The Complex Nature of Soft Tissue Sarcomas, Including Retroperitoneal Sarcomas

  • Fabio GrizziEmail author
  • Elena Monica Borroni
  • Dorina Qehajaj
  • Sanja Stifter
  • Maurizio Chiriva-Internati
  • Ferdinando C. M. Cananzi
Part of the Updates in Surgery book series (UPDATESSURG)

3.1 The Complexity of Retroperitoneal Sarcomas

Human cancer remains one of the most complex diseases and, despite the impressive advances that have been made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still widely debated [1]. Cancer is also recognized as a highly heterogeneous disease. In addition, somatic mutations and epigenetic changes, many of which are specific to the individual neoplasm have been reported [2]. Soft tissue sarcomas are uncommon, but generally aggressive tumors which disproportionately affect children and young adults [3]. These cancers have a high rate of morbidity and mortality, and their overall incidence has been increasing at an estimated rate of 26% over the last 2 decades [3]. It is known that the retroperitoneum can host a large group of benign as well as malignant tumors [4]. Retroperitoneal sarcomas are rare and represent a small group of all sarcomas, approximately 15% [5],...


  1. 1.
    Grizzi F, Di Ieva A, Russo C et al (2006) Cancer initiation and progression: an unsimplifiable complexity. Theor Biol Med Model 3:37PubMedPubMedCentralCrossRefGoogle Scholar
  2. 2.
    Widschwendter M, Jones A, Evans I et al; FORECEE (4C) Consortium (2018) Epigenomebased cancer risk prediction: rationale, opportunities and challenges. Nat Rev Clin Oncol 15(5):292–309PubMedGoogle Scholar
  3. 3.
    Halcrow PW, Dancer M, Panteah M et al (2016) Molecular changes associated with tumor initiation and progression of soft tissue sarcomas: targeting the genome and epigenome. Prog Mol Biol Transl Sci 144:323–380PubMedCrossRefGoogle Scholar
  4. 4.
    Strauss DC, Hayes AJ, Thomas JM (2011) Retroperitoneal tumours: review of management. Ann R Coll Surg Engl 93(4):275–280PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Porpiglia AS, Reddy SS, Farma JM (2016) Retroperitoneal sarcomas. Surg Clin North Am 96(5):993–1001PubMedCrossRefGoogle Scholar
  6. 6.
    Clark MA, Fisher C, Judson I, Thomas JM (2005) Soft-tissue sarcomas in adults. N Engl J Med 353(7):701–711PubMedCrossRefGoogle Scholar
  7. 7.
    Soini Y (2016) Epigenetic and genetic changes in soft tissue sarcomas: a review. APMIS 124(11):925–934PubMedCrossRefGoogle Scholar
  8. 8.
    Sigston EAW, Williams BRG (2017) An emergence framework of carcinogenesis. Front Oncol 7:198PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Gérard C, Goldbeter A (2016) Dynamics of the mammalian cell cycle in physiological and pathological conditions. Wiley Interdiscip Rev Syst Biol Med 8(2):140–156PubMedCrossRefGoogle Scholar
  10. 10.
    Grizzi F, Chiriva-Internati M (2006) Cancer: looking for simplicity and finding complexity. Cancer Cell Int 6:4PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Sell S, Nicolini A, Ferrari P, Biava PM (2016) Cancer: a problem of developmental biology; scientific evidence for reprogramming and differentiation therapy. Curr Drug Targets 17(10):1103–1110PubMedCrossRefGoogle Scholar
  12. 12.
    Segal NH, Pavlidis P, Antonescu CR et al (2003) Classification and subtype prediction of adult soft tissue sarcoma by functional genomics. Am J Pathol 163(2):691–700PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Strong LC, Williams WR, Tainsky MA (1992) The Li-Fraumeni syndrome: from clinical epidemiology to molecular genetics. Am J Epidemiol 135(2):190–199PubMedCrossRefGoogle Scholar
  14. 14.
    Stratton MR, Moss S, Warren W et al (1990) Mutation of the p53 gene in human soft tissue sarcomas: association with abnormalities of the RB1 gene. Oncogene 5(9):1297–1301PubMedGoogle Scholar
  15. 15.
    Kruzelock RP, Hansen MF (1995) Molecular genetics and cytogenetics of sarcomas. Hematol Oncol Clin North Am 9(3):513–540PubMedCrossRefGoogle Scholar
  16. 16.
    Skapek SX, Chui CH (2000) Cytogenetics and the biologic basis of sarcomas. Curr Opin Oncol 12(4):315–322PubMedCrossRefGoogle Scholar
  17. 17.
