LouisGoogle Scholar
  19. 19.
    de Leeuw B, Balemans M, Olde Weghuis D, Geurts van Kessel A (1995) Identification of two alternative fusion genes, SYT-SXX1 and SYT-SSX2, in t(X;18)(p11.2;q11.2)-positive synovial sarcomas. Hum Mol Genet 4(6):1097–1099PubMedGoogle Scholar
  20. 20.
    Kawai A, Woodruff J, Healey J, Brennan M, Antonescu C, Ladanyi M (1998) SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 338(3):153–160PubMedGoogle Scholar
  21. 21.
    Patel K, Szabo S, Hernandez V (2008) Dermatofibrosarcoma protuberans COL1A1-PDGFB fusion is identified in virtually all dermatofibrosarcoma protuberans cases when investigated by newly developed multiplex reverse transcription polymerase chain reaction and fluoresence in situ hybridization assays. Hum Pathol 39(2):184–193PubMedGoogle Scholar
  22. 22.
    Naeem R, Lux M, Huang S, Naber S, Corson J, Fletcher J (1995) Ring chromosomes in dermatofibrosarcoma protuberans are composed of interspersed sequences from chromosomes 17 and 22. Am J Pathol 147(6):1553–1558PubMedGoogle Scholar
  23. 23.
    Terrier-Lacombe M, Guillou L, Maire G (2003) Dermatofibrosarcoma protuberans, giant cell fibroblastoma, and hybrid lesions in children: clinicopathologic comparative analysis of 28 cases with molecular data–a study from the French Federation of Cancer Centers Sarcoma Group. Am J Surg Pathol 27(1):27–39PubMedGoogle Scholar
  24. 24.
    Rutkowski P, Van Glabbeke M, Rankin C (2010) Imatinib mesylate in advanced dermatofibrosarcoma protuberans: pooled analysis of two phase II clinical trials. J Clin Oncol 28(10):1772–1779PubMedGoogle Scholar
  25. 25.
    Knezevish S, McFadden D, Tao W, Lim J, Sorensen P (1998) A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet 18(2):184–187Google Scholar
  26. 26.
    Knezevish S, Garnett M, Pysher T, Beckwith J, Grundy P, Sorensen P (1998) ETV6-NTRK3 gene fusions and trisomy 11 establish a histogenetic link between mesoblastic nephroma and congenital fibrosarcoma. Cancer Res 58(22):5046–5048Google Scholar
  27. 27.
    Tognon C, Knezevich S, Huntsman D (2002) Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell 2:367–376PubMedGoogle Scholar
  28. 28.
    Schofield D, Fletcher J, Grier H, Yunis E (1994) Fibrosarcoma in infants and children: application of new techniques. Am J Surg Pathol 18(1):14–24PubMedGoogle Scholar
  29. 29.
    Argani P, Fritsch M, Kadkol S, Schuster A, Beckwith J, Perlman E (2000) Detection of the ETV6-NTRK3 chimeric RNA of infantile fibrosarcoma/cellular congenital mesoblastic nephroma in paraffin-embedded tissue: application to challenging pediatric renal stromal tumors. Mod Pathol 13(1):29–36PubMedGoogle Scholar
  30. 30.
    Storlazzi C, Mertens F, Nascimento A (2003) Fusion of the FUS and BBF2H7 genes in low grade fibromyxoid sarcoma. Hum Mol Genet 12:2349–2358PubMedGoogle Scholar
  31. 31.
    Mertens F, Fletcher C, Antonescu C (2005) Clinicopathologic and molecular genetic characterization of low-grade fibromyxoid sarcoma, and cloning of a novel FUS/CREB3L1 fusion gene. Lab Invest 85:408–415PubMedGoogle Scholar
  32. 32.
    Flanagan A, Delaney D, O’Donnell P (2010) The benefits of molecular pathology in the diagnosis of musculoskeletal disease: part 1 of a two part review: soft tissue tumors. Skeletal Radiol 39:105–115PubMedGoogle Scholar
  33. 33.
    Hirota S, Isozaki K, Moriyama Y (1998) Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279(5350):577–580PubMedGoogle Scholar
  34. 34.
    Hirota S, Ohashi A, Nishida T (2003) Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors. Gastroenterology 125(3):660–667PubMedGoogle Scholar
  35. 35.
    Debiec-Rychter M, Sciot R, Le C (2006) KIT mutations and dose selection for imatinib in patients with advanced gastrointestinal stromal tumours. Eur J Cancer 42(8):1093–1103PubMedGoogle Scholar
  36. 36.
