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Thymic Tumors and Lymphomas: The Clinical Impact of Their Underlying Molecular Features

  • Francesca Pentimalli
  • Daniela Barone
  • Antonio Giordano
Chapter
Part of the Current Clinical Pathology book series (CCPATH)

Abstract

Although rare, mediastinal tumors often present a challenge for both the physicians and the pathologists. Here we focus on the molecular features underlying thymic tumors and lymphomas, which are the most common malignancies occurring in the anterior compartment of the mediastinum. We discuss both established and recently discovered molecular alterations that can overall serve as diagnostic, prognostic, and predictive factors or possibly as targets for therapeutic intervention.

Keywords

Thymic epithelial tumors Thymomas Thymic carcinoma Lymphoma Diffuse large B-cell lymphoma (DLBCL) Primary mediastinal large B-cell lymphoma (PMLBCL) Classical Hodgkin lymphoma (cHL) Mediastinal gray zone lymphoma (MGZL) 

References

  1. 1.
    Shields TW. General thoracic surgery. 1st ed. Philadelphis, PA: Lea and Febiger; 1972.Google Scholar
  2. 2.
    Liu W, Deslauriers J. Mediastinal divisions and compartments. Thorac Surg Clin. 2011;21(2):183–90, viii.PubMedCrossRefPubMedCentralGoogle Scholar
  3. 3.
    Carter BW, Tomiyama N, Bhora FY, Rosado de Christenson ML, Nakajima J, Boiselle PM, et al. A modern definition of mediastinal compartments. J Thorac Oncol. 2014;9(9 Suppl 2):S97–101.PubMedCrossRefPubMedCentralGoogle Scholar
  4. 4.
    Carter BW, Benveniste MF, Madan R, Godoy MC, de Groot PM, Truong MT, et al. ITMIG classification of mediastinal compartments and multidisciplinary approach to mediastinal masses. Radiographics. 2017;37(2):413–36.PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Duwe BV, Sterman DH, Musani AI. Tumors of the mediastinum. Chest. 2005;128(4):2893–909.PubMedCrossRefPubMedCentralGoogle Scholar
  6. 6.
    Carter BW, Okumura M, Detterbeck FC, Marom EM. Approaching the patient with an anterior mediastinal mass: a guide for radiologists. J Thorac Oncol. 2014;9(9 Suppl 2):S110–8.PubMedCrossRefPubMedCentralGoogle Scholar
  7. 7.
    Carter BW, Marom EM, Detterbeck FC. Approaching the patient with an anterior mediastinal mass: a guide for clinicians. J Thorac Oncol. 2014;9(9 Suppl 2):S102–9.PubMedCrossRefPubMedCentralGoogle Scholar
  8. 8.
    Azizad S, Sannananja B, Restrepo CS. Solid tumors of the mediastinum in adults. Semin Ultrasound CT MR. 2016;37(3):196–211.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    den Bakker MA, Marx A, Mukai K, Strobel P. Mesenchymal tumours of the mediastinum—part I. Virchows Arch. 2015;467(5):487–500.CrossRefGoogle Scholar
  10. 10.
    Travis WD, Brambilla E, Muller-Hermelink HK, Harris CC. Pathology and genetics of tumours of the lung, pleura, thymus and heart. Lyon, France: IARC Press; 2004.Google Scholar
  11. 11.
    Engels EA. Epidemiology of thymoma and associated malignancies. J Thorac Oncol. 2010;5(10 Suppl 4):S260–5.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Scorsetti M, Leo F, Trama A, D’Angelillo R, Serpico D, Macerelli M, et al. Thymoma and thymic carcinomas. Crit Rev Oncol Hematol. 2016;99:332–50.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG. WHO classification of tumours of the lung, pleura, thymus and heart. 4th ed. Lyon, France: IARC Press; 2015.Google Scholar
  14. 14.
    Marx A, Chan JK, Coindre JM, Detterbeck F, Girard N, Harris NL, et al. The 2015 World Health Organization classification of tumors of the thymus: continuity and changes. J Thorac Oncol. 2015;10(10):1383–95.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Leisibach P, Schneiter D, Soltermann A, Yamada Y, Weder W, Jungraithmayr W. Prognostic value of immunohistochemical markers in malignant thymic epithelial tumors. J Thorac Dis. 2016;8(9):2580–91.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Tseng YL. Thymic carcinoma: a rare cancer requiring special attention. Formos J Surg. 2011;44(4):136–40.CrossRefGoogle Scholar
  17. 17.
    Kubonishi I, Takehara N, Iwata J, Sonobe H, Ohtsuki Y, Abe T, et al. Novel t(15;19)(q15;p13) chromosome abnormality in a thymic carcinoma. Cancer Res. 1991;51(12):3327–8.PubMedPubMedCentralGoogle Scholar
  18. 18.
    Lamarca A, Moreno V, Feliu J. Thymoma and thymic carcinoma in the target therapies era. Cancer Treat Rev. 2013;39(5):413–20.PubMedCrossRefPubMedCentralGoogle Scholar
  19. 19.
