Non‐Hodgkin Lymphomas


Non‐Hodgkin lymphomas (NHLs) are malignant neoplasms of lymphoid cells, the predominant cells of the immune system. This term encompasses lymphocytes and their precursor as well as their progeny cells and natural killer cells. The defining characteristics of NHLs are their gene and microribonucleic acid (miRNA) expression patterns, which differ for each lymphoma subtype and also from those of closely related normal cell types. This is a consequence of a broad range of genetic changes – including gross changes at chromosomal level, namely translocations, whole or partial chromosome losses and other, smaller changes in individual genes ranging from point mutations to deletions that result in modifications of the molecular pathways of cells that cause corresponding modifications in cell behaviour. The genetic changes that give rise directly to NHLs are induced by physical, chemical or biological environmental agents (rarely, genetic changes that predispose to lymphomas may be inherited or present from birth) or the presence of viral sequences capable of modifying normal gene expression pattern and/or molecular pathways in the relevant cell type. At the clinical level, the behaviour of malignant lymphomas varies from indolent to aggressive. Lymphomas may be observed, treated with chemotherapy or with various combinations of chemotherapy, radiation and occasionally surgery (e.g. splenectomy).

Key Concepts:

  • NHLs are malignant neoplasms that arise from lymphoid cells, the predominant cells of the immune system, which include lymphocytes and their precursor and progeny cells.

  • The immediate cause of lymphomas is genetic change, often chromosomal aberrations such as translocations, but this may be predisposed to by infections, particularly those that influence immunoregulation.

  • Clinical distinctions such as nodal and extranodal lymphomas or bone marrow involvement, once the primary means of identifying diseases, do not have taxonomic significance (i.e. they are not, in themselves, indicators of a different disease).

  • Mature lymphoid cells express an antigen‐binding receptor that is the external starting point of a major signalling pathway extending to the cell nucleus that is critical to lymphoid cell proliferation; mutations in this signalling pathway may simulate tonic expression of the TCR or BCR, even if the latter are normal, therefore, giving rise to inappropriate cell proliferation in the absence of antigen.

  • The requirement of the adaptive immune system for antibodies to be able to bind tightly to antigen, which is achieved by selection of the antibody with the ‘best fit’ to antigen in the germinal follicle through a process of somatic mutation within the antibody variable region (see immune system and also class switching), a process mediated by activation‐induced cytidine deaminase, can result in significant structural rearrangements within the antibody molecule, including double‐strand breaks in the DNA. These processes, which have been shown to increase the risk of developing chromosomal translocations in mice, are probably relevant to the genesis of major cytogenetic changes in human lymphoid cells, some of which may be pertinent to lymphoma development.

  • Some chronic infections and inflammatory processes cause activation of lymphoid cells, and predisposition to lymphoma development.

  • Inherited (e.g. XLP) and acquired immunodeficiencies (e.g. HIV) may increase the risk of lymphoma development by modifying regulation of the immune system.

  • Understanding the molecular mechanisms of lymphomagenesis as well as the molecular changes associated with lymphocyte differentiation can lead to targeted approaches to therapy, that is, the development of molecules which bind with high specificity to identified molecular targets, and either modify their actions or enable the introduction of a high local concentration of toxin or radionuclide, in either case producing a potentially therapeutic effect which is likely to be more specific and less toxic than conventional chemotherapy.

  • When chronic infection leads to lymphoma, treatment of the underlying disease may induce complete remission and sometimes cure.

  • In general, the more aggressive (rapidly progressive) lymphomas respond well to intensive therapy, and a proportion of such cases can be cured although recent research has suggested that some indolent lymphomas are also potentially curable by drugs that alter the microenvironment they require for survival.

Keywords: lymphoma; neoplasia; T cells; B cells; NK cells; chromosomal translocation; gene expression patterns; chemotherapy

Figure 1.

Diagrammatic depiction of a chromosomal translocation between two hypothetical chromosomes, A and B, in which an enhancer, associated with a gene on chromosome A, is juxtaposed to a gene containing three exons, 1, 2 and 3, on chromosome B. This results in increased expression of the gene on the derivative B chromosome.