    Lasota J, Miettinen M (2008) Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumors. Histopathology 53(3):245–266PubMedGoogle Scholar
  37. 37.
    Andersson J, Bumming P, Meis-Kindblom JM (2006) Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis. Gastroenterology 130(6):1573–1581PubMedGoogle Scholar
  38. 38.
    Miettinen M, Sobin L, Lasota J (2005) Gastrointestinal stromal tumors of the stomach: a clinicopathologic, immunohistochemical, and molecular genetic study of 1765 cases with long-term follow-up. Am J Surg Pathol 29(1):52–68PubMedGoogle Scholar
  39. 39.
    Antonescu C, Sommer G, Sarran L (2003) Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors. Clin Cancer Res 9(9):3329–3337PubMedGoogle Scholar
  40. 40.
    Lasota J, Corless C, Heinrich M (2008) Clinicopathologic profile of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases. Mod Pathol 21(4):476–484PubMedGoogle Scholar
  41. 41.
    Lasota J, Dansonka-Mieszkowska A, Sobin L, Miettinen M (2004) A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. Lab Invest 84(7):874–883PubMedGoogle Scholar
  42. 42.
    Heinrich M, Corless C, Blanke C (2006) Molecular correlates of imatinib resistance in gastrointestinal stromals tumors. J Clin Oncol 24(29):4764–4774PubMedGoogle Scholar
  43. 43.
    Debiec-Rychter M, Dumez H, Judson I (2004) Use of c-KIT/PDGFRA mutational analysis to predict the clinical response to imatinib in patients with advanced gastrointestinal stromal tumours entered on phase I and II studies of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 40(5):689–695PubMedGoogle Scholar
  44. 44.
    Heinrich M, Corless C, Demetri G (2005) Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21(23):4342–4349Google Scholar
  45. 45.
    Sandberg A (2004) Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: liposarcoma. Cancer Genet Cytogenet 155(1):1–24PubMedGoogle Scholar
  46. 46.
    Powers M, Wang W-L, Hernandez V (2010) Detection of myxoid liposarcoma-associated FUS-DDIT3 rearrangement variants including a newly identified breakpoint using an optimized RT-PCR assay. Mod Pathol 23(10):1307–1315PubMedGoogle Scholar
  47. 47.
    Barretina J, Taylor BS, Banerji S, Ramos AH, Lagos-Quintana M, Decarolis PL, Shah K, Socci ND, Weir BA, Ho A, Chiang DY, Reva B, Mermel CH, Getz G, Antipin Y, Beroukhim R, Major JE, Hatton C, Nicoletti R, Hanna M, Sharpe T, Fennell TJ, Cibulskis K, Onofrio RC, Saito T, Shukla N, Lau C, Nelander S, Silver SJ, Sougnez C, Viale A, Winckler W, Maki RG, Garraway LA, Lash A, Greulich H, Root DE, Sellers WR, Schwartz GK, Antonescu CR, Lander ES, Varmus HE, Ladanyi M, Sander C, Meyerson M, Singer S (2010) Subtype-specific genomic alterations define new targets for soft-tissue sarcoma therapy. Nat Genet 42(8):715–721PubMedGoogle Scholar
  48. 48.
    Binh M, Sastre-Garau X, Guillou L (2005) MDM2 and CDK4 immunostainings are useful adjuncts in diagnosing well-differentiated and dedifferentiated liposarcoma subtypes: a comparative analysis of 559 soft tissue neoplasms with genetic data. Am J Surg Pathol 29(10):1340–1347PubMedGoogle Scholar
  49. 49.
    Bridge J, Sreekantaiah C, Neff J, Sandberg A (1991) Cytogenetic findings in clear cell sarcoma of tendons and aponeuroses: malignant melanoma of soft parts. Cancer Genet Cytogenet 52(1):101–106PubMedGoogle Scholar
  50. 50.
    Zucman J, Delattre O, Desmaze C (1993) EWS and ATF-1 gene fusion induced by t(12;22) translocation in malignant melanoma of soft parts. Nat Genet 4(4):341–345PubMedGoogle Scholar
  51. 51.
    Heimann P, Devalck C, Debusscher C, Sariban E, Vamos E (1998) Alveolar soft part sarcoma: further evidence by FISH for the involvement of chromosome band 17q25. Genes Chromosomes Cancer 23(2):194–197PubMedGoogle Scholar
  52. 52.
    Ladanyi M, Lui M, Antonescu C (2001) The der(17)t(X;17)(p11;q25) of human alveolar soft part sarcoma fuses the TFE3 transcription factor gene to ASPL, a novel gene at 17q25. Oncogene 20(1):48–57PubMedGoogle Scholar
  53. 53.