    Strobel P, Hohenberger P, Marx A. Thymoma and thymic carcinoma: molecular pathology and targeted therapy. J Thorac Oncol. 2010;5(10 Suppl 4):S286–90.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Inoue M, Starostik P, Zettl A, Strobel P, Schwarz S, Scaravilli F, et al. Correlating genetic aberrations with World Health Organization-defined histology and stage across the spectrum of thymomas. Cancer Res. 2003;63(13):3708–15.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Penzel R, Hoegel J, Schmitz W, Blaeker H, Morresi-Hauf A, Aulmann S, et al. Clusters of chromosomal imbalances in thymic epithelial tumours are associated with the WHO classification and the staging system according to Masaoka. Int J Cancer. 2003;105(4):494–8.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Inoue M, Marx A, Zettl A, Strobel P, Muller-Hermelink HK, Starostik P. Chromosome 6 suffers frequent and multiple aberrations in thymoma. Am J Pathol. 2002;161(4):1507–13.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Petrini I, Wang Y, Zucali PA, Lee HS, Pham T, Voeller D, et al. Copy number aberrations of genes regulating normal thymus development in thymic epithelial tumors. Clin Cancer Res. 2013;19(8):1960–71.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Petrini I, Meltzer PS, Zucali PA, Luo J, Lee C, Santoro A, et al. Copy number aberrations of BCL2 and CDKN2A/B identified by array-CGH in thymic epithelial tumors. Cell Death Dis. 2012;3:e351.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Pentimalli F. BCL2: a 30-year tale of life, death and much more to come. Cell Death Differ. 2018;25(1):7–9.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Petrini I, Meltzer PS, Kim IK, Lucchi M, Park KS, Fontanini G, et al. A specific missense mutation in GTF2I occurs at high frequency in thymic epithelial tumors. Nat Genet. 2014;46(8):844–9.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Gene mutation may signal indolent thymus cancer. Cancer Discov. 2014;4(9):OF4.Google Scholar
  28. 28.
    Kelly RJ, Petrini I, Rajan A, Wang Y, Giaccone G. Thymic malignancies: from clinical management to targeted therapies. J Clin Oncol. 2011;29(36):4820–7.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Scarpino S, Di Napoli A, Stoppacciaro A, Antonelli M, Pilozzi E, Chiarle R, et al. Expression of autoimmune regulator gene (AIRE) and T regulatory cells in human thymomas. Clin Exp Immunol. 2007;149(3):504–12.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Ionescu DN, Sasatomi E, Cieply K, Nola M, Dacic S. Protein expression and gene amplification of epidermal growth factor receptor in thymomas. Cancer. 2005;103(3):630–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Pan CC, Chen PC, Wang LS, Lee JY, Chiang H. Expression of apoptosis-related markers and HER-2/neu in thymic epithelial tumours. Histopathology. 2003;43(2):165–72.PubMedCrossRefGoogle Scholar
  32. 32.
    Weissferdt A, Lin H, Woods D, Tang X, Fujimoto J, Wistuba II, et al. HER family receptor and ligand status in thymic carcinoma. Lung Cancer. 2012;77(3):515–21.PubMedCrossRefGoogle Scholar
  33. 33.
    Rajan A, Girard N, Marx A. State of the art of genetic alterations in thymic epithelial tumors. J Thorac Oncol. 2014;9(9 Suppl 2):S131–6.PubMedCrossRefGoogle Scholar
  34. 34.
    Tiseo M, Damato A, Longo L, Barbieri F, Bertolini F, Stefani A, et al. Analysis of a panel of druggable gene mutations and of ALK and PD-L1 expression in a series of thymic epithelial tumors (TETs). Lung Cancer. 2017;104:24–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Merveilleux du Vignaux C, Maury JM, Girard N. Novel agents in the treatment of thymic malignancies. Curr Treat Options in Oncol. 2017;18(9):52.CrossRefGoogle Scholar
  36. 36.
    Zucali PA, Petrini I, Lorenzi E, Merino M, Cao L, Di Tommaso L, et al. Insulin-like growth factor-1 receptor and phosphorylated AKT-serine 473 expression in 132 resected thymomas and thymic carcinomas. Cancer. 2010;116(20):4686–95.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Girard N, Teruya-Feldstein J, Payabyab EC, Riely GJ, Rusch VW, Kris MG, et al. Insulin-like growth factor-1 receptor expression in thymic malignancies. J Thorac Oncol. 2010;5(9):1439–46.PubMedCrossRefGoogle Scholar
  38. 38.
    Mimae T, Tsuta K, Kondo T, Nitta H, Grogan TM, Okada M, et al. Protein expression and gene copy number changes of receptor tyrosine kinase in thymomas and thymic carcinomas. Ann Oncol. 2012;23(12):3129–37.PubMedCrossRefGoogle Scholar
  39. 39.
    Omatsu M, Kunimura T, Mikogami T, Hamatani S, Shiokawa A, Masunaga A, et al. Immunohistochemical analysis of thymic carcinoma focusing on the possibility of molecular targeted and hormonal therapies. Gen Thorac Cardiovasc Surg. 2012;60(12):803–10.PubMedCrossRefGoogle Scholar
  40. 40.
    Kim DJ, Yang WI, Kim SH, Park IK, Chung KY. Expression of neurotrophin receptors in surgically resected thymic epithelial tumors. Eur J Cardiothorac Surg. 2005;28(4):611–6.PubMedCrossRefGoogle Scholar
  41. 41.
    Pfister F, Hussain H, Belharazem D, Busch S, Simon-Keller K, Becker D, et al. Vascular architecture as a diagnostic marker for differentiation of World Health Organization thymoma subtypes and thymic carcinoma. Histopathology. 2017;70(5):693–703.PubMedCrossRefGoogle Scholar
  42. 42.
    Lattanzio R, La Sorda R, Facciolo F, Sioletic S, Lauriola L, Martucci R, et al. Thymic epithelial tumors express vascular endothelial growth factors and their receptors as potential targets of antiangiogenic therapy: a tissue micro array-based multicenter study. Lung Cancer. 2014;85(2):191–6.PubMedCrossRefGoogle Scholar
  43. 43.
    Sasaki H, Yukiue H, Kobayashi Y, Nakashima Y, Moriyama S, Kaji M, et al. Elevated serum vascular endothelial growth factor and basic fibroblast growth factor levels in patients with thymic epithelial neoplasms. Surg Today. 2001;31(11):1038–40.PubMedCrossRefGoogle Scholar
  44. 44.
    Berardi R, Brunelli A, Pagliaretta S, Paolucci V, Conti A, Goteri G, et al. Impact of VEGF, VEGFR, PDGFR, HIF and ERCC1 gene polymorphisms on thymic malignancies outcome after thymectomy. Oncotarget. 2015;6(22):19305–15.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Wang Y, Thomas A, Lau C, Rajan A, Zhu Y, Killian JK, et al. Mutations of epigenetic regulatory genes are common in thymic carcinomas. Sci Rep. 2014;4:7336.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Saito M, Fujiwara Y, Asao T, Honda T, Shimada Y, Kanai Y, et al. The genomic and epigenomic landscape in thymic carcinoma. Carcinogenesis. 2017;38(11):1084–91.PubMedCrossRefGoogle Scholar
  47. 47.
    Radovich M, Solzak JP, Hancock BA, Conces ML, Atale R, Porter RF, et al. A large microRNA cluster on chromosome 19 is a transcriptional hallmark of WHO type A and AB thymomas. Br J Cancer. 2016;114(4):477–84.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Bellissimo T, Russo E, Ganci F, Vico C, Sacconi A, Longo F, et al. Circulating miR-21-5p and miR-148a-3p as emerging non-invasive biomarkers in thymic epithelial tumors. Cancer Biol Ther. 2016;17(1):79–82.PubMedCrossRefGoogle Scholar
  49. 49.
    Bellissimo T, Ganci F, Gallo E, Sacconi A, Tito C, De Angelis L, et al. Thymic Epithelial Tumors phenotype relies on miR-145-5p epigenetic regulation. Mol Cancer. 2017;16(1):88.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Mokhtar M, Kondo K, Namura T, Ali AH, Fujita Y, Takai C, et al. Methylation and expression profiles of MGMT gene in thymic epithelial tumors. Lung Cancer. 2014;83(2):279–87.PubMedCrossRefGoogle Scholar
  51. 51.
    Lee HS, Jang HJ, Shah R, Yoon D, Hamaji M, Wald O, et al. Genomic analysis of thymic epithelial tumors identifies novel subtypes associated with distinct clinical features. Clin Cancer Res. 2017;23(16):4855–64.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Radovich M, Pickering CR, Felau I, Ha G, Zhang H, Jo H, et al. The integrated genomic landscape of thymic epithelial tumors. Cancer Cell. 2018;33(2):244–58.e10.PubMedCrossRefGoogle Scholar
  53. 53.
    Badve S, Goswami C, Gokmen-Polar Y, Nelson RP, Jr., Henley J, Miller N, et al. Molecular analysis of thymoma. PLoS One 2012;7(8):e42669.Google Scholar
  54. 54.
    Gokmen-Polar Y, Cook RW, Goswami CP, Wilkinson J, Maetzold D, Stone JF, et al. A gene signature to determine metastatic behavior in thymomas. PLoS One. 2013;8(7):e66047.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Mineo TC, Mineo D, Onorati I, Cufari ME, Ambrogi V. New predictors of response to neoadjuvant chemotherapy and survival for invasive thymoma: a retrospective analysis. Ann Surg Oncol. 2010;17(11):3022–9.PubMedCrossRefGoogle Scholar
  56. 56.
    Strollo DC, Rosado-de-Christenson ML, Jett JR. Primary mediastinal tumors: part II. Tumors of the middle and posterior mediastinum. Chest. 1997;112(5):1344–57.PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Mey U, Hitz F, Lohri A, Pederiva S, Taverna C, Tzankov A, et al. Diagnosis and treatment of diffuse large B-cell lymphoma. Swiss Med Wkly. 2012;142:w13511.PubMedGoogle Scholar
  58. 58.
    Martelli M, Ferreri AJ, Agostinelli C, Di Rocco A, Pfreundschuh M, Pileri SA. Diffuse large B-cell lymphoma. Crit Rev Oncol Hematol. 2013;87(2):146–71.PubMedCrossRefGoogle Scholar
  59. 59.
    Weisenburger DD. Environmental epidemiology of non-Hodgkin’s lymphoma in eastern Nebraska. Am J Ind Med. 1990;18(3):303–5.PubMedCrossRefGoogle Scholar
  60. 60.
    Swerdlow S, Campo E, Harris N, Jaffe E, Pileri S, Stein H, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon, France: IARC Press; 2008.Google Scholar
  61. 61.
    De Vita S, Sacco C, Sansonno D, Gloghini A, Dammacco F, Crovatto M, et al. Characterization of overt B-cell lymphomas in patients with hepatitis C virus infection. Blood. 1997;90(2):776–82.PubMedGoogle Scholar
  62. 62.
    Luppi M, Longo G, Ferrari MG, Barozzi P, Marasca R, Morselli M, et al. Clinico-pathological characterization of hepatitis C virus-related B-cell non-Hodgkin’s lymphomas without symptomatic cryoglobulinemia. Ann Oncol. 1998;9(5):495–8.PubMedCrossRefGoogle Scholar
  63. 63.
    Abrams DI, Kaplan LD, McGrath MS, Volberding PA. AIDS-related benign lymphadenopathy and malignant lymphoma: clinical aspects and virologic interactions. AIDS Res. 1986;2(Suppl 1):S131–40.PubMedGoogle Scholar
  64. 64.
    Gloghini A, Dolcetti R, Carbone A. Lymphomas occurring specifically in HIV-infected patients: from pathogenesis to pathology. Semin Cancer Biol. 2013;23(6:457–67.CrossRefGoogle Scholar
  65. 65.
    Wang F, Xu RH, Han B, Shi YX, Luo HY, Jiang WQ, et al. High incidence of hepatitis B virus infection in B-cell subtype non-Hodgkin lymphoma compared with other cancers. Cancer. 2007;109(7):1360–4.PubMedCrossRefGoogle Scholar
  66. 66.
    Deng L, Song Y, Young KH, Hu S, Ding N, Song W, et al. Hepatitis B virus-associated diffuse large B-cell lymphoma: unique clinical features, poor outcome, and hepatitis B surface antigen-driven origin. Oncotarget. 2015;6(28):25061–73.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Castillo JJ, Beltran BE, Miranda RN, Paydas S, Winer ES, Butera JN. Epstein-barr virus-positive diffuse large B-cell lymphoma of the elderly: what we know so far. Oncologist. 2011;16(1):87–96.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Oyama T, Ichimura K, Suzuki R, Suzumiya J, Ohshima K, Yatabe Y, et al. Senile EBV+ B-cell lymphoproliferative disorders: a clinicopathologic study of 22 patients. Am J Surg Pathol. 2003;27(1):16–26.PubMedCrossRefGoogle Scholar
  69. 69.
    Carbone PP, Kaplan HS, Musshoff K, Smithers DW, Tubiana M. Report of the committee on Hodgkin’s disease staging classification. Cancer Res. 1971;31(11):1860–1.PubMedPubMedCentralGoogle Scholar
  70. 70.
    Lister TA, Crowther D, Sutcliffe SB, Glatstein E, Canellos GP, Young RC, et al. Report of a committee convened to discuss the evaluation and staging of patients with Hodgkin’s disease: cotswolds meeting. J Clin Oncol. 1989;7(11):1630–6.PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Betancourt-Garcia RD, Garcia-Pallas MV, Pacheco E, Castro J, Cabanillas F. Diffuse large-cell lymphoma. Part I: clinical features, histology and prognosis. P R Health Sci J. 2009;28(1):5–11.PubMedPubMedCentralGoogle Scholar
  72. 72.
    Caimi PF, Hill BT, Hsi ED, Smith MR. Clinical approach to diffuse large B cell lymphoma. Blood Rev. 2016;30(6):477–91.PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Sehn LH, Berry B, Chhanabhai M, Fitzgerald C, Gill K, Hoskins P, et al. The revised International Prognostic Index (R-IPI) is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R-CHOP. Blood. 2007;109(5):1857–61.PubMedCrossRefPubMedCentralGoogle Scholar
  74. 74.
    Lichtenstein AK, Levine A, Taylor CR, Boswell W, Rossman S, Feinstein DI, et al. Primary mediastinal lymphoma in adults. Am J Med. 1980;68(4):509–14.PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Harris NL, Jaffe ES, Stein H, Banks PM, Chan JK, Cleary ML, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361–92.PubMedPubMedCentralGoogle Scholar
  76. 76.
    Bhatt VR, Mourya R, Shrestha R, Armitage JO. Primary mediastinal large B-cell lymphoma. Cancer Treat Rev. 2015;41(6):476–85.PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Steidl C, Gascoyne RD. The molecular pathogenesis of primary mediastinal large B-cell lymphoma. Blood. 2011;118(10):2659–69.PubMedCrossRefGoogle Scholar
  78. 78.
    Oschlies I, Burkhardt B, Salaverria I, Rosenwald A, d’Amore ES, Szczepanowski M, et al. Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica. 2011;96(2):262–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Martelli M, Ferreri AJ, Johnson P. Primary mediastinal large B-cell lymphoma. Crit Rev Oncol Hematol. 2008;68(3):256–63.PubMedCrossRefGoogle Scholar
  80. 80.
    Punnett A, Tsang RW, Hodgson DC. Hodgkin lymphoma across the age spectrum: epidemiology, therapy, and late effects. Semin Radiat Oncol. 2010;20(1):30–44.PubMedCrossRefPubMedCentralGoogle Scholar
  81. 81.
    Gobbi PG, Ferreri AJ, Ponzoni M, Levis A. Hodgkin lymphoma. Crit Rev Oncol Hematol. 2013;85(2):216–37.PubMedCrossRefPubMedCentralGoogle Scholar
  82. 82.
    Hjalgrim H, Engels EA. Infectious aetiology of Hodgkin and non-Hodgkin lymphomas: a review of the epidemiological evidence. J Intern Med. 2008;264(6):537–48.PubMedCrossRefPubMedCentralGoogle Scholar
  83. 83.
    Herbst H, Pallesen G, Weiss LM, Delsol G, Jarrett RF, Steinbrecher E, et al. Hodgkin’s disease and Epstein-Barr virus. Ann Oncol. 1992;3(Suppl 4):27–30.PubMedCrossRefPubMedCentralGoogle Scholar
  84. 84.
    Armstrong AA, Alexander FE, Paes RP, Morad NA, Gallagher A, Krajewski AS, et al. Association of Epstein-Barr virus with pediatric Hodgkin’s disease. Am J Pathol. 1993;142(6):1683–8.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Brown JR, Neuberg D, Phillips K, Reynolds H, Silverstein J, Clark JC, et al. Prevalence of familial malignancy in a prospectively screened cohort of patients with lymphoproliferative disorders. Br J Haematol. 2008;143(3):361–8.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Townsend W, Linch D. Hodgkin’s lymphoma in adults. Lancet. 2012;380(9844):836–47.PubMedCrossRefPubMedCentralGoogle Scholar
  87. 87.
    Ansell SM. Hodgkin lymphoma: 2016 update on diagnosis, risk-stratification, and management. Am J Hematol. 2016;91(4):434–42.PubMedCrossRefPubMedCentralGoogle Scholar
  88. 88.
    Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International prognostic factors project on advanced Hodgkin’s disease. N Engl J Med. 1998;339(21):1506–14.PubMedCrossRefPubMedCentralGoogle Scholar
  89. 89.
    Campo E, Swerdlow SH, Harris NL, Pileri S, Stein H, Jaffe ES. The 2008 WHO classification of lymphoid neoplasms and beyond: evolving concepts and practical applications. Blood. 2011;117(19):5019–32.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Grant C, Dunleavy K, Eberle FC, Pittaluga S, Wilson WH, Jaffe ES. Primary mediastinal large B-cell lymphoma, classic Hodgkin lymphoma presenting in the mediastinum, and mediastinal gray zone lymphoma: what is the oncologist to do? Curr Hematol Malig Rep. 2011;6(3):157–63.PubMedCrossRefPubMedCentralGoogle Scholar
  91. 91.
    Dunleavy K, Grant C, Eberle FC, Pittaluga S, Jaffe ES, Wilson WH. Gray zone lymphoma: better treated like hodgkin lymphoma or mediastinal large B-cell lymphoma? Curr Hematol Malig Rep. 2012;7(3):241–7.PubMedCrossRefPubMedCentralGoogle Scholar
  92. 92.
    Wilson WH, Pittaluga S, Nicolae A, Camphausen K, Shovlin M, Steinberg SM, et al. A prospective study of mediastinal gray-zone lymphoma. Blood. 2014;124(10):1563–9.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Sarkozy C, Molina T, Ghesquieres H, Michallet AS, Dupuis J, Damotte D, et al. Mediastinal gray zone lymphoma: clinico-pathological characteristics and outcomes of 99 patients from the Lymphoma Study Association. Haematologica. 2017;102(1):150–9.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Quintanilla-Martinez L, Fend F. Mediastinal gray zone lymphoma. Haematologica. 2011;96:496–9.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Cazals-Hatem D, Andre M, Mounier N, Copin MC, Divine M, Berger F, et al. Pathologic and clinical features of 77 Hodgkin’s lymphoma patients treated in a lymphoma protocol (LNH87): a GELA study. Am J Surg Pathol. 2001;25(3):297–306.PubMedCrossRefPubMedCentralGoogle Scholar
  96. 96.
    Hans CP, Weisenburger DD, Greiner TC, Gascoyne RD, Delabie J, Ott G, et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood. 2004;103(1):275–82.PubMedCrossRefPubMedCentralGoogle Scholar
  97. 97.
    Choi WW, Weisenburger DD, Greiner TC, Piris MA, Banham AH, Delabie J, et al. A new immunostain algorithm classifies diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer Res. 2009;15(17):5494–502.PubMedCrossRefPubMedCentralGoogle Scholar
  98. 98.
    Testoni M, Zucca E, Young KH, Bertoni F. Genetic lesions in diffuse large B-cell lymphomas. Ann Oncol. 2015;26(6):1069–80.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Lo Coco F, Ye BH, Lista F, Corradini P, Offit K, Knowles DM, et al. Rearrangements of the BCL6 gene in diffuse large cell non-Hodgkin’s lymphoma. Blood. 1994;83(7):1757–9.PubMedPubMedCentralGoogle Scholar
  100. 100.
    Ye BH, Chaganti S, Chang CC, Niu H, Corradini P, Chaganti RS, et al. Chromosomal translocations cause deregulated BCL6 expression by promoter substitution in B cell lymphoma. EMBO J. 1995;14(24):6209–17.PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Phan RT, Dalla-Favera R. The BCL6 proto-oncogene suppresses p53 expression in germinal-centre B cells. Nature. 2004;432(7017):635–9.PubMedCrossRefPubMedCentralGoogle Scholar
  102. 102.
    Basso K, Schneider C, Shen Q, Holmes AB, Setty M, Leslie C, et al. BCL6 positively regulates AID and germinal center gene expression via repression of miR-155. J Exp Med. 2012;209(13):2455–65.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Shustik J, Han G, Farinha P, Johnson NA, Ben Neriah S, Connors JM, et al. Correlations between BCL6 rearrangement and outcome in patients with diffuse large B-cell lymphoma treated with CHOP or R-CHOP. Haematologica. 2010;95(1):96–101.PubMedCrossRefPubMedCentralGoogle Scholar
  104. 104.
    Akyurek N, Uner A, Benekli M, Barista I. Prognostic significance of MYC, BCL2, and BCL6 rearrangements in patients with diffuse large B-cell lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab. Cancer. 2012;118(17):4173–83.PubMedCrossRefPubMedCentralGoogle Scholar
  105. 105.
    Copie-Bergman C, Gaulard P, Leroy K, Briere J, Baia M, Jais JP, et al. Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study. J Clin Oncol. 2009;27(33):5573–9.PubMedCrossRefPubMedCentralGoogle Scholar
  106. 106.
    Iqbal J, Sanger WG, Horsman DE, Rosenwald A, Pickering DL, Dave B, et al. BCL2 translocation defines a unique tumor subset within the germinal center B-cell-like diffuse large B-cell lymphoma. Am J Pathol. 2004;165(1):159–66.PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Saito M, Novak U, Piovan E, Basso K, Sumazin P, Schneider C, et al. BCL6 suppression of BCL2 via Miz1 and its disruption in diffuse large B cell lymphoma. Proc Natl Acad Sci U S A. 2009;106(27):11294–9.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Schuetz JM, Johnson NA, Morin RD, Scott DW, Tan K, Ben-Nierah S, et al. BCL2 mutations in diffuse large B-cell lymphoma. Leukemia. 2012;26(6):1383–90.PubMedCrossRefPubMedCentralGoogle Scholar
  109. 109.
