Aetiology

Non-Hodgkin's lymphoma (NHL) has been associated with viral and bacterial infection:[25][26][27][28][29][30][31][32][33]​​​​​[34][35][36]

  • HIV with B-cell lymphoma (e.g., Burkitt's lymphoma, diffuse large B-cell lymphoma [DLBCL], primary central nervous system lymphoma [PCNSL])

  • Epstein-Barr virus (EBV) with B-cell lymphoma (e.g., DLBCL, PCNSL, Burkitt's lymphoma) and T-cell lymphoma (e.g., peripheral T-cell lymphoma, extranodal NK/T-cell lymphoma

  • Hepatitis C virus (HCV) with splenic marginal zone lymphoma and DLBCL

  • Human T-cell lymphotrophic virus type 1 (HTLV-1) with adult T-cell leukaemia/lymphoma (ATLL)

  • Kaposi sarcoma-associated herpesvirus/human herpesvirus 8 (KSHV/HHV8) with primary effusion lymphoma (in patients with HIV), DLBCL, and germinotropic lymphoproliferative disorder

  • Coxiella burnetii with B-cell lymphoma

NHL has been associated with the following immune-related disorders/conditions:[37][38][39][40]​​​[41][42][43]​​​​

  • Autoimmune disorders (e.g., Sjogren syndrome, rheumatoid arthritis, coeliac disease, systemic lupus erythematosus, haemolytic anemi)

  • Immunodeficiency disorders (e.g., common variable immunodeficiency)

  • Inherited immunodeficiency disease (e.g., Wiskott-Aldrich syndrome, ataxia-telangiectasia, and Klinefelter syndrome).

  • Acquired immunodeficiency state (e.g., post-transplant)

Other aetiological factors for NHL

Occupational exposure to certain pesticides has been associated with NHL (e.g., phenoxy herbicides with DLBCL).[44][45][46]

Use of immunomodulatory drugs, such as tumour necrosis factor (TNF)-alpha antagonists (e.g., infliximab, adalimumab), is associated with an increased risk for NHL.[47]

Breast implants are associated with an increased risk of anaplastic large cell lymphoma (ALCL).​[21][24][48][49][50]​​​​​​​ ​​Most cases of breast implant-associated ALCL (BIA-ALCL) have occurred with textured implants, but there have been reports of BIA-ALCL with smooth-surface implants.​​[22]​​ Median time from implant to diagnosis of BIA-ALCL is approximately 8 years.​[22]

Pathophysiology

NHLs are a heterogeneous group of lymphoid malignancies that originate from B cells, T cells, or natural killer (NK) cells.[1][2] These lymphoid malignancies develop in lymphoid tissue (e.g., lymph nodes, spleen) or other parts of the body (e.g., central nervous system, gastrointestinal tract, liver, skin), depending on the subtype.

B-cell lymphoma

  • B cells originate and mature in the bone marrow. They leave bone marrow to undergo subsequent differentiation in secondary lymphoid tissues (e.g., lymph nodes, spleen) where they perform their function.[51]

  • B-cell lymphoma develops when normal B cell differentiation is subverted by cells undergoing clonal proliferation following multi-step accumulation of genetic abnormalities (e.g., mutations, chromosome translocations, viral oncogenesis).[52][53]

  • Genetic abnormalities can occur at various stages of B cell development. But most B-cell lymphomas (including DLBCL, follicular lymphoma, Burkitt's lymphoma) arise at the germinal centre reaction stage, when B cells are most vulnerable to genetic alterations and oncogenic transformation.[52][54]​​[55]

  • Indolent follicular lymphoma can undergo histological transformation to aggressive DLBCL, most commonly the germinal centre B-cell-like (GCB) subtype.[56]

T-cell lymphoma

  • T cells originate in the bone marrow and then migrate to the thymus where they mature. The process of maturation begins with T cells developing a functional T-cell receptor (TCR) and then developing into CD4+/CD8+ cells.[57]

  • Genetic abnormalities (e.g., mutations, chromosome translocations, viral oncogenesis) can occur at different stages of T-cell development and can lead to different malignant phenotypes.[58][59]

