Molecular Diagnostics in Non-Hodgkin Lymphoma

  • Suraj PratapEmail author
  • Teresa A. Scordino


Non-Hodgkin Lymphomas (NHLs) are a diverse collection of malignant neoplasms of lymphoid cell origin which include all the malignant lymphomas that are not classified as Hodgkin lymphoma. NHL is the sixth most common type of cancer diagnosed in men and women in the United Kingdom. In the United States of America the past four decades have seen nearly an 80% rise in the incidence of NHL, one of the largest increases observed among any cancer. With improved understanding of biology, data from sequential disease-based clinical trials as well as better supportive care, the outcome of NHL has improved dramatically over the last several decades. Using conventional therapy, depending on subtype and stage, the majority of young adults with NHL can be cured. New insights into the molecular pathogenesis of NHL combined with recent headways in molecular biology and genetics have led to the discovery of several oncogenic pathways involved in lymphomagenesis, which in turn has augmented the diagnostic and therapeutic approaches for NHL patients. This review describes the presentation and evaluation of NHL and summarizes the current concepts about molecular diagnostics of the common subtypes.



The authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.


  1. 1.
    Steven H, Swerdlow EC, Harris NL, et al. WHO classification of tumours of haematopoietic and lymphoid tissues. Lyon: International Agency for Research on Cancer; 2008. p. 274–88.Google Scholar
  2. 2.
    Perry AM, Jacques D, Nathwani BN, et al. Classification of non-Hodgkin lymphoma in seven geographic regions around the world: review of 4539 cases from the international non-Hodgkin lymphoma classification Project. Blood. 2015;126:1484.Google Scholar
  3. 3.
    Smith A, Crouch S, Lax S, et al. Lymphoma incidence, survival and prevalence 2004–2014: sub-type analyses from the UK’s Haematological Malignancy Research Network. Br J Cancer. 2015;112(9):1575–84.PubMedPubMedCentralGoogle Scholar
  4. 4.
    Naresh K, Srinivas V, Soman C. Distribution of various subtypes of non-Hodgkin’s lymphoma in India: a study of 2773 lymphomas using REAL and WHO Classifications. Ann Oncol. 2000;11(suppl_1):S63–7.Google Scholar
  5. 5.
    Arora N, Manipadam MT, Nair S. Frequency and distribution of lymphoma types in a tertiary care hospital in South India: analysis of 5115 cases using the World Health Organization 2008 classification and comparison with world literature. Leuk Lymphoma. 2013;54(5):1004–11.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Anderson T, Chabner BA, Young RC, et al. Malignant lymphoma I. The histology and staging of 473 patients at the National Cancer Institute. Cancer. 1982;50(12):2699–707.PubMedGoogle Scholar
  7. 7.
    Economopoulos T, Papageorgiou S, Pappa V, et al. Monoclonal gammopathies in B-cell non-Hodgkin’s lymphomas. Leuk Res. 2003;27(6):505–8.PubMedGoogle Scholar
  8. 8.
    Jeffers M, Milton J, Herriot R, McKean M. Fine needle aspiration cytology in the investigation on non-Hodgkin’s lymphoma. J Clin Pathol. 1998;51(3):189–96.PubMedPubMedCentralGoogle Scholar
  9. 9.
    Hehn ST, Grogan TM, Miller TP. Utility of fine-needle aspiration as a diagnostic technique in lymphoma. J Clin Oncol. 2004;22(15):3046–52.PubMedGoogle Scholar
  10. 10.
    Dong HY, Harris NL, Preffer FI, Pitman MB. Fine-needle aspiration biopsy in the diagnosis and classification of primary and recurrent lymphoma: a retrospective analysis of the utility of cytomorphology and flow cytometry. Mod Pathol. 2001;14(5):472–81.PubMedGoogle Scholar
  11. 11.
    Horwitz SM, Zelenetz AD, Gordon LI, et al. NCCN guidelines insights: non-Hodgkin’s lymphomas, version 3.2016. J Natl Compr Cancer Netw. 2016;14(9):1067–79.Google Scholar
  12. 12.
    Byrne G Jr. Rappaport classification of non-Hodgkin’s lymphoma: histologic features and clinical significance. Cancer Treat Rep. 1977;61(6):935–44.PubMedGoogle Scholar
  13. 13.
    Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood. 1994;84(5):1361–92.Google Scholar
  14. 14.
    Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol. 1999;17(12):3835–49.PubMedGoogle Scholar
  15. 15.
    Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32(27):3059–67.PubMedPubMedCentralGoogle Scholar
  16. 16.
    Jaffe E. Classification of natural killer (NK) cell and NK-like T-cell malignancies [editorial; comment]. Blood. 1996;87:1207–10.PubMedGoogle Scholar
  17. 17.
    Van Dongen J, Langerak A, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 concerted action BMH4-CT98-3936. Leukemia. 2003;17(12):2257–317.PubMedGoogle Scholar
  18. 18.
    Klein U, Goossens T, Fischer M, et al. Somatic hypermutation in normal and transformed human B cells. Immunol Rev. 1998;162:261–80.PubMedGoogle Scholar
  19. 19.
    Kuppers R, Rajewsky K, Hansmann ML. Diffuse large cell lymphomas are derived from mature B cells carrying V region genes with a high load of somatic mutation and evidence of selection for antibody expression. Eur J Immunol. 1997;27(6):1398–405.PubMedGoogle Scholar
  20. 20.
    Kuppers R, Zhao M, Hansmann ML, Rajewsky K. Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. EMBO J. 1993;12(13):4955–67.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Shen HM, Peters A, Baron B, Zhu X, Storb U. Mutation of BCL-6 gene in normal B cells by the process of somatic hypermutation of Ig genes. Science. 1998;280(5370):1750–2.Google Scholar
  22. 22.
    Lo Coco F, Gaidano G, Louie DC, Offit K, Chaganti RS. Dalla-Favera R. p53 mutations are associated with histologic transformation of follicular lymphoma. Blood. 1993;82(8):2289–95.PubMedPubMedCentralGoogle Scholar
  23. 23.
    Elenitoba-Johnson KS, Gascoyne RD, Lim MS, Chhanabai M, Jaffe ES, Raffeld M. Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymphoma. Blood. 1998;91(12):4677–85.PubMedGoogle Scholar
  24. 24.
    Tagawa H, Suguro M, Tsuzuki S, et al. Comparison of genome profiles for identification of distinct subgroups of diffuse large B-cell lymphoma. Blood. 2005;106(5):1770–7.PubMedGoogle Scholar
  25. 25.
    Huang JZ, Sanger WG, Greiner TC, et al. The t (14; 18) defines a unique subset of diffuse large B-cell lymphoma with a germinal center B-cell gene expression profile. Blood. 2002;99(7):2285–90.PubMedGoogle Scholar
  26. 26.
    Pasqualucci L, Dalla-Favera R. The genetic landscape of diffuse large B-cell lymphoma. Paper presented at Seminars in Hematology, 2015.Google Scholar
  27. 27.
    Rosenwald A, Wright G, Chan WC, et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N Engl J Med. 2002;346(25):1937–47.PubMedPubMedCentralGoogle Scholar
  28. 28.
    Houldsworth J, Olshen AB, Cattoretti G, et al. Relationship between REL amplification, REL function, and clinical and biologic features in diffuse large B-cell lymphomas. Blood. 2004;103(5):1862–8.PubMedGoogle Scholar
  29. 29.
    Bea S, Zettl A, Wright G, 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.PubMedPubMedCentralGoogle Scholar
  30. 30.
    Compagno M, Lim WK, Grunn A, et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature. 2009;459(7247):717–21.PubMedPubMedCentralGoogle Scholar
  31. 31.
    Kato M, Sanada M, Kato I, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459(7247):712–6.Google Scholar
  32. 32.
    Alizadeh AA, Eisen MB, Davis RE, et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature. 2000;403(6769):503–11.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Karube K, Enjuanes A, Dlouhy I, et al. Integrating genomic alterations in diffuse large B-cell lymphoma identifies new relevant pathways and potential therapeutic targets. Leukemia. 2018;32(3):675–84.Google Scholar
  34. 34.
    Schmitz, Roland, et al. “Genetics and pathogenesis of diffuse large B-cell lymphoma.” New England Journal of Medicine 378.15 (2018): 1396–1407.Google Scholar
  35. 35.
    Chapuy, Bjoern, et al. “Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes.” Nature medicine 24.5 (2018):679.Google Scholar
  36. 36.