Figure 2.

Diagrammatic depiction of a chromosomal translocation between two hypothetical chromosomes, A and B, in which two or three‐exon genes are fused to form a four‐exon gene consisting of the first two exons of the gene on chromosome A and the last two exons of the gene on chromosome B.

Figure 3.

Diagrammatic depiction of five different chromosomal translocations in which the promoters of various genes (P1–P5) – heavy‐ and light‐chain immunoglobulin (IgH and IgL), heat shock protein 69(HSP069), RhoH and L‐Plastin – are juxtaposed to the BCL‐6 gene. In each case, the Bcl‐6 gene is overexpressed. The fact that many different translocations (those shown here represent just some of the translocations found, each in a different tumour) can cause overexpression of BCL‐6 has led to the term ‘promiscuous’ in the context of the use of multiple promoters.

Figure 4.

B‐cell lymphomas and some associated translocations. From left to right, in the lower part of the figure, the most common B‐cell lymphomas are depicted in the context of the components of secondary (germinal) follicles in lymphoid tissue – morphology and immunophenotype of these lymphomas closely resemble those of normal cells of the secondary follicle. The lymphomas are small lymphocytic lymphoma, nodal marginal cell lymphoma, MCL, BL, diffuse large B‐cell lymphoma (DLBCL) and, again, lymphocytic lymphoma (which includes both ‘prefollicular’ and ‘postfollicular’ subtypes). The components of the secondary follicle are labelled MaZ (marginal zone), MZ (mantle zone) and GC (germinal centre). In the upper part of the figure, a stem cell differentiating into precursor B cells is depicted. Four different translocations are shown as though occurring in precursor B cells (see text for discussion). The arrows pointing to the lymphoma cells indicate which translocation is associated with each of the lymphomas, except for small lymphocytic lymphoma and nodal MZL, in which, to date, nonrandom chromosomal translocations have not been observed. Although essentially all mantle zone lymphomas and BLs, and the majority of FLs, bear the indicated translocations, only a small fraction of DLBCLs have 3;14 translocations.



Alizadeh AA, Eisen MB, Davis RE et al. (2000) Distinct types of diffuse large B‐cell lymphoma identified by gene expression profiling. Nature 403: 503–511.

Ballester B, Ramuz O, Gisselbrecht C et al. (2006) Gene expression profiling identifies molecular subgroups among nodal peripheral T‐cell lymphomas. Oncogene 25(10): 1560–1570.

Bellan C, Lazzi S, Hummel M et al. (2005) Immunoglobulin gene analysis reveals 2 distinct cells of origin for EBV‐positive and EBV‐negative Burkitt lymphomas. Blood 106(3): 1031–1036.

Bosch F, Ferrer A, Villamor N et al. (2008) Fludarabine, cyclophosphamide, and mitoxantrone as initial therapy of chronic lymphocytic leukemia: high response rate and disease eradication. Clinical Cancer Research 14(1): 155–161. doi:10.1158/1078‐0432.CCR‐07‐1371.

Calin GA, Sevignani C, Dumitru CD et al. (2004) Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proceedings of the National Academy of Sciences of the USA 101(9): 2999–3004.

Campbell LJ (2005) Cytogenetics of lymphomas. Pathology 37: 493–507.

Chang DK, Sui J, Geng S et al. (2012) Humanization of an anti‐CCR4 antibody that kills cutaneous T‐cell lymphoma cells and abrogates suppression by T‐regulatory cells. Molecular Cancer Therapeutics 11(11): 2451–2461. doi:10.1158/1535‐7163.MCT‐12‐0278.

Cheson BD (2006) Radioimmunotherapy of non‐Hodgkin's lymphomas. Current Drug Targets 7: 1293–1300.

Cinti C, Leoncini L, Nyongo A et al. (2000) Genetic alterations of the retinoblastoma‐related gene RB2/p130 identify different pathogenetic mechanisms in and among Burkitt's lymphoma subtypes. American Journal of Pathology 156(3): 751–760.

Dave S, Fu K, Wright GW et al. (2006) Molecular diagnosis of Burkitt's lymphoma. New England Journal of Medicine 354(23): 2431–2442.