NK-cell lymphoma

  • NK cells originate in the bone marrow where they remain and mature, or they migrate to secondary lymphoid tissue (e.g., tonsils, spleen, lymph nodes) and mature.[60] 

  • Genetic abnormalities and Epstein-Barr virus infection are involved in the development of NK-cell lymphomas, but the exact mechanism is unclear.[61][62]

Classification

The 5th edition of the World Health Organization classification of haematolymphoid tumours: lymphoid neoplasms[1]

Mature B-cell neoplasms

  • Pre-neoplastic and neoplastic small lymphocytic proliferations

    • Monoclonal B-cell lymphocytosis

    • Chronic lymphocytic leukaemia/small lymphocytic lymphoma

  • Splenic B-cell lymphomas and leukaemias

    • Hairy cell leukaemia

    • Splenic marginal zone lymphoma

    • Splenic diffuse red pulp small B-cell lymphoma

    • Splenic B-cell lymphoma/leukaemia with prominent nucleoli

  • Lymphoplasmacytic lymphoma

    • IgM-lymphoplasmacytic lymphoma (Waldenström's macroglobulinaemia)

    • Non-Waldenström's macroglobulinaemia type lymphoplasmacytic lymphoma

  • Marginal zone lymphoma

    • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

    • Primary cutaneous marginal zone lymphoma

    • Nodal marginal zone lymphoma

    • Paediatric marginal zone lymphoma

  • Follicular lymphoma

    • In situ follicular B-cell neoplasm

    • Follicular lymphoma

      • Classic follicular lymphoma

      • Follicular large B-cell lymphoma

      • Follicular lymphoma with uncommon features (e.g., blastoid or large centrocyte variant cytological features; or predominantly diffuse growth pattern)

    • Paediatric-type follicular lymphoma

    • Duodenal-type follicular lymphoma

  • Cutaneous follicle centre lymphoma

    • Primary cutaneous follicle centre lymphoma

  • Mantle cell lymphoma

    • In situ mantle cell neoplasm

    • Mantle cell lymphoma

    • Leukaemic non-nodal mantle cell lymphoma

  • Transformations of indolent B-cell lymphomas

  • Large B-cell lymphomas

    • Diffuse large B-cell lymphoma, not otherwise specified (NOS)

      • Germinal centre B-cell-like (GCB) subtype

      • Activated B-cell-like (ABC) subtype

    • T-cell/histiocyte-rich large B-cell lymphoma

    • Diffuse large B-cell lymphoma/high grade B-cell lymphoma with MYC and BCL2 rearrangements

    • ALK-positive large B-cell lymphoma

    • Large B-cell lymphoma with IRF4 rearrangement

    • High-grade B-cell lymphoma with 11q aberrations

    • Lymphomatoid granulomatosis

    • Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma

    • Diffuse large B-cell lymphoma associated with chronic inflammation

    • Fibrin-associated large B-cell lymphoma

    • Fluid overload-associated large B-cell lymphoma

    • Plasmablastic lymphoma

    • Primary large B-cell lymphoma of immune-privileged sites (e.g., central nervous system [CNS], vitreoretina, testis)

    • Primary cutaneous diffuse large B-cell lymphoma, leg type

    • Intravascular large B-cell lymphoma

    • Primary mediastinal large B-cell lymphoma

    • Mediastinal gray zone lymphoma

    • High-grade B-cell lymphoma, NOS

  • Burkitt's lymphoma

  • Kaposi's sarcoma herpesvirus (KSHV)/human herpesvirus 8 (HHV8)-associated B-cell lymphoid proliferations and lymphomas

    • Primary effusion lymphoma

    • KSHV/HHV8-positive diffuse large B-cell lymphoma

    • KSHV/HHV8-positive germinotropic lymphoproliferative disorder

  • Lymphoid proliferations and lymphomas associated with immune deficiency and dysregulation

    • Hyperplasias arising in immune deficiency/dysregulation

    • Polymorphic lymphoproliferative disorders arising in immune deficiency/dysregulation

    • EBV-positive mucocutaneous ulcer

    • Lymphomas arising in immune deficiency/dysregulation (e.g., lymphomas associated with HIV infection)