    Mitton B, Federman N (2012) Alveolar soft part sarcomas: molecular pathogenesis and implications for novel targeted therapies. Sarcoma 2012:428789PubMedGoogle Scholar
  54. 54.
    Biegel J, Allen C, Kawasaki K (1996) Narrowing the critical region for a rhabdoid tumor locus in 22q11. Genes Chromosomes Cancer 16(2):94–105PubMedGoogle Scholar
  55. 55.
    Versteege I, Sevenet N, Lange J (1998) Truncating mutations of hSNF5/INI1 in aggressive paediatric cancer. Nature 394(6689):203–206PubMedGoogle Scholar
  56. 56.
    Modena P, Lualdi E, Facchinetti F (2005) SMARCB1/INI1 tumor suppressor gene is frequently inactivated in epithelioid sarcomas. Cancer Res 65(10):4012–4019PubMedGoogle Scholar
  57. 57.
    Kreiger P, Judkins A, Russo P (2009) Loss of INI1 expression defines a unique subset of pediatric undifferentiated soft tissue sarcomas. Mod Pathol 22(1):142–150PubMedGoogle Scholar
  58. 58.
    Jackson E, Sievert A, Gai X (2009) Genomic analysis using high-density single nucleotide polymorphism-based oligonucleotide arrays and multiplex ligation-dependent probe amplification provides a comprehensive analysis of INI1/SMARCB1 in malignant rhabdoid tumors. Clin Cancer Res 15(6):1923–1930PubMedGoogle Scholar
  59. 59.
    Bovee J, Cleton-Jansen A, Wuyts W, Caethoven G, Taminiau A, Bakker E, Van Hul W, Cornelisse C, Hogendoorn P (1999) EXT-mutation analysis and loss of heterozygosity in sporadic and hereditary osteochondromas and secondary chondrosarcomas. Am J Hum Genet 65(3):689–698PubMedGoogle Scholar
  60. 60.
    Mertens F, Rydholm A, Kreicbergs A, Willen H, Jonsson K, Heim S, Mitelman F, Mandahl N (1994) Loss of chromosome band 8q24 in sporadic osteocartilaginous exostoses. Genes Chromosomes Cancer 9:8–12PubMedGoogle Scholar
  61. 61.
    Bridge J, Nelson M, Orndal C, Bhatia P, Neff J (1988) Clonal karyotypic abnormalities of the hereditary multiple exostoses chromosomal loci 8q24.1 (EXT1) and 11p11-12 (EXT2) in patients with sporadic and hereditary osteochondromas. Cancer 82:1657–1663Google Scholar
  62. 62.
    Gunawan B, Weber M, Bergmann F, Wildberger J, Niethard F, Fuzesi L (2000) Clonal chromosome abnormalities in enchondromas and chondrosarcomas. Cancer Genet Cytogenet 120:127–130PubMedGoogle Scholar
  63. 63.
    Bridge J, Persons D, Neff J, Bhatia P (1992) Clonal karyotypic aberrations in enchondromas. Cancer Detect Prev 16:215–219PubMedGoogle Scholar
  64. 64.
    Halbert A, Harrison W, Hicks M, Davino N, Cooley L (1998) Cytogenetic analysis of a scapular chondromyxoid fibroma. Cancer Genet Cytogenet 104:52–56PubMedGoogle Scholar
  65. 65.
    Safar A, Nelson M, Neff J, Maale G, Bayani J, Squire J, Bridge J (2000) Recurrent anomalies of 6q25 in chondromyxoid fibroma. Hum Pathol 31:306–311PubMedGoogle Scholar
  66. 66.
    Sawyer J, Swanson C, Lukacs J, Nicholas R, North P, Thomas J (1998) Evidence of an association between 6q13-21 chromosome aberrations and locally aggressive behavior in patients with cartilage tumors. Cancer 82:474–483PubMedGoogle Scholar
  67. 67.
    Granter S, Renshaw A, Kozakewich H, Fletcher J (1998) The pericentromeric inversion, inv (6)(p25q13), is a novel diagnostic marker in chondromyxoid fibroma. Mod Pathol 11:1273–1276Google Scholar
  68. 68.
    Tallini G, Dorfman H, Brys P, Dal Cin P, de Wever I, Fletcher C, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Sciot R, van den Berghe H, Vanni R, Willen H (2002) Correlation between clinicopathological features and karyotype in 100 cartilaginous and chordoid tumors. A report from the chromosomes and morphology (CHAMP) collaborative study group. J Pathol 196:194–203PubMedGoogle Scholar
  69. 69.