Davies AJ, Rosenwald A, Wright G et al. (2007) Transformation of follicular lymphoma to diffuse large B‐cell lymphoma proceeds by distinct oncogenic mechanisms. British Journal of Haematology 136: 286–293.

Dearden CE and Matutes E (2006) Alemtuzumab in T‐cell lymphoproliferative disorders. Best Practice & Research Clinical Haematology 19(4): 795–810.

De Leval L, Richman DS, Thielen I et al. (2007) The gene expression profile of nodal peripheral T‐cell lymphoma demonstrates a molecular link between angioimmunoblastic T‐cell lymphoma (AITL) and follicular helper T (TFH) cells. Blood 109(11): 4952–4963.

Doebele RC, Pilling AB, Aisner DL et al. (2012) Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non‐small cell lung cancer. Clinical Cancer Research 18(5): 1472–1482. doi:10.1158/1078‐0432.CCR‐11‐2906.

Duarte RF, Canals C, Onida F et al. (2010) Allogeneic hematopoietic cell transplantation for patients with mycosis fungoides and Sézary syndrome: a retrospective analysis of the Lymphoma Working Party of the European Group for Blood and Marrow Transplantation. Journal of Clinical Oncology 28(29): 4492–4499.

Ferrando AA, Neuberg DS, Staunton J et al. (2002) Gene expression signatures define novel oncogenic pathways in T‐cell acute lymphoblastic leukemia. Cancer Cell 1(1): 75–87.

Fisher RI, Gaynor ER, Dahlberg S et al. (1993) Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non‐Hodgkin's lymphoma. New England Journal of Medicine 8(328): 1002–1006.

Fulci V, Chiaretti S, Goldoni M et al. (2007) Quantitative technologies establish a novel microRNA profile of chronic lymphocytic leukemia. Blood 109(11): 4944–4951.

Gelmann EP, Psallidopoulos MC, Papas TS and Dalla‐Favera R (1983) Identification of reciprocal translocation sites within the c‐myc oncogene and immunoglobulin mu locus in a Burkitt lymphoma. Nature 306(5945): 799–803.

Gkotzamanidou M and Papadimitriou CA (2013) Peripheral T‐cell lymphoma: the role of hematopoietic stem cell transplantation. Critical Reviews in Oncology/Hematology. doi:10.1016/j.critrevonc.2013.08.016 [Epub ahead of print].

Glass E and Viale PH (2013) Histone deacetylase inhibitors: novel agents in cancer treatment. Clinical Journal of Oncology Nursing 17(1): 34–40. doi:10.1188/13.CJON.34‐40.

Harjunpaa A, Taskinen M, Nykter M et al. (2006) Differential gene expression in non‐malignant tumour microenvironment is associated with outcome in follicular lymphoma patients treated with rituximab and CHOP. British Journal of Haematology 135: 33–42.

Henrickson SE, Hartmann EM, Ott G and Rosenwald A (2007) Gene expression profiling in malignant lymphomas. Advances in Experimental Medicine and Biology 593: 134–146.

Hummel M, Bentink S, Berger H et al. (2006) A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. New England Journal of Medicine 354: 2419–2430.

International Non‐Hodgkin's Lymphoma Prognostic Factors Project (1993) A predictive model for aggressive non‐Hodgkin's lymphoma. New England Journal of Medicine 329: 987–994.

van der Jagt R (2013) Bendamustine for indolent non‐Hodgkin lymphoma in the front‐line or relapsed setting: a review of pharmacokinetics and clinical trial outcomes. Expert Review of Hematology 6(5): 525–537. doi:10.1586/17474086.2013.841538.

van Kester MS, Borg MK, Zoutman WH et al. (2012) A meta‐analysis of gene expression data identifies a molecular signature characteristic for tumor‐stage mycosis fungoides. Journal of Investigative Dermatology 132(8): 2050–2059.

Lamant L, Reyniès A, Duplantier MM et al. (2007) Gene expression profiling of systemic anaplastic large‐cell lymphoma reveals differences based on ALK status and two distinct morphologic ALK+ subtypes. Blood 109(5): 2156–2164.