    • Inborn error of immunity-associated lymphoid proliferations and lymphomas

Mature T-cell and natural killer (NK)-cell neoplasms

  • Mature T-cell and NK-cell leukaemias

    • T-prolymphocytic leukaemia

    • T-large granular lymphocytic leukaemia

    • NK-large granular lymphocytic leukaemia

    • Adult T-cell leukaemia/lymphoma

    • Sézary syndrome

    • Aggressive NK-cell leukaemia

  • Primary cutaneous T-cell lymphomas

    • Primary cutaneous CD4+ small or medium T-cell lymphoproliferative disorder

    • Primary cutaneous acral CD8+ lymphoproliferative disorder

    • Mycosis fungoides

    • Primary cutaneous CD30+ T-cell lymphoproliferative disorder

      • Lymphomatoid papulosis

      • Primary cutaneous anaplastic large cell lymphoma

    • Subcutaneous panniculitis-like T-cell lymphoma

    • Primary cutaneous gamma/delta T-cell lymphoma

    • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

    • Primary cutaneous peripheral T-cell lymphoma, NOS

  • Intestinal T-cell and NK-cell lymphoid proliferations and lymphomas

    • Indolent T-cell lymphoma of the gastrointestinal tract

    • Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract

    • Enteropathy-associated T-cell lymphoma

    • Monomorphic epitheliotropic intestinal T-cell lymphoma

    • Intestinal T-cell lymphoma, NOS

  • Hepatosplenic T-cell lymphoma

  • Anaplastic large cell lymphoma

    • ALK-positive anaplastic large cell lymphoma

    • ALK-negative anaplastic large cell lymphoma

    • Breast implant-associated anaplastic large cell lymphoma

  • Nodal T-follicular helper (TFH) cell lymphoma

    • Nodal TFH cell lymphoma, angioimmunoblastic-type

    • Nodal TFH cell lymphoma, follicular-type

    • Nodal TFH cell lymphoma, NOS

  • Other peripheral T-cell lymphomas

    • Peripheral T-cell lymphoma, NOS

  • EBV-positive NK/T-cell lymphomas

    • EBV-positive nodal T- and NK-cell lymphoma

    • Extranodal NK/T-cell lymphoma

  • EBV-positive T- and NK-cell lymphoid proliferations and lymphomas of childhood

    • Severe mosquito bite allergy

    • Hydroa vacciniforme lymphoproliferative disorder

    • Systemic chronic active EBV disease

    • Systemic EBV-positive T-cell lymphoma of childhood

International Consensus Classification of mature lymphoid and histiocytic/dendritic cell neoplasms[2]

Mature B-cell neoplasms

  • Chronic lymphocytic leukaemia/small lymphocytic lymphoma

  • Monoclonal B-cell lymphocytosis

    • Chronic lymphocytic leukaemia type

    • Non-chronic lymphocytic leukaemia type

  • B-cell prolymphocytic leukaemia

  • Splenic marginal zone lymphoma

  • Hairy cell leukaemia

  • Splenic B-cell lymphoma/leukaemia, unclassifiable (provisional)

    • Splenic diffuse red pulp small B-cell lymphoma (provisional)

    • Hairy cell leukaemia-variant (provisional)

  • Lymphoplasmacytic lymphoma

    • Waldenström's macroglobulinaemia

  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma)

  • Primary cutaneous marginal zone lymphoproliferative disorder

  • Nodal marginal zone lymphoma

    • Paediatric nodal marginal zone lymphoma (provisional)

  • Follicular lymphoma

    • In situ follicular neoplasia

    • Duodenal-type follicular lymphoma

  • BCL2-R-negative, CD23-positive follicle centre lymphoma (provisional)

  • Primary cutaneous follicle centre lymphoma

  • Paediatric-type follicular lymphoma

  • Testicular follicular lymphoma

  • Large B-cell lymphoma with IRF4 rearrangement

  • Mantle cell lymphoma

    • In situ mantle cell neoplasia

    • Leukaemic non-nodal mantle cell lymphoma

  • Diffuse large B-cell lymphoma, not otherwise specified (NOS)

    • Germinal centre B-cell subtype

    • Activated B-