    Schrage Y, Bovee J (2005) Bone tumors: an overview. Atlas Genet Cytogenet Oncol Haematol. http://documents.crevues.inist.fr/bitstream/2042/38197/1-03205
  70. 70.
    Bridge J, Bhatia P, Anderson J, Neff J (1993) Biologic and clinical significance of cytogenetic and molecular cytogenetic abnormalities in benign and malignant cartilaginous lesions. Cancer Genet Cytogenet 69:79–90PubMedGoogle Scholar
  71. 71.
    Mandahl N, Gustafson P, Mertens F, Akerman M, Baldetorp B, Gisselsson D, Knuutila S, Bauer H, Larsson O (2002) Cytogenetic aberrations and their prognostic impact in chondrosarcoma. Genes Chromosomes Cancer 33:188–200PubMedGoogle Scholar
  72. 72.
    Bridge J, DeBoer J, Travis J, Johansson S, Elmberger G, Noel S, Neff J (1994) Simultaneous interphase cytogenetic analysis and fluorescence immunophenotyping of dedifferentiated chondrosarcoma. Implications for histopathogenesis. Am J Pathol 144:215–220PubMedGoogle Scholar
  73. 73.
    Bovee J, Cleton-Jansen A, Rosenberg C, Taminiau A, Cornelisse C, Hogendoorn P (1999) Molecular genetic characterization of both components of a dedifferentiated chondrosarcoma, with implications for its histogenesis. J Pathol 189:454–462PubMedGoogle Scholar
  74. 74.
    O’Malley D, Opheim K, Barry T, Chapman D, Emond M, Conrad E, Norwood T (2001) Chromosomal changes in a dedifferentiated chondrosarcoma: a case report and review of the literature. Cancer Genet Cytogenet 124:105–111PubMedGoogle Scholar
  75. 75.
    Swarts S, Neff J, Johansson S, Bridge J (1996) Cytogenetic analysis of dedifferentiated chondrosarcoma. Cancer Genet Cytogenet 89:49–51PubMedGoogle Scholar
  76. 76.
    Naumann S, Krallman P, Unni K, Fidler M, Neff J, Bridge J (2002) Translocation der(13;21)(q10;q10) in skeletal and extraskeletal mesenchymal chondrosarcoma. Mod Pathol 15:572–576PubMedGoogle Scholar
  77. 77.
    Baruffi M, Volpon J, Neto J, Casartelli C (2001) Osteoid osteomas with chromosome alterations involving 22q. Cancer Genet Cytogenet 124:127–131PubMedGoogle Scholar
  78. 78.
    Knuutila S, Autio K, Aalto Y (2000) Online access to CGH data of DNA sequence copy number changes. Am J Pathol 157:689PubMedGoogle Scholar
  79. 79.
    Forus A, Florenes V, Maelandsom G, Fodstad O, Myklebost O (1994) The protooncogene CHOP/GADD153, involved in growth arrest and DNA damage response, is amplified in a subset of human sarcomas. Cancer Genet Cytogenet 78:165–171PubMedGoogle Scholar
  80. 80.
    Khatib Z, Matsushime H, Valentine M, Shapiro D, Sherr C, Look A (1993) Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res 53:5535–5541PubMedGoogle Scholar
  81. 81.
    Momand J, Zambetti G, Olson D, George D, Levine A (1992) The mdm-2 oncogene product forms a complex with the p53 protein and inhibits p53-mediated transactivation. Cell 69:1237–1245PubMedGoogle Scholar
  82. 82.
    Oliner J, Kinzler K, Meltzer P, Gerorge D, Vogelstein B (1992) Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature 358:80–83PubMedGoogle Scholar
  83. 83.
    Roberts W, Douglass E, Peiper S, Houghton P, Look A (1989) Amplification of the gli gene in childhood sarcomas. Cancer Res 49:5407–5413PubMedGoogle Scholar
  84. 84.
    Smith S, Weiss S, Jankowski S, Coccia M, Meltzer P (1992) SAS amplification in soft tissue sarcomas. Cancer Res 52:3746–3749PubMedGoogle Scholar
  85. 85.
    Atiye J, Wolf M, Kaur S, Monni O, Böhling T, Kivioja A, Tas E, Serra M, Tarkkanen M, Knuutila S (2005 Feb) Gene amplifications in osteosarcoma – CGH microarray analysis. Genes Chromosomes Cancer 42(2):158–163PubMedGoogle Scholar
  86. 86.
    Ladanyi M, Cha C, Lewis R, Jhanwar S, Huvos A, Healey J (1993) MDM2 gene amplification in metastatic osteosarcoma. Cancer Res 53:16–18PubMedGoogle Scholar
  87. 87.
    Berner J, Forus A, Elkahloun A, Meltzer P, Fodstad O, Myklebost O (1996) Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas. Genes Chromosomes Cancer 17:254–259PubMedGoogle Scholar
  88. 88.
    Forus A, Florenes V, Maelandsom G, Fodstad O, Myklebost O (1994) 12q13-14 amplica in human sarcomas without MDM2 include CDK4, SAS and GADD153/CHOP. Cancer Genet Cytogenet 77:200Google Scholar
  89. 89.
    Maelandsom G, Berner J, Florenes V, Forus A, Hovig E, Fodstad O, Myklebost O (1995) Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcoma – relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer 72:393–398Google Scholar
  90. 90.
    Stock C, Kager L, Fink F, Gadner H, Ambros P (2000) Chromosomal regions involved in the pathogenesis of osteosarcomas. Genes Chromosomes Cancer 28:329–336PubMedGoogle Scholar
  91. 91.
    Tarkkanen M, Bohling T, Gamberi G, Ragazzini P, Benassi M, Kivioja A, Kallio P, Elomaa I, Picci P, Knuutila S (1998) Comparative genomic hybridization of low-grade central osteosarcoma. Mod Pathol 11:421–426PubMedGoogle Scholar
  92. 92.
    Mertens F, Mandahl N, Orndal C, Baldetorp B, Bauer H, Rydholm A, Wiebe T, Willen H, Akerman M, Heim S, Mitelman F (1993) Cytogenetic findings in 33 osteosarcomas. Int J Cancer 55:44–50PubMedGoogle Scholar
  93. 93.
    Sinovic J, Bridge J, Neff J (1992) Ring chromosome in parosteal osteosarcoma. Clinical and diagnostic significance. Cancer Genet Cytogenet 62:50–52PubMedGoogle Scholar
  94. 94.
    Szymanska J, Mandahl N, Mertens F, Tarkkanen M, Karaharju E, Knuutila S (1996) Ring chromosomes in parosteal osteosarcoma contain sequences from 12q13-15: a combined cytogenetic and comparative genomic hybridization study. Genes Chromosomes Cancer 16:31–34PubMedGoogle Scholar
  95. 95.
    Mertens F, Larramendy M, Gustavsson A, Gisselsson D, Rydholm A, Brosjo O, Mitelman F, Knuutila S, Mandahl N (2000) Radiation-associated sarcomas are characterized by complex karyotypes with frequent rearrangements of chromosome are 3p. Cancer Genet Cytogenet 116(89–96)Google Scholar
  96. 96.
    Tarkkanen M, Wiklund T, Virolainen M, Larramendy M, Mandahl N, Mertens F, Blomqvist C, Tukiainen E, Miettinen M, Elomaa I, Knuutila S (2001) Comparative genomic hybridization of postirradiation sarcomas. Cancer 92:1992–1998PubMedGoogle Scholar
  97. 97.
    Nellissery M, Padalecki S, Brkanac Z, Singer F, Roodman G, Unni K, Leach R, Hansen M (1998) Evidence for a novel osteosarcoma tumor-suppressor gene in the chromosome 18 region genetically linked with Paget disease of bone. Am J Hum Genet 63:817–824PubMedGoogle Scholar
  98. 98.
    Nilsson M, Domanski H, Mertens F, Mandahl N (2004) Molecular cytogenetic characterization of recurrent translocation breakpoints in bizarre parosteal osteochondromatous proliferation (Nora’s lesion). Hum Pathol 35(9):1063–1069PubMedGoogle Scholar
  99. 99.
    Bridge J, Swarts S, Buresh C, Nelson M, Degenhardt J, Spanier S, Maale G, Meloni A, Lynch J, Neff J (1999) Trisomies 8 and 20 characterize a subgroup of benign fibrous lesions arising in both soft tissue and bone. Am J Pathol 154:729–733PubMedGoogle Scholar
  100. 100.
    Schwartz H, Dahir G, Butler M (1993) Telomere reduction in giant cell tumor of bone and with aging. Cancer Genet Cytogenet 71:132–138PubMedGoogle Scholar
  101. 101.
    Bridge J, Neff J, Mouron B (1992) Giant cell tumor of bone. Chromosomal analysis of 48 specimens and review of the literature. Cancer Genet Cytogenet 58:2–13PubMedGoogle Scholar
  102. 102.
    Panagopoulos I, Mertens F, Domanski H, Isaksson M, Brosjo O, Gustafson P, Mandahl N (2001) No EWS/FLI1 fusion transcripts in giant-cell tumors of bone. Int J Cancer 93:769–772PubMedGoogle Scholar
  103. 103.
    Sciot R, Dorfman H, Brys P, Dal Cin P, De Wever I, Fletcher C, Jonson K, Mandahl N, Mertens F, Mitelman F, Rosai J, Rydholm A, Samson I, Tallini G, Van den Berghe H, Vanni R, Willen H (2000) Cytogenetic-morphologic correlations in aneurysmal bone cyst, giant cell tumor of bone and combined lesions. A report from the CHAMP study group. Mod Pathol 13:1206–1210PubMedGoogle Scholar
  104. 104.
    Tarkkanen M, Kaipanien A, Karaharju E, Bohling T, Szymanska J, Helio H, Kivioja A, Elomaa I, Knuutila S (1993) Cytogenetic study of 249 consecutive patients examined for a bone tumor. Cancer Genet Cytogenet 68:1–21PubMedGoogle Scholar
  105. 105.
    Zheng M, Siu P, Papadimitriou J, Wood D, Murch A (1999) Telomeric fusion is a major cytogenetic aberration of giant cell tumors of bone. Pathology 31:373–378PubMedGoogle Scholar
  106. 106.
    Scheil S, Bruderlein S, Liehr T, Starke H, Herms J, Schulte M, Moller P (2001) Genome-wide analysis of sixteen chordomas by comparative genomic hybridization and cytogenetics of the first human chordoma cell line, U-CH1. Genes Chromosomes Cancer 32:203–211PubMedGoogle Scholar
  107. 107.
    Miozzo M, Dalpra L, Riva P, Volonta M, Macciardi F, Pericotti S, Tibiletti M, Cerati M, Rohde K, Larizza L, Fuhrman Conti A (2000) A tumor suppressor locus in familial and sporadic chordoma maps to 1p36. Int J Cancer 87:68–72PubMedGoogle Scholar
  108. 108.
    Hazelbag H, Van den Broek L, Fleuren G, Taminiau A, Hogendoorn P (1997) Distribution of extracellular matrix components in adamantinoma of long bones suggests fibrous-to-epithelial transformation. Hum Pathol 28:183–188PubMedGoogle Scholar
  109. 109.
    Kanamori M, Antonescu C, Scott M, Bridge R, Neff J, Spanier S, Scarborough M, Vergara G, Rosenthal H, Bridge J (2001) Extra copies of chromosomes 7, 8, 12, 19, and 21 are recurrent in adamantinoma. J Mol Diagn 3:16–21PubMedGoogle Scholar
  110. 110.
    Mandahl N, Heim S, Rydholm A, Willen H, Mitelman F (1989) Structural chromosome aberrations in an adamantinoma. Cancer Genet Cytogenet 42:187–190PubMedGoogle Scholar
  111. 111.
    Sozzi G, Miozzo M, Di Palma S, Minelli A, Calderone C, Danesino C, Pastorino U, Pierotti M, Della Porta G (1990) Involvement of the region 13q14 in a patient with adamantinoma of the long bones. Hum Genet 85:513–515PubMedGoogle Scholar
  112. 112.
    Panoutsakopoulos G, Pandis N, Kyriazoglou I, Gustafson P, Mertens F, Mandahl N (1999) Recurrent t(16;17)(q22;p13) in aneurysmal bone cysts. Genes Chromosomes Cancer 26:265–266PubMedGoogle Scholar
  113. 113.
    Oliveira A, Perez-Atayde A, Inwards C, Medeiros F, Derr V, Hsi B (2004) USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol 165(5):1773–1780PubMedGoogle Scholar
  114. 114.
    Oliveira A, Hsi B, Weremowicz S, Rosenberg A, Dal Cin P, Joseph N (2004) USP6 (Tre2) fusion oncogenes in aneurysmal bone cyst. Cancer Res 64(6):1920–1923PubMedGoogle Scholar
  115. 115.
    Oliveira A, Perez-Atayde A, Dal Cin P, Gebhardt M, Chen C, Neff J (2005) Aneurysmal bone cyst variant translocations upregulate USP6 transcription by promoter swapping with the ZNF9, COL1A1, TRAP150, and OMD genes. Oncogene 24:3419–3426PubMedGoogle Scholar
  116. 116.
    Oliveira A, Chou M, Perez-Atayde A, Rosenberg A (2006) Aneurysmal bone cyst: a neoplasm driven by upregulation of the USP6 oncogene. J Clin Oncol 24(1):e1PubMedGoogle Scholar
  117. 117.
    Bianco P, Rimminucci M, Majolagbe A, Kuznetsov S, Collins M, Mankani M (2000) Mutations of the GNAS1 gene, stromal cell dysfunction, and osteomalacic changes in non-McCune-Albright fibrous dysplasia of bone. J Bone Miner Res 15(1):120–128PubMedGoogle Scholar
  118. 118.
    Pisters PW, Leung DH, Woodruff J, Shi W, Brennan MF (1996) Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14(5):1679–1689PubMedGoogle Scholar
  119. 119.
    Kumar V, Abbas A, Fausto N, Aster J (2010) Robbins & Cotran pathologic basis of disease, 8th edn. Elsevier, PhiladelphiaGoogle Scholar
  120. 120.
    Agaram N, Wong G, Guo T (2008) Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 47:853–859PubMedGoogle Scholar
  121. 121.
    Agaimy A, Terracciano T, Dirnhofer S (2009) V600E BRAF mutations are alternative early molecular events in a subset of IT/PDGFRA wild-type gastrointestinal stromal tumors. J Clin Pathol 62:613–616PubMedGoogle Scholar
  122. 122.
    Judson I (2010) Targeted therapies in soft tissue sarcomas. Ann Oncol 21(Suppl 7):277–280Google Scholar
  123. 123.
    Wardelmann E, Schildhaus H, Merkelbach-Bruse S (2010) Soft tissue sarcoma: from molecular diagnosis to selection of treatment. Pathological diagnosis of soft tissue sarcoma amid molecular biology and targeted therapies. Ann Oncol 21(Suppl 7):265–269Google Scholar
  124. 124.
    Janeway KA, Kim SY, Lodish M, Nose V, Rustin P, Gaal J, Dahia PL, Liegl B, Ball ER, Raygada M, Lai AH, Kelly L, Hornick JL, O’Sullivan M, de Krijger RR, Dinjens WN, Demetri GD, Antonescu CR, Fletcher JA, Helman L, Stratakis CA (2011) Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations. Proc Natl Acad Sci U S A 108(1):314–318PubMedGoogle Scholar
  125. 125.
    Kelly-Downs E, Rubin B (2011) Gastrointestinal stromal tumors: molecular mechanisms and targeted therapies. Pathol Res Int 2011:7Google Scholar
  126. 126.
    Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, Verweij J, McArthur G, Judson IR, Heinrich MC, Morgan JA, Desai J, Fletcher CD, George S, Bello CL, Huang X, Baum CM, Casali PG (2006) Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet 368(9544):1329–1338PubMedGoogle Scholar
  127. 127.
    Quek R, George S (2010) Update on the treatment of gastrointestinal stromal tumors (GISTs): role of imatinib. Biologics Targets Ther 4:19–31Google Scholar
  128. 128.
    Weiss S, Goldblum J (eds) (2008) Enzinger and Weiss’s soft tissue tumors. Mosby Elsevier, St. LouisGoogle Scholar
  129. 129.
    Blay J, El Sayadi H, Thiesse P (2008) Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol 19:821–822PubMedGoogle Scholar
  130. 130.
    Cassier P, Stacchiotti S, Gelderblom H (2010) Imatinib mesylate for the treatment of locally advanced and/or metastatic pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). In: ASCO annual meeting; 2010, Chicago. J Clin Oncol 28:15s (suppl; abstr 10012)Google Scholar
  131. 131.
    Ravia V, Wang W, Lewis V (2011) Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr Opin Oncol 23:361–366Google Scholar
  132. 132.
    Spurrell EL, Fisher C, Thomas JM, Judson IR (2005) Prognostic factors in advanced synovial sarcoma: an analysis of 104 patients treated at the Royal Marsden Hospital. Ann Oncol 16(3):437–444PubMedGoogle Scholar
  133. 133.
    Canter RJ, Qin LX, Maki RG, Brennan MF, Ladanyi M, Singer S (2008) A synovial sarcoma-specific preoperative nomogram supports a survival benefit to ifosfamide-based chemotherapy and improves risk stratification for patients. Clin Cancer Res 14(24):8191–8197PubMedGoogle Scholar
  134. 134.
    Subbiah V, Kurzrock R (2011) Phase 1 clinical trials for sarcomas: cutting edge. Curr Opin Oncol 23:352–360PubMedGoogle Scholar
  135. 135.
    Sleijfer S, Ray-Coquard I, Papai Z (2009) Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group (EORTC study 62043). J Clin Oncol 27(19):3126–3132PubMedGoogle Scholar
  136. 136.
    Dobashi Y, Suzuki S, Sato E (2009) EGFR-dependent and independent activation of Akt/mTOR cascade in bone and soft tissue tumors. Mod Pathol 22(10):128–140Google Scholar
  137. 137.
    Mancuso T, Mezzelani A, Riva C (2000) Analysis of SYT-SSX fusion transcripts and bcl-2 expression and phosphorylation status in synovial sarcoma. Lab Invest 80(6):805–813PubMedGoogle Scholar
  138. 138.
    Joyner D, Albritton K, Bastar J (2006) G3139 antisense oligonucleotide directed against antiapoptotic bcl-2 enhances doxorubicin cytotoxicity in the FU-SY-1 synovial sarcoma line. J Orthop Res 24(3):474–480PubMedGoogle Scholar
  139. 139.
    Weiss S (2002) Soft tissue sarcomas: lessons from the past, challenges for the future. Mod Pathol 15(1):77–86PubMedGoogle Scholar
  140. 140.
    Mills S, Carter D, Greenson J (eds) (2009) Sternberg’s diagnostic surgical pathology, 5th edn. Lippincott Williams & Wikins, PhiladelphiaGoogle Scholar
  141. 141.
    Henricks W, Chu Y, Goldblum J, Weiss S (1997) Dedifferentiated liposarcoma: a clinicopathological analysis of 155 cases with a proposal for an expanded definition of dedifferentiation. Am J Surg Pathol 21(3):271–281PubMedGoogle Scholar
  142. 142.
    McCormick D, Mentzel T, Beham A, Fletcher C (1994) Dedifferentiated liposarcoma: clinicopathologic analysis of 32 cases suggesting a better prognostic subgroup among pleomorphic sarcomas. Am J Surg Pathol 18(12):1213–1223PubMedGoogle Scholar
  143. 143.
    Singer S, Antonescu C, Riedel E, Brennan M, Pollock R (2003) Histologic subtype and margin of resection predict pattern of recurrence and survival for retroperitoneal liposarcoma. Ann Surg 238(3):358–371PubMedGoogle Scholar
  144. 144.
    Yang J, Du X, Chen K, Ylipaa A, Lazar AJ, Trent J, Lev D, Pollock R, Hao X, Hunt K, Zhang W (2009) Genetic aberrations in soft tissue leiomyosarcoma. Cancer Lett 275(1):1–8PubMedGoogle Scholar
  145. 145.
    Hernando E, Charytonowicz E, Dudas ME, Menendez S, Matushansky I, Mills J, Socci ND, Behrendt N, Ma L, Maki RG, Pandolfi PP, Cordon-Cardo C (2007) The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med 13(6):748–753PubMedGoogle Scholar
  146. 146.
    Longtin R (2003) Ewing’s sarcoma: a miracle drug waiting to happen? J Natl Cancer Inst 95(21):1574–1576PubMedGoogle Scholar
  147. 147.
    Pinto A, Dickman P, Parham D (2011) Pathobiologic markers of the Ewing sarcoma family of tumors: state of the art and prediction of behaviour. Sarcoma 2011:15Google Scholar
  148. 148.
    Pappo A, Pater S (2010) Activity of R1507, a monoclonal antibody to the insulin-like growth factor-1 receptor (IGF1R), in patients with recurrent or refractory Ewing’s sarcoma family of tumors (ESFT): results of a phase II SARC study. In: Proceedings of the ASCO annual meeting. June 4–8, Chicago, ILGoogle Scholar
  149. 149.
    Cho D, Shook D, Shimasaki N, Chang Y, Fujisaki H, Campana D (2010) Cytotoxicity of activated natural killer cells against pediatric solid tumors. Clin Cancer Res 16(15):3901–3909PubMedGoogle Scholar
  150. 150.
    Ahn Y, Weigel B, Verneris M (2010) Killing the killer: natural killer cells to treat Ewing’s sarcoma. Clin Cancer Res 16:3819–3821PubMedGoogle Scholar
  151. 151.
    Karosas A (2010) Ewing’s sarcoma. Am J Health Syst Pharm 67(19):1599–1605PubMedGoogle Scholar
  152. 152.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • Evita B. Henderson-Jackson
    • 1
  • Anthony Conley
    • 2
  • Marilyn M. Bui
    • 1
    Email author
  1. 1.Department of Anatomic PathologyH. Lee Moffitt Cancer Center and Research Institute, University of South Florida, College of MedicineTampaUSA
  2. 2.Department of SarcomaH. Lee Moffitt Cancer Center and Research Institute, University of South Florida, College of MedicineTampaUSA

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