    Karpeh MS, Brennan MF, Cance WG et al (1995) Altered patterns of retinoblastoma gene product expression in adult soft-tissue sarcomas. Br J Cancer 72(4):986–991PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Xiao X, Garbutt CC, Hornicek F et al (2018) Advances in chromosomal translocations and fusion genes in sarcomas and potential therapeutic applications. Cancer Treat Rev 63:61–70PubMedCrossRefGoogle Scholar
  19. 19.
    Jones KB (2018) What’s in a name? Cell fate reprogramming in sarcomagenesis. Cancer Cell 33(1):5–7PubMedCrossRefGoogle Scholar
  20. 20.
    Drummond CJ, Hanna JA, Garcia MR et al (2018) Hedgehog pathway drives fusionnegative rhabdomyosarcoma initiated from non-myogenic endothelial progenitors. Cancer Cell 33(1):108–124.e5PubMedCrossRefGoogle Scholar
  21. 21.
    Oda Y, Yamamoto H, Kohashi K et al (2017) Soft tissue sarcomas: from a morphological to a molecular biological approach. Pathol Int 67(9):435–446PubMedCrossRefGoogle Scholar
  22. 22.
    Hamacher R, Bauer S (2017) Preclinical models for translational sarcoma research. Curr Opin Oncol 29(4):275–285PubMedCrossRefGoogle Scholar
  23. 23.
    Ramón y Cajal S, Castellvi J, Hümmer S et al (2018) Beyond molecular tumor heterogeneity: protein synthesis takes control. Oncogene 37(19):2490–2501PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Chowell D, Napier J, Gupta R et al (2018) Modeling the subclonal evolution of cancer cell populations. Cancer Res 78(3):830–839PubMedCrossRefGoogle Scholar
  25. 25.
    Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481(7381):306–313PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Osman S, Lehnert BE, Elojeimy S et al (2013) A comprehensive review of the retro-peritoneal anatomy, neoplasms, and pattern of disease spread. Curr Probl Diagn Radiol 42(5):191–208PubMedCrossRefGoogle Scholar
  27. 27.
    Loewenstein S, Lubezky N, Nizri E et al (2016) Adipose-induced retroperitoneal soft tissue sarcoma tumorigenesis: a potential crosstalk between sarcoma and fat cells. Mol Cancer Res 14(12):1254–1265PubMedCrossRefGoogle Scholar
  28. 28.
    Grizzi F, Chiriva-Internati M (2005) The complexity of anatomical systems. Theor Biol Med Model 2:26PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Ogino J, Asanuma H, Hatanaka Y et al (2013) Validity and reproducibility of Ki-67 assessment in gastrointestinal stromal tumors and leiomyosarcomas. Pathol Int 63(2):102–107PubMedCrossRefGoogle Scholar
  30. 30.
    Ehnman M, Larsson O (2015) Microenvironmental targets in sarcoma. Front Oncol 5:248PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Tomlinson J, Barsky SH, Nelson S et al (1999) Different patterns of angiogenesis in sarcomas and carcinomas. Clin Cancer Res 5(11):3516–3522PubMedGoogle Scholar
  32. 32.
    West CC, Brown NJ, Mangham DC et al (2005) Microvessel density does not predict outcome in high grade soft tissue sarcoma. Eur J Surg Oncol 31(10):1198–1205PubMedCrossRefGoogle Scholar
  33. 33.
    D’Angelo SP, Shoushtari AN, Agaram NP et al (2015) Prevalence of tumor-infiltrating lymphocytes and PD-L1 expression in the soft tissue sarcoma microenvironment. Hum Pathol 46(3):357–365PubMedCrossRefGoogle Scholar
  34. 34.
    Berghuis D, Santos SJ, Baelde HJ et al (2011) Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression. J Pathol 223(3):347–357PubMedCrossRefGoogle Scholar
  35. 35.
    Sorbye SW, Kilvaer T, Valkov A et al (2011) Prognostic impact of lymphocytes in soft tissue sarcomas. PLoS One 6(1):e14611PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Tseng WW, Demicco EG, Lazar AJ et al (2012) Lymphocyte composition and distribution in inflammatory, well-differentiated retroperitoneal liposarcoma: clues to a potential adaptive immune response and therapeutic implications. Am J Surg Pathol 36(6):941–944PubMedCrossRefGoogle Scholar
  37. 37.
    Blees A, Januliene D, Hofmann T et al (2017) Structure of the human MHC-I peptideloading complex. Nature 551(7681):525–528PubMedGoogle Scholar
  38. 38.