    Iqbal J, Meyer PN, Smith LM, Johnson NA, Vose JM, Greiner TC, et al. BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab. Clin Cancer Res. 2011;17(24):7785–95.PubMedCrossRefPubMedCentralGoogle Scholar
  110. 110.
    Visco C, Tzankov A, Xu-Monette ZY, Miranda RN, Tai YC, Li Y, et al. Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study. Haematologica. 2013;98(2):255–63.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Kusumoto S, Kobayashi Y, Sekiguchi N, Tanimoto K, Onishi Y, Yokota Y, et al. Diffuse large B-cell lymphoma with extra Bcl-2 gene signals detected by FISH analysis is associated with a “non-germinal center phenotype”. Am J Surg Pathol. 2005;29(8):1067–73.PubMedPubMedCentralGoogle Scholar
  112. 112.
    Iqbal J, Neppalli VT, Wright G, Dave BJ, Horsman DE, Rosenwald A, et al. BCL2 expression is a prognostic marker for the activated B-cell-like type of diffuse large B-cell lymphoma. J Clin Oncol. 2006;24(6):961–8.PubMedCrossRefPubMedCentralGoogle Scholar
  113. 113.
    Nowakowski GS, Czuczman MS. ABC, GCB, and double-hit diffuse large B-cell lymphoma: does subtype make a difference in therapy selection? Am Soc Clin Oncol Educ Book. 2015:e449–57.Google Scholar
  114. 114.
    Yoon SO, Jeon YK, Paik JH, Kim WY, Kim YA, Kim JE, et al. MYC translocation and an increased copy number predict poor prognosis in adult diffuse large B-cell lymphoma (DLBCL), especially in germinal centre-like B cell (GCB) type. Histopathology. 2008;53(2):205–17.PubMedCrossRefPubMedCentralGoogle Scholar
  115. 115.
    Perry AM, Mitrovic Z, Chan WC. Biological prognostic markers in diffuse large B-cell lymphoma. Cancer Control. 2012;19(3):214–26.PubMedCrossRefPubMedCentralGoogle Scholar
  116. 116.
    Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, et al. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011;117(8):2451–9.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Wigle TJ, Knutson SK, Jin L, Kuntz KW, Pollock RM, Richon VM, et al. The Y641C mutation of EZH2 alters substrate specificity for histone H3 lysine 27 methylation states. FEBS Lett. 2011;585(19):3011–4.PubMedCrossRefPubMedCentralGoogle Scholar
  118. 118.
    Qi W, Chan H, Teng L, Li L, Chuai S, Zhang R, et al. Selective inhibition of Ezh2 by a small molecule inhibitor blocks tumor cells proliferation. Proc Natl Acad Sci U S A. 2012;109(52):21360–5.PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Garapaty-Rao S, Nasveschuk C, Gagnon A, Chan EY, Sandy P, Busby J, et al. Identification of EZH2 and EZH1 small molecule inhibitors with selective impact on diffuse large B cell lymphoma cell growth. Chem Biol. 2013;20(11):1329–39.PubMedCrossRefPubMedCentralGoogle Scholar
  120. 120.
    Song X, Zhang L, Gao T, Ye T, Zhu Y, Lei Q, et al. Selective inhibition of EZH2 by ZLD10A blocks H3K27 methylation and kills mutant lymphoma cells proliferation. Biomed Pharmacother. 2016;81:288–94.PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Honma D, Kanno O, Watanabe J, Kinoshita J, Hirasawa M, Nosaka E, et al. Novel orally bioavailable EZH1/2 dual inhibitors with greater antitumor efficacy than an EZH2 selective inhibitor. Cancer Sci. 2017;108(10):2069–78.PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Pasqualucci L, Dominguez-Sola D, Chiarenza A, Fabbri G, Grunn A, Trifonov V, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471(7337):189–95.PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Chigrinova E, Mian M, Shen Y, Greiner TC, Chan WC, Vose JM, et al. Integrated profiling of diffuse large B-cell lymphoma with 7q gain. Br J Haematol. 2011;153(4):499–503.PubMedCrossRefPubMedCentralGoogle Scholar
  124. 124.
    Jardin F, Jais JP, Molina TJ, Parmentier F, Picquenot JM, Ruminy P, et al. Diffuse large B-cell lymphomas with CDKN2A deletion have a distinct gene expression signature and a poor prognosis under R-CHOP treatment: a GELA study. Blood. 2010;116(7):1092–104.PubMedCrossRefPubMedCentralGoogle Scholar
  125. 125.
    Monti S, Chapuy B, Takeyama K, Rodig SJ, Hao Y, Yeda KT, et al. Integrative analysis reveals an outcome-associated and targetable pattern of p53 and cell cycle deregulation in diffuse large B cell lymphoma. Cancer Cell. 2012;22(3):359–72.PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Steidl C, Shah SP, Woolcock BW, Rui L, Kawahara M, Farinha P, et al. MHC class II transactivator CIITA is a recurrent gene fusion partner in lymphoid cancers. Nature. 2011;471(7338):377–81.PubMedPubMedCentralCrossRefGoogle Scholar
  127. 127.
    Trinh DL, Scott DW, Morin RD, Mendez-Lago M, An J, Jones SJ, et al. Analysis of FOXO1 mutations in diffuse large B-cell lymphoma. Blood. 2013;121(18):3666–74.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Dominguez-Sola D, Kung J, Holmes AB, Wells VA, Mo T, Basso K, et al. The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity. 2015;43(6):1064–74.PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Weniger MA, Barth TF, Moller P. Genomic alterations in Hodgkin’s lymphoma. Int J Hematol. 2006;83(5):379–84.PubMedCrossRefPubMedCentralGoogle Scholar
  130. 130.
    Kapp U, Yeh WC, Patterson B, Elia AJ, Kagi D, Ho A, et al. Interleukin 13 is secreted by and stimulates the growth of Hodgkin and Reed-Sternberg cells. J Exp Med. 1999;189(12):1939–46.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Skinnider BF, Elia AJ, Gascoyne RD, Patterson B, Trumper L, Kapp U, et al. Signal transducer and activator of transcription 6 is frequently activated in Hodgkin and Reed-Sternberg cells of Hodgkin lymphoma. Blood. 2002;99(2):618–26.PubMedCrossRefGoogle Scholar
  132. 132.
    Falzetti D, Crescenzi B, Matteuci C, Falini B, Martelli MF, Van Den Berghe H, et al. Genomic instability and recurrent breakpoints are main cytogenetic findings in Hodgkin’s disease. Haematologica. 1999;84(4):298–305.PubMedGoogle Scholar
  133. 133.
    Martin-Subero JI, Gesk S, Harder L, Sonoki T, Tucker PW, Schlegelberger B, et al. Recurrent involvement of the REL and BCL11A loci in classical Hodgkin lymphoma. Blood. 2002;99(4):1474–7.PubMedCrossRefGoogle Scholar
  134. 134.
    Cabannes E, Khan G, Aillet F, Jarrett RF, Hay RT. Mutations in the IkBa gene in Hodgkin’s disease suggest a tumour suppressor role for IkappaBalpha. Oncogene. 1999;18(20):3063–70.PubMedCrossRefPubMedCentralGoogle Scholar
  135. 135.
    Emmerich F, Theurich S, Hummel M, Haeffker A, Vry MS, Dohner K, et al. Inactivating I kappa B epsilon mutations in Hodgkin/Reed-Sternberg cells. J Pathol. 2003;201(3):413–20.PubMedCrossRefGoogle Scholar
  136. 136.
    Trumper LH, Brady G, Bagg A, Gray D, Loke SL, Griesser H, et al. Single-cell analysis of Hodgkin and Reed-Sternberg cells: molecular heterogeneity of gene expression and p53 mutations. Blood. 1993;81(11):3097–115.PubMedGoogle Scholar
  137. 137.
    Muschen M, Re D, Brauninger A, Wolf J, Hansmann ML, Diehl V, et al. Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells. Cancer Res. 2000;60(20):5640–3.PubMedPubMedCentralGoogle Scholar
  138. 138.
    Seitz V, Hummel M, Anagnostopoulos I, Stein H. Analysis of BCL-6 mutations in classic Hodgkin disease of the B- and T-cell type. Blood. 2001;97(8):2401–5.PubMedCrossRefGoogle Scholar
  139. 139.
    Joos S, Granzow M, Holtgreve-Grez H, Siebert R, Harder L, Martin-Subero JI, et al. Hodgkin’s lymphoma cell lines are characterized by frequent aberrations on chromosomes 2p and 9p including REL and JAK2. Int J Cancer. 2003;103(4):489–95.PubMedCrossRefGoogle Scholar
  140. 140.
    Barth TF, Martin-Subero JI, Joos S, Menz CK, Hasel C, Mechtersheimer G, et al. Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood. 2003;101(9):3681–6.PubMedCrossRefGoogle Scholar
  141. 141.
    Joos S, Menz CK, Wrobel G, Siebert R, Gesk S, Ohl S, et al. Classical Hodgkin lymphoma is characterized by recurrent copy number gains of the short arm of chromosome 2. Blood. 2002;99(4):1381–7.PubMedCrossRefGoogle Scholar
  142. 142.
    Re D, Benenson E, Wolf J, Diehl V, Staratschek-Jox A. Lack of BCL10 mutations in Hodgkin’s disease-derived cell lines. Br J Haematol. 2000;109(2):420–2.PubMedCrossRefGoogle Scholar
  143. 143.
    Cochet O, Frelin C, Peyron JF, Imbert V. Constitutive activation of STAT proteins in the HDLM-2 and L540 Hodgkin lymphoma-derived cell lines supports cell survival. Cell Signal. 2006;18(4):449–55.PubMedCrossRefGoogle Scholar
  144. 144.
    Weniger MA, Melzner I, Menz CK, Wegener S, Bucur AJ, Dorsch K, et al. Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation. Oncogene. 2006;25(18):2679–84.PubMedCrossRefGoogle Scholar
  145. 145.
    Kupper M, Joos S, von Bonin F, Daus H, Pfreundschuh M, Lichter P, et al. MDM2 gene amplification and lack of p53 point mutations in Hodgkin and Reed-Sternberg cells: results from single-cell polymerase chain reaction and molecular cytogenetic studies. Br J Haematol. 2001;112(3):768–75.PubMedCrossRefGoogle Scholar
  146. 146.
    Yamamoto R, Nishikori M, Kitawaki T, Sakai T, Hishizawa M, Tashima M, et al. PD-1-PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma. Blood. 2008;111(6):3220–4.PubMedCrossRefGoogle Scholar
  147. 147.
    Green MR, Monti S, Rodig SJ, Juszczynski P, Currie T, O’Donnell E, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268–77.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Garcia MJ, Martinez-Delgado B, Cebrian A, Martinez A, Benitez J, Rivas C. Different incidence and pattern of p15INK4b and p16INK4a promoter region hypermethylation in Hodgkin’s and CD30-Positive non-Hodgkin’s lymphomas. Am J Pathol. 2002;161(3):1007–13.PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Sanchez-Aguilera A, Delgado J, Camacho FI, Sanchez-Beato M, Sanchez L, Montalban C, et al. Silencing of the p18INK4c gene by promoter hypermethylation in Reed-Sternberg cells in Hodgkin lymphomas. Blood. 2004;103(6):2351–7.PubMedCrossRefGoogle Scholar
  150. 150.
    Murray PG, Qiu GH, Fu L, Waites ER, Srivastava G, Heys D, et al. Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin’s lymphoma. Oncogene. 2004;23(6):1326–31.PubMedCrossRefGoogle Scholar
  151. 151.
    Dukers DF, van Galen JC, Giroth C, Jansen P, Sewalt RG, Otte AP, et al. Unique polycomb gene expression pattern in Hodgkin’s lymphoma and Hodgkin’s lymphoma-derived cell lines. Am J Pathol. 2004;164(3):873–81.PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Kluiver J, Poppema S, de Jong D, Blokzijl T, Harms G, Jacobs S, et al. BIC and miR-155 are highly expressed in Hodgkin, primary mediastinal and diffuse large B cell lymphomas. J Pathol. 2005;207(2):243–9.PubMedCrossRefGoogle Scholar
  153. 153.
    Rossi D, Cerri M, Capello D, Deambrogi C, Berra E, Franceschetti S, et al. Aberrant somatic hypermutation in primary mediastinal large B-cell lymphoma. Leukemia. 2005;19:2363–6.PubMedCrossRefGoogle Scholar
  154. 154.
    Scarpa A, Moore PS, Rigaud G, Inghirami G, Montresor M, Menegazzi M, et al. Molecular features of primary mediastinal B-cell lymphoma: involvement of p16INK4A, p53 and c-myc. Br J Haematol. 1999;107(1):106–13.PubMedCrossRefGoogle Scholar
  155. 155.
    Tsang P, Cesarman E, Chadburn A, Liu YF, Knowles DM. Molecular characterization of primary mediastinal B cell lymphoma. Am J Pathol. 1996;148(6):2017–25.PubMedPubMedCentralGoogle Scholar
  156. 156.
    Capello D, Vitolo U, Pasqualucci L, Quattrone S, Migliaretti G, Fassone L, et al. Distribution and pattern of BCL-6 mutations throughout the spectrum of B-cell neoplasia. Blood. 2000;95(2):651–9.PubMedGoogle Scholar
  157. 157.
    Savage KJ, Monti S, Kutok JL, Cattoretti G, Neuberg D, De Leval L, et al. The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood. 2003;102(12):3871–9.PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Weniger MA, Gesk S, Ehrlich S, Martin-Subero JI, Dyer MJ, Siebert R, et al. Gains of REL in primary mediastinal B-cell lymphoma coincide with nuclear accumulation of REL protein. Genes Chromosomes Cancer. 2007;46(4):406–15.PubMedCrossRefGoogle Scholar
  159. 159.
    Bea S, Zettl A, Wright G, Salaverria I, Jehn P, Moreno V, et al. Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood. 2005;106(9):3183–90.PubMedPubMedCentralCrossRefGoogle Scholar
  160. 160.
    Wessendorf S, Barth TF, Viardot A, Mueller A, Kestler HA, Kohlhammer H, et al. Further delineation of chromosomal consensus regions in primary mediastinal B-cell lymphomas: an analysis of 37 tumor samples using high-resolution genomic profiling (array-CGH). Leukemia. 2007;21(12):2463–9.PubMedCrossRefGoogle Scholar
  161. 161.
    Takahashi H, Feuerhake F, Monti S, Kutok JL, Aster JC, Shipp MA. Lack of IKBA coding region mutations in primary mediastinal large B-cell lymphoma and the host response subtype of diffuse large B-cell lymphoma. Blood. 2006;107:844–5.PubMedCrossRefGoogle Scholar
  162. 162.
    Joos S, Otano-Joos MI, Ziegler S, Bruderlein S, du Manoir S, Bentz M, et al. Primary mediastinal (thymic) B-cell lymphoma is characterized by gains of chromosomal material including 9p and amplification of the REL gene. Blood. 1996;87(4):1571–8.PubMedGoogle Scholar
  163. 163.
    Joos S, Kupper M, Ohl S, von Bonin F, Mechtersheimer G, Bentz M, et al. Genomic imbalances including amplification of the tyrosine kinase gene JAK2 in CD30+ Hodgkin cells. Cancer Res. 2000;60(3):549–52.PubMedGoogle Scholar
  164. 164.
    Roberts RA, Wright G, Rosenwald AR, Jaramillo MA, Grogan TM, Miller TP, et al. Loss of major histocompatibility class II gene and protein expression in primary mediastinal large B-cell lymphoma is highly coordinated and related to poor patient survival. Blood. 2006;108(1):311–8.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Eberle FC, Salaverria I, Steidl C, Summers TA Jr, Pittaluga S, Neriah SB, et al. Gray zone lymphoma: chromosomal aberrations with immunophenotypic and clinical correlations. Mod Pathol. 2011;24(12):1586–97.PubMedCrossRefGoogle Scholar
  166. 166.
    Eberle FC, Rodriguez-Canales J, Wei L, Hanson JC, Killian JK, Sun HW, et al. Methylation profiling of mediastinal gray zone lymphoma reveals a distinctive signature with elements shared by classical Hodgkin’s lymphoma and primary mediastinal large B-cell lymphoma. Haematologica. 2011;96(4):558–66.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Francesca Pentimalli
    • 1
  • Daniela Barone
    • 1
  • Antonio Giordano
    • 2
    • 3
  1. 1.Oncology Research Center of Mercogliano (CROM), Istituto Nazionale Tumori-IRCCS-Fondazione G. PascaleNaplesItaly
  2. 2.Sbarro Institute for Cancer Research and Molecular Medicine and Center for Biotechnology, College of Science and Technology, Temple UniversityPhiladelphiaUSA
  3. 3.Department of Medicine, Surgery and NeuroscienceUniversity of SienaSienaItaly

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