Lawrie CH, Soneji S, Marafioti T et al. (2007) MicroRNA expression distinguishes between germinal center B cell‐like and activated B cell‐like subtypes of diffuse large B cell lymphoma. International Journal of Cancer 121(5): 1156–1161.

Lenze D, Leoncini L, Hummel M et al. (2011) The different epidemiologic subtypes of Burkitt lymphoma share a homogenous microRNA profile distinct from diffuse large B‐cell lymphoma. Leukemia 25(12): 1869–1876.

Leucci E, Cocco M, Onnis A et al. (2008) MYC translocation‐negative classical Burkitt lymphoma cases: an alternative pathogenetic mechanism involving miRNA deregulation. Journal of Pathology 216(4): 440–450.

Leucci E, Onnis A, Cocco M et al. (2010) B‐cell differentiation in EBV‐positive Burkitt lymphoma is impaired at posttranscriptional level by miRNA‐altered expression. International Journal of Cancer 126(6): 1316–1326.

Lieber MR, Yu K and Raghavan SC (2006) Roles of nonhomologous DNA end joining, V(D)J recombination, and class switch recombination in chromosomal translocations. DNA Repair 5: 1234–1245.

Magrath I, Adde M, Shad A et al. (1996) Adults and children with small non‐cleaved‐cell lymphoma have a similar excellent outcome when treated with the same chemotherapy regimen. Journal of Clinical Oncology 14: 925–934.

Magrath IT (1981) Lymphocyte differentiation: an essential basis for the comprehension of lymphoid neoplasia. Journal of the National Cancer Institute 67: 501–514.

Marcus R and Hagenbeek A (2007) The therapeutic use of rituximab in non‐Hodgkin's lymphoma. European Journal of Haematology 67(Suppl.): 5–14.

Martinez‐Delgado B, Melendez B, Cuadros M et al. (2004) Expression profiling of T‐cell lymphomas differentiates peripheral and lymhpoblastic lymphomas and defines serviva related genes. Clinical Cancer Research 10(15): 4971–4982.

Mi S, Lu J, Sun M et al. (2007) MicroRNA expression signatures accurately discriminate acute lymphoblastic leukemia from acute myeloid leukemia. Proceedings of the National Academy of Sciences of the USA 104(50): 19971–19976.

Milpied N (2013) Myeloablation for lymphoma – Question answered? New England Journal of Medicine 369: 1750–1751. doi:10.1056/NEJMe1309182.

Montes‐Moreno S, Martinez N, Sanchez‐Espiridión B et al. (2011) miRNA expression in diffuse large B‐cell lymphoma treated with chemoimmunotherapy. Blood 118(4): 1034–1040.

Onnis A, De Falco G, Antonicelli G et al. (2010) Alteration of microRNAs regulated by c‐Myc in Burkitt lymphoma. PLoS One 5(9): e12960.

Pasqualucci L, Bereschenko O, Niu H et al. (2003) Molecular pathogenesis of non‐Hodgkin's lymphoma: the role of Bcl‐6. Leukemia Lymphoma 44(Suppl. 3): S5–S12.

Piccaluga PP, Agostinelli C, Califano A et al. (2007) Gene expression analysis of peripheral T cell lymphoma, unspecified, reveals distinct profiles and new potential therapeutic targets. Journal of Clinical Investigation 117(3): 823–834.

Piccaluga PP, De Falco G and Kustagi M (2011) Gene expression analysis uncovers similarity and differences among Burkitt lymphoma subtypes. Blood 117(13): 3596–3608.

Reiter A, Schrappe M, Ludwig WD et al. (2000) Intensive ALLtype therapy without local radiotherapy provides a 90% eventfree survival for children with T‐cell lymphoblastic lymphoma: a BFM group report. Blood 95: 416–421.

Reiter A, Schrappe M, Tiemann M et al. (1999) Improved treatment results in childhood B‐cell neoplasms with tailored intensification of therapy: a report of the Berlin–Frankfurt–Munster Group trial NHLBFM 90. Blood 94: 3294–3306.