    Cigudosa JC, Parsa NZ, Louie DC, et al. Cytogenetic analysis of 363 consecutively ascertained diffuse large B-cell lymphomas. Genes Chromosomes Cancer. 1999;25(2):123–33.Google Scholar
  37. 37.
    Gascoyne RDCE, Jaffe ES, et al. Diffuse large B cell lymphoma NOS. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 291–7.Google Scholar
  38. 38.
    Kluin PMHN, Stein H, et al. High-grade B cell lymphoma. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 335–40.Google Scholar
  39. 39.
    Barrans S, Crouch S, Smith A, et al. Rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma treated in the era of rituximab. J Clin Oncol. 2010;28(20):3360–5.Google Scholar
  40. 40.
    Rowley JD. Chromosome studies in the non-Hodgkin's lymphomas: the role of the 14;18 translocation. J Clin Oncol. 1988;6(5):919–25.PubMedGoogle Scholar
  41. 41.
    Bloomfield CD, Arthur DC, Frizzera G, Levine EG, Peterson BA, Gajl-Peczalska KJ. Nonrandom chromosome abnormalities in lymphoma. Cancer Res. 1983;43(6):2975–84.PubMedGoogle Scholar
  42. 42.
    Leroux D, Monteil M, Sotto J, et al. Variant t (2; 18) translocation in a follicular lymphoma. Br J Haematol. 1990;75(2):290–2.PubMedGoogle Scholar
  43. 43.
    Lin P, Jetly R, Lennon PA, Abruzzo LV, Prajapati S, Medeiros LJ. Translocation (18; 22)(q21; q11) in B-cell lymphomas: a report of 4 cases and review of the literature. Hum Pathol. 2008;39(11):1664–72.PubMedGoogle Scholar
  44. 44.
    Johnson NA, Al-Tourah A, Brown C, Connors JM, Gascoyne RD, Horsman DE. Prognostic significance of secondary cytogenetic alterations in follicular lymphomas. Genes Chromosom Cancer. 2008;47(12):1038–48.PubMedGoogle Scholar
  45. 45.
    Tilly H, Rossi A, Stamatoullas A, et al. Prognostic value of chromosomal abnormalities in follicular lymphoma. Blood. 1994;84(4):1043–9.PubMedGoogle Scholar
  46. 46.
    Bosga-Bouwer AG, van Imhoff GW, Boonstra R, et al. Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t (14; 18), 3q27, or other translocations: t (14; 18) and 3q27 are mutually exclusive. Blood. 2003;101(3):1149–54.PubMedGoogle Scholar
  47. 47.
    Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011;476(7360):298–303.PubMedPubMedCentralGoogle Scholar
  48. 48.
    Pastore A, Jurinovic V, Kridel R, et al. Integration of gene mutations in risk prognostication for patients receiving first-line immunochemotherapy for follicular lymphoma: a retrospective analysis of a prospective clinical trial and validation in a population-based registry. Lancet Oncol. 2015;16(9):1111–22.PubMedGoogle Scholar
  49. 49.
    Pasqualucci L, Dominguez-Sola D, Chiarenza A, et al. Inactivating mutations of acetyltransferase genes in B-cell lymphoma. Nature. 2011;471(7337):189–95.PubMedPubMedCentralGoogle Scholar
  50. 50.
    Swerdlow SHCE, Seto M, et al. Mantle cell lymphoma. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. revised 4th ed. Lyon: IARC Press; 2017. p. 285–90.Google Scholar
  51. 51.
    Musgrove EA, Caldon CE, Barraclough J, Stone A, Sutherland RL. Cyclin D as a therapeutic target in cancer. Nat Rev Cancer. 2011;11(8):558–72.PubMedGoogle Scholar
  52. 52.
    Espinet B, Salaverria I, Beà S, et al. Incidence and prognostic impact of secondary cytogenetic aberrations in a series of 145 patients with mantle cell lymphoma. Genes Chromosom Cancer. 2010;49(5):439–51.PubMedGoogle Scholar
  53. 53.
    Eskelund CW, Dahl C, Hansen JW, et al. TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy. Blood. 2017;130(17):1903–10.PubMedGoogle Scholar
  54. 54.
    Onaindia A, Medeiros LJ, Patel KP. Clinical utility of recently identified diagnostic, prognostic, and predictive molecular biomarkers in mature B-cell neoplasms. Mod Pathol. 2017;30(10):1338–66.PubMedGoogle Scholar
  55. 55.
    Du M, Diss TC, Xu C, Peng H, Isaacson PG, Pan L. Ongoing mutation in MALT lymphoma immunoglobulin gene suggests that antigen stimulation plays a role in the clonal expansion. Leukemia. 1996;10(7):1190–7.PubMedGoogle Scholar
  56. 56.
    Cook JRIP, Chott A, Nakamura S, Muller-Hermelink HK, Harris NL, Swerdlow SH. Extranodal marginal zone lymphoma of mucosa-assoiated lymphoid tissue (MALT lymphoma). In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017.Google Scholar
  57. 57.
    Zucca E, Bertoni F. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood. 2016;127(17):2082–92.PubMedGoogle Scholar
  58. 58.
    Thieblemont C, Bertoni F, Copie-Bergman C, Ferreri AJ, Ponzoni M. Chronic inflammation and extra-nodal marginal-zone lymphomas of MALT-type. Paper presented at Seminars in Cancer Biology, 2014.Google Scholar
  59. 59.
    Pyris MAIP, Swerdlow SH, Thieblemont C, Pittaluga S, Rossi D, Harris NL. Splenic marginal zone lymphoma. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 223–5.Google Scholar
  60. 60.
    Campo EPS, Jaffe ES, Nathwani BN, Stein H, Muller-Hermelink HK. Nodal marginal zone lymphoma. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 263–5.Google Scholar
  61. 61.
    Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM. Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci. 1982;79(24):7824–7.PubMedGoogle Scholar
  62. 62.
    Capello D, Carbone A, Pastore C, Gloghini A, Saglio G, Gaidano G. Point mutations of the BCL-6 gene in Burkitt's lymphoma. Br J Haematol. 1997;99(1):168–70.PubMedGoogle Scholar
  63. 63.
    Hamilton-Dutoit SJ, Pallesen G, Franzmann MB, et al. AIDS-related lymphoma. Histopathology, immunophenotype, and association with Epstein-Barr virus as demonstrated by in situ nucleic acid hybridization. Am J Pathol. 1991;138(1):149–63.PubMedPubMedCentralGoogle Scholar
  64. 64.
    Schmitz R, Ceribelli M, Pittaluga S, Wright G, Staudt LM. Oncogenic mechanisms in Burkitt lymphoma. Cold Spring Harb Perspect Med. 2014;4(2).Google Scholar
  65. 65.
    Campo EGP, Montserrat E, Harris NL, Muller-Hermelink HK, Stein H, Swerdlow SH. Chronic lymphocytic leukaemia/small lymphocytic lymphoma. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 216–21.Google Scholar
  66. 66.
    Rai KR, Jain P. Chronic lymphocytic leukemia (CLL)—then and now. Am J Hematol. 2016;91(3):330–40.PubMedGoogle Scholar
  67. 67.
    Hallek M, Cheson BD, Catovsky D, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on chronic lymphocytic leukemia updating the National Cancer Institute–working group 1996 guidelines. Blood. 2008;111(12):5446–56.PubMedPubMedCentralGoogle Scholar
  68. 68.
    Marti GE, Rawstron AC, Ghia P, et al. Diagnostic criteria for monoclonal B-cell lymphocytosis. Br J Haematol. 2005;130(3):325–32.PubMedGoogle Scholar
  69. 69.
    Rawstron AC, Bennett FL, O'Connor SJ, et al. Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med. 2008;359(6):575–83.PubMedGoogle Scholar
  70. 70.
    Fazi C, Scarfò L, Pecciarini L, et al. General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood. 2011;118(25):6618–25.PubMedGoogle Scholar
  71. 71.
    Hsi ED. Pathologic and molecular genetic features of chronic lymphocytic leukemia. Paper presented at Seminars in Oncology, 2012.Google Scholar
  72. 72.
    Rodríguez AE, Hernández JÁ, Benito R, et al. Molecular characterization of chronic lymphocytic leukemia patients with a high number of losses in 13q14. PLoS One. 2012;7(11):e48485.PubMedPubMedCentralGoogle Scholar
  73. 73.
    Matutes E, Oscier D, Garcia-Marco J, et al. Trisomy 12 defines a group of CLL with atypical morphology: correlation between cytogenetic, clinical and laboratory features in 544 patients. Br J Haematol. 1996;92(2):382–8.PubMedGoogle Scholar
  74. 74.
    Puiggros A, Blanco G, Espinet B. Genetic abnormalities in chronic lymphocytic leukemia: where we are and where we go. Biomed Res Int. 2014;2014:1–13.Google Scholar
  75. 75.
    Hamblin TJ, Davis Z, Gardiner A, Oscier DG, Stevenson FK. Unmutated Ig V H genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood. 1999;94(6):1848–54.PubMedGoogle Scholar
  76. 76.
    Dürig J, Naschar M, Schmücker U, et al. CD38 expression is an important prognostic marker in chronic lymphocytic leukaemia. Leukemia. 2002;16(1):30–5.PubMedGoogle Scholar
  77. 77.
    Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003;101(12):4944–51.PubMedGoogle Scholar
  78. 78.
    Amaya-Chanaga CI, Rassenti LZ. Biomarkers in chronic lymphocytic leukemia: clinical applications and prognostic markers. Best Pract Res Clin Haematol. 2016;29(1):79–89.PubMedGoogle Scholar
  79. 79.
    Ghia EM, Jain S, Widhopf GF, et al. Use of IGHV3–21 in chronic lymphocytic leukemia is associated with high-risk disease and reflects antigen-driven, post–germinal center leukemogenic selection. Blood. 2008;111(10):5101–8.PubMedPubMedCentralGoogle Scholar
  80. 80.
    Rossi D, Rasi S, Spina V, et al. Integrated mutational and cytogenetic analysis identifies new prognostic subgroups in chronic lymphocytic leukemia. Blood. 2013;121(8):1403–12.PubMedPubMedCentralGoogle Scholar
  81. 81.
    Foucar KFB, Stein H. Hairy cell leukaemia. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 226–8.Google Scholar
  82. 82.
    Bosch F, Campo E, Jares P, et al. Increased expression of the PRAD-1/CCND1 gene in hairy cell leukaemia. Br J Haematol. 1995;91(4):1025–30.PubMedGoogle Scholar
  83. 83.
    Basso K, Liso A, Tiacci E, et al. Gene expression profiling of hairy cell leukemia reveals a phenotype related to memory B cells with altered expression of chemokine and adhesion receptors. J Exp Med. 2004;199(1):59–68.PubMedPubMedCentralGoogle Scholar
  84. 84.
    Tiacci E, Trifonov V, Schiavoni G, et al. BRAF mutations in hairy-cell leukemia. N Engl J Med. 2011;364(24):2305–15.PubMedPubMedCentralGoogle Scholar
  85. 85.
    Tiacci E, Schiavoni G, Forconi F, et al. Simple genetic diagnosis of hairy cell leukemia by sensitive detection of the BRAF-V600E mutation. Blood. 2012;119(1):192–5.PubMedGoogle Scholar
  86. 86.
    Turakhia S, Lanigan C, Hamadeh F, Swerdlow SH, Tubbs RR, Cook JR. Immunohistochemistry for BRAF V600E in the differential diagnosis of hairy cell leukemia vs other splenic B-cell lymphomas. Am J Clin Pathol. 2015;144(1):87–93.PubMedGoogle Scholar
  87. 87.
    Andrulis M, Penzel R, Weichert W, von Deimling A, Capper D. Application of a BRAF V600E mutation-specific antibody for the diagnosis of hairy cell leukemia. Am J Surg Pathol. 2012;36(12):1796–800.PubMedGoogle Scholar
  88. 88.
    Swerdlow SHCJ, Sohani AR, Pileri SA, Harris NL, Jaffe ES, Stein H. Lymphoplasmacytic lymphoma. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 232–5.Google Scholar
  89. 89.
    Morice WG, Chen D, Kurtin PJ, Hanson CA, McPhail ED. Novel immunophenotypic features of marrow lymphoplasmacytic lymphoma and correlation with Waldenström’s macroglobulinemia. Mod Pathol. 2009;22(6):807–16.PubMedGoogle Scholar
  90. 90.
    Swerdlow SH, Kuzu I, Dogan A, et al. The many faces of small B cell lymphomas with plasmacytic differentiation and the contribution of MYD88 testing. Virchows Arch. 2016;468(3):259–75.PubMedGoogle Scholar
  91. 91.
    Owen RG, Barrans SL, Richards SJ, et al. Waldenström macroglobulinemia: development of diagnostic criteria and identification of prognostic factors. Am J Clin Pathol. 2001;116(3):420–8.PubMedGoogle Scholar
  92. 92.
    Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenström macroglobulinemia. Blood. 2014;123(18):2791–6.PubMedGoogle Scholar
  93. 93.
    Treon SP, Xu L, Yang G, et al. MYD88 L265P somatic mutation in Waldenström’s macroglobulinemia. N Engl J Med. 2012;367(9):826–33.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Schmidt J, Federmann B, Schindler N, et al. MYD88 L265P and CXCR4 mutations in lymphoplasmacytic lymphoma identify cases with high disease activity. Br J Haematol. 2015;169(6):795–803.PubMedGoogle Scholar
  95. 95.
    Cao Y, Hunter ZR, Liu X, et al. CXCR4 WHIM-like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD88L265P-directed survival signalling in Waldenström macroglobulinaemia cells. Br J Haematol. 2015;168(5):701–7.PubMedGoogle Scholar
  96. 96.
    Hunter ZR, Xu L, Yang G, et al. The genomic landscape of Waldenström macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014;123(11):1637–46.PubMedGoogle Scholar
  97. 97.
    Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127(20):2375–90.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Iqbal J, Wright G, Wang C, et al. Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphoma. Blood. 2014;123(19):2915–23.PubMedPubMedCentralGoogle Scholar
  99. 99.
    Harris ME. International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol. 2008;26:4124–30.Google Scholar
  100. 100.
    Falini BL-RL, Campo E, Jaffe ES, Gascoyne RD, Stein H, Muller-Hermelink HL, Kinney MC. Anaplastic large cell lymphoma, ALK-positive. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 413–8.Google Scholar
  101. 101.
    Foss H-D, Anagnostopoulos I, Araujo I, et al. Anaplastic large-cell lymphomas of T-cell and null-cell phenotype express cytotoxic molecules. Blood. 1996;88(10):4005–11.Google Scholar
  102. 102.
    van der Krogt J-A, Bempt MV, Ferreiro JF, et al. Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC-and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene. Haematologica. 2017;102(9):1605–16.PubMedPubMedCentralGoogle Scholar
  103. 103.
    Hallberg B, Palmer RH. Mechanistic insight into ALK receptor tyrosine kinase in human cancer biology. Nat Rev Cancer. 2013;13(10):685–700.PubMedGoogle Scholar
  104. 104.
    Werner MT, Zhao C, Zhang Q, Wasik MA. Nucleophosmin-anaplastic lymphoma kinase: the ultimate oncogene and therapeutic target. Blood. 2017;129(7):823–31.Google Scholar
  105. 105.
    Lamant L, De Reynies A, Duplantier M-M, et al. Gene-expression profiling of systemic anaplastic large-cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. Blood. 2007;109(5):2156–64.PubMedPubMedCentralGoogle Scholar
  106. 106.
    Crescenzo R, Abate F, Lasorsa E. T-cell project: prospective collection of data in patients with peripheral T-cell lymphoma and the AIRC 5xMille consortium “Genetics-Driven Targeted Management of Lymphoid Malignancies”. Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma. Cancer Cell. 2015;27(5):744.Google Scholar
  107. 107.
    Castellar ERP, Jaffe ES, Said JW, et al. ALK-negative anaplastic large cell lymphoma is a genetically heterogeneous disease with widely disparate clinical outcomes. Blood. 2014;124(9):1473–80.Google Scholar
  108. 108.
    Zeng Y, Feldman AL. Genetics of anaplastic large cell lymphoma. Leuk Lymphoma. 2016;57(1):21–7.PubMedGoogle Scholar
  109. 109.
    Pileri SAWD, Sng I, et al. Peripheral T cell lymphoma, NOS. In: Swerdlow S, Campo E, Harris N, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. Revised 4th ed. Lyon: IARC Press; 2017. p. 403–7.Google Scholar
  110. 110.
    Nelson M, Horsman DE, Weisenburger DD, et al. Cytogenetic abnormalities and clinical correlations in peripheral T-cell lymphoma. Br J Haematol. 2008;141(4):461–9.PubMedPubMedCentralGoogle Scholar
  111. 111.
    Boddicker RL, Razidlo GL, Dasari S, et al. Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma. Blood. 2016;128(9):1234–45.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  1. 1.Jimmy Everest Section of Pediatric Hematology-OncologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA
  2. 2.Department of PathologyUniversity of Oklahoma Health Sciences CenterOklahoma CityUSA

Personalised recommendations