    Berghuis D, de Hooge AS, Santos SJ et al (2009) Reduced human leukocyte antigen expression in advanced-stage Ewing sarcoma: implications for immune recognition. J Pathol 218(2):222–231PubMedCrossRefGoogle Scholar
  39. 39.
    Garcia-Lora A, Martinez M, Algarra I et al (2003) MHC class I-deficient metastatic tumor variants immunoselected by T lymphocytes originate from the coordinated downregulation of APM components. Int J Cancer 106(4):521–527PubMedCrossRefGoogle Scholar
  40. 40.
    Dunn GP, Bruce AT, Ikeda H et al (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998PubMedCrossRefGoogle Scholar
  41. 41.
    Leone P, Shin EC, Perosa F et al (2013) MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J Natl Cancer Inst 105(16):1172–1187PubMedCrossRefGoogle Scholar
  42. 42.
    Bukur J, Jasinski S, Seliger B (2012) The role of classical and non-classical HLA class I antigens in human tumors. Semin Cancer Biol 22(4):350–358PubMedCrossRefGoogle Scholar
  43. 43.
    del Campo AB, Carretero J, Aptsiauri N, Garrido F (2012) Targeting HLA class I expression to increase tumor immunogenicity. Tissue Antigens 79(3):147–154PubMedCrossRefGoogle Scholar
  44. 44.
    Seliger B, Ritz U, Ferrone S (2006) Molecular mechanisms of HLA class I antigen abnormalities following viral infection and transformation. Int J Cancer 118(1):129–138PubMedCrossRefGoogle Scholar
  45. 45.
    Heemels MT, Ploegh H (1995) Generation, translocation, and presentation of MHC class I-restricted peptides. Annu Rev Biochem 64:463–491PubMedCrossRefGoogle Scholar
  46. 46.
    Ortmann B, Copeman J, Lehner PJ et al (1997) A critical role for tapasin in the assembly and function of multimeric MHC class I-TAP complexes. Science 277(5330):1306–1309PubMedCrossRefGoogle Scholar
  47. 47.
    Lehner PJ, Surman MJ, Cresswell P (1998) Soluble tapasin restores MHC class I expression and function in the tapasin-negative cell line .220. Immunity 8(2):221–231PubMedCrossRefGoogle Scholar
  48. 48.
    Pamer E, Cresswell P (1998) Mechanisms of MHC class I–restricted antigen processing. Annu Rev Immunol 16:323–358PubMedCrossRefGoogle Scholar
  49. 49.
    Peh CA, Burrows SR, Barnden M et al (1998) HLA-B27-restricted antigen presentation in the absence of tapasin reveals polymorphism in mechanisms of HLA class I peptide loading. Immunity 8(5):531–542PubMedCrossRefGoogle Scholar
  50. 50.
    Barnden MJ, Purcell AW, Gorman JJ, McCluskey J (2000) Tapasin-mediated retention and optimization of peptide ligands during the assembly of class I molecules. J Immunol 165(1):322–330PubMedCrossRefGoogle Scholar
  51. 51.
    Garbi N, Tan P, Diehl AD et al (2000) Impaired immune responses and altered peptide repertoire in tapasin-deficient mice. Nat Immunol 1(3):234–238PubMedCrossRefGoogle Scholar
  52. 52.
    Grandea AG 3rd, Golovina TN, Hamilton SE et al (2000) Impaired assembly yet normal trafficking of MHC class I molecules in tapasin mutant mice. Immunity 13(2):213–222PubMedCrossRefGoogle Scholar
  53. 53.
    Purcell AW, Gorman JJ, Garcia-Peydro M et al (2001) Quantitative and qualitative influences of tapasin on the class I peptide repertoire. J Immunol 166(2):1016–1027PubMedCrossRefGoogle Scholar
  54. 54.
    Ogino T, Bandoh N, Hayashi T et al (2003) Association of tapasin and HLA class I antigen down-regulation in primary maxillary sinus squamous cell carcinoma lesions with reduced survival of patients. Clin Cancer Res 9(11):4043–4051PubMedGoogle Scholar
  55. 55.
    Anichini A, Mortarini R, Nonaka D et al (2006) Association of antigen-processing machinery and HLA antigen phenotype of melanoma cells with survival in American Joint Committee on Cancer stage III and IV melanoma patients. Cancer Res 66(12):6405–6411PubMedCrossRefGoogle Scholar
  56. 56.
    Liu Y, Komohara Y, Domenick N et al (2012) Expression of antigen processing and presenting molecules in brain metastasis of breast cancer. Cancer Immunol Immunother 61(6):789–801PubMedCrossRefGoogle Scholar
  57. 57.
    Seliger B (2008) Molecular mechanisms of MHC class I abnormalities and APM components in human tumors. Cancer Immunol Immunother 57(11):1719–1726PubMedCrossRefGoogle Scholar
  58. 58.
    Ogino T, Shigyo H, Ishii H et al (2006) HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 66(18):9281–9289PubMedCrossRefGoogle Scholar
  59. 59.
    Campoli M, Chang CC, Ferrone S (2002) HLA class I antigen loss, tumor immune escape and immune selection. Vaccine 20(Suppl 4):A40–A45PubMedCrossRefGoogle Scholar
  60. 60.
    Seliger B, Cabrera T, Garrido F, Ferrone S (2002) HLA class I antigen abnormalities and immune escape by malignant cells. Semin Cancer Biol 12(1):3–13PubMedCrossRefGoogle Scholar
  61. 61.
    Chang CC, Campoli M, Ferrone S (2003) HLA class I defects in malignant lesions: what have we learned? Keio J Med 52(4):220–229PubMedCrossRefGoogle Scholar
  62. 62.
    Atkins D, Ferrone S, Schmahl GE et al (2004) Down-regulation of HLA class I antigen processing molecules: an immune escape mechanism of renal cell carcinoma? J Urol 171(2 Pt 1):885–889PubMedCrossRefGoogle Scholar
  63. 63.
    Campoli M, Chang CC, Oldford SA et al (2004) HLA antigen changes in malignant tumors of mammary epithelial origin: molecular mechanisms and clinical implications. Breast Dis 20:105–125PubMedCrossRefGoogle Scholar
  64. 64.
    Facoetti A, Nano R, Zelini P et al (2005) Human leukocyte antigen and antigen processing machinery component defects in astrocytic tumors. Clin Cancer Res 11(23):8304–8311PubMedCrossRefGoogle Scholar
  65. 65.
    Ferris RL, Hunt JL, Ferrone S (2005) Human leukocyte antigen (HLA) class I defects in head and neck cancer: molecular mechanisms and clinical significance. Immunol Res 33(2):113–133PubMedCrossRefGoogle Scholar
  66. 66.
    Kloor M, Becker C, Benner A et al (2005) Immunoselective pressure and human leukocyte antigen class I antigen machinery defects in microsatellite unstable colorectal cancers. Cancer Res 65(14):6418–6424PubMedCrossRefGoogle Scholar
  67. 67.
    Meissner M, Reichert TE, Kunkel M et al (2005) Defects in the human leukocyte antigen class I antigen processing machinery in head and neck squamous cell carcinoma: association with clinical outcome. Clin Cancer Res 11(7):2552–2560PubMedCrossRefGoogle Scholar
  68. 68.
    Raffaghello L, Prigione I, Bocca P et al (2005) Multiple defects of the antigen-processing machinery components in human neuroblastoma: immunotherapeutic implications. Oncogene 24(29):4634–4644PubMedCrossRefGoogle Scholar
  69. 69.
    Vitale M, Pelusi G, Taroni B et al (2005) HLA class I antigen down-regulation in primary ovary carcinoma lesions: association with disease stage. Clin Cancer Res 11(1):67–72PubMedGoogle Scholar
  70. 70.
    Bangia N, Ferrone S (2006) Antigen presentation machinery (APM) modulation and soluble HLA molecules in the tumor microenvironment: do they provide tumor cells with escape mechanisms from recognition by cytotoxic T lymphocytes? Immunol Invest 35(3– 4):485–503PubMedCrossRefGoogle Scholar
  71. 71.
    Chang CC, Ogino T, Mullins DW et al (2006) Defective human leukocyte antigen class I-associated antigen presentation caused by a novel beta2-microglobulin loss-of-function in melanoma cells. J Biol Chem 281(27):18763–18773PubMedCrossRefGoogle Scholar
  72. 72.
    Ferris RL, Whiteside TL, Ferrone S (2006) Immune escape associated with functional defects in antigen-processing machinery in head and neck cancer. Clin Cancer Res 12(13):3890–3895PubMedCrossRefGoogle Scholar
  73. 73.
    López-Albaitero A, Nayak JV, Ogino T et al (2006) Role of antigen-processing machinery in the in vitro resistance of squamous cell carcinoma of the head and neck cells to recognition by CTL. J Immunol 176(6):3402–3409PubMedCrossRefGoogle Scholar
  74. 74.
    Chang CC, Ferrone S (2007) Immune selective pressure and HLA class I antigen defects in malignant lesions. Cancer Immunol Immunother 56(2):227–236PubMedCrossRefGoogle Scholar
  75. 75.
    Seliger B, Stoehr R, Handke D et al (2010) Association of HLA class I antigen abnormalities with disease progression and early recurrence in prostate cancer. Cancer Immunol Immunother 59(4):529–540PubMedCrossRefGoogle Scholar
  76. 76.
    Campoli M, Ferrone S (2008) HLA antigen changes in malignant cells: epigenetic mechanisms and biologic significance. Oncogene 27(45):5869–5885PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    del Campo AB, Kyte JA, Carretero J et al (2014) Immune escape of cancer cells with beta2-microglobulin loss over the course of metastatic melanoma. Int J Cancer 134(1):102–113PubMedCrossRefGoogle Scholar
  78. 78.
    Fairweather M, Gonzalez RJ, Strauss D, Raut CP (2018) Current principles of surgery for retroperitoneal sarcomas. J Surg Oncol 117(1):33–41PubMedCrossRefGoogle Scholar
  79. 79.
    Segal NH, Blachere NE, Guevara-Patiño JA et al (2005) Identification of cancer-testis genes expressed by melanoma and soft tissue sarcoma using bioinformatics. Cancer Immun 5(1):2PubMedGoogle Scholar
  80. 80.
    Roszik J, Wang WL, Livingston JA et al (2017) Overexpressed PRAME is a potential immunotherapy target in sarcoma subtypes. Clin Sarcoma Res 7:11PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Pollack SM, Ingham M, Spraker MB, Schwartz GK (2018) Emerging targeted and immune-based therapies in sarcoma. J Clin Oncol 36(2):125–135PubMedCrossRefGoogle Scholar
  82. 82.
    Salmaninejad A, Zamani MR, Pourvahedi M et al (2016) Cancer/testis antigens: expression, regulation, tumor invasion, and use in immunotherapy of cancers. Immunol Invest 45(7):619–640PubMedCrossRefGoogle Scholar
  83. 83.
    Chiriva-Internati M, Grizzi F, Bright RK, Martin Kast W (2004) Cancer immunotherapy: avoiding the road to perdition. J Transl Med 2(1):26PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Iura K, Maekawa A, Kohashi K et al (2017) Cancer-testis antigen expression in synovial sarcoma: NY-ESO-1, PRAME, MAGEA4, and MAGEA1. Hum Pathol 61:130–139PubMedCrossRefGoogle Scholar
  85. 85.
    Iura K, Kohashi K, Hotokebuchi Y et al (2015) Cancer-testis antigens PRAME and NY-ESO-1 correlate with tumour grade and poor prognosis in myxoid liposarcoma. J Pathol Clin Res 1(3):144–159PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Iura K, Kohashi K, Ishii T et al (2017) MAGEA4 expression in bone and soft tissue tumors: its utility as a target for immunotherapy and diagnostic marker combined with NY-ESO-1. Virchows Arch 471(3):383–392PubMedCrossRefGoogle Scholar
  87. 87.
    Groisberg R, Hong DS, Behrang A et al (2017) Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials. J Immunother Cancer 5(1):100PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Zheng B, Ren T, Huang Y, Guo W (2018) Apatinib inhibits migration and invasion as well as PD-L1 expression in osteosarcoma by targeting STAT3. Biochem Biophys Res Commun 495(2):1695–1701PubMedCrossRefGoogle Scholar
  89. 89.
    Machado I, López-Guerrero JA, Scotlandi K et al (2018) Immunohistochemical analysis and prognostic significance of PD-L1, PD-1, and CD8+ tumor-infiltrating lymphocytes in Ewing’s sarcoma family of tumors (ESFT). Virchows Arch 472(5):815–824PubMedCrossRefGoogle Scholar
  90. 90.
    Boxberg M, Steiger K, Lenze U et al (2018) PD-L1 and PD-1 and characterization of tumorinfiltrating lymphocytes in high grade sarcomas of soft tissue — prognostic implications and rationale for immunotherapy. Oncoimmunology 7(3):e1389366PubMedCrossRefGoogle Scholar
  91. 91.
    Zhu Z, Jin Z, Zhang M et al (2017) Prognostic value of programmed death-ligand 1 in sarcoma: a meta-analysis. Oncotarget 8(35):59570–59580PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag Italia 2019

Authors and Affiliations

  • Fabio Grizzi
    • 1
    Email author
  • Elena Monica Borroni
  • Dorina Qehajaj
  • Sanja Stifter
  • Maurizio Chiriva-Internati
  • Ferdinando C. M. Cananzi
  1. 1.Department of Immunology and InflammationHumanitas Clinical and Research CenterRozzano, MilanItaly

Personalised recommendations