Rosenwald A and Ott G (2008) Burkitt lymphoma versus diffuse large B‐cell lymphoma. Annals of Oncology 19(4): iv67–iv69.

Salaverria I, Beà S, Lopez‐Guillermo A et al. (2008) Genomic profiling reveals different genetic aberrations in systemic ALK‐positive and ALK‐negative anaplastic large cell lymphomas. British Journal of Haematology 140(5): 516–526.

Sandhu SK, Croce CM and Garzon R (2011) Micro‐RNA expression and function in lymphomas. Advances in Hematology 2011: 347137.

Schulz H, Bohlius JF, Trelle S et al. (2007) Immunochemotherapy with rituximab and overall survival in patients with indolent or mantle cell lymphoma: a systematic review and meta‐analysis. Journal of the National Cancer Institute 99: 706–714.

Sebban C, Mounier N, Brousse N et al. (2006) Standard chemotherapy with interferon compared with CHOP followed by high‐dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF‐94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 108(8): 2540–2544.

Shivakumar L and Armitage JO (2006) Bcl‐2 gene expression as a predictor of outcome in diffuse large B‐cell lymphoma. Clinical Lymphoma and Myeloma 6: 455–457.

Soulier J, Clappier E, Cayuela JM et al. (2005) HOXA genes are included in genetic and biologic networks defining human acute T‐cell leukemia (T‐ALL). Blood 106(1): 274–286.

Swerdlow S, Campo E, Harris NL et al. (2008) WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th edn. Lyon, France: IARC Press.

Tracey L, Villuendas R, Dotor AM et al. (2003) Mycosis fungoides shows concurrent deregulation of multiple genes involved in the TNF signaling pathway: an expression profile study. Blood 102: 1042–1050.

Tsimberidou AM, Catovsky D, Schlette E et al. (2006) Outcomes in patients with splenic marginal zone lymphoma and marginal zone lymphoma treated with rituximab with or without chemotherapy or chemotherapy alone. Cancer 107(1): 125–135.

Zinzani PL, Vose JM, Czuczman MS et al. (2013) Long‐term follow‐up of lenalidomide in relapsed/refractory mantle cell lymphoma: subset analysis of the NHL‐003 study. Annals of Oncology 24(11): 2892–2897.

Further Reading

Bander NH, Czuczman MS and Younes A (2012) Antibody‐drug conjugate technology development for hematologic disorders. Clinical Advances in Hematology and Oncology 10(8 Suppl. 10): 1–16.

Barrett DM, Singh N and Porter DL et al. 2013 Chimeric antigen receptor therapy for cancer. Annual Review of Medicine [Epub ahead of print].

Magrath I, Bhatia K, Boffetta P et al. (eds) (2010) The Lymphoid Neoplasms, 3rd edn. London: Hodder.

Suzuki R (2012) NK/T‐cell lymphomas: pathobiology, prognosis and treatment paradigm. Current Oncology Reports 14(5): 395–402. doi:10.1007/s11912‐012‐0245‐9.

Terriou L, Bonnet S, Debarri H et al. (2013) Brentuximab vedotin: new treatment for CD30+ lymphomas. Bulletin du Cancer 100(7–8): 775–779. doi:10.1684/bdc.2013.1778.

Tobinai K, Takahashi T and Akinaga S (2012) Targeting chemokine receptor CCR4 in adult T‐cell leukemia‐lymphoma and other T‐cell lymphomas. Current Hematologic Malignancy Reports 7(3): 235–240. doi:10.1007/s11899‐012‐0124‐3.

Vignon M, Venon MD, Hermine O and Delarue R (2013) Management of mantle cell lymphoma in the elderly: current and potential strategies. Drugs and Aging [Epub ahead of print].

Wilcox RA (2011) Cutaneous T‐cell lymphoma: update on diagnosis, risk‐stratification, and management. American Journal of Hematology 86(11): 928–948. 10.1002/ajh.22139. Review.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Magrath, Ian T, Bellan, Christiana, Leoncini, Lorenzo, and Venkatesh, Hemachandra(Jun 2014) Non‐Hodgkin Lymphomas. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0002171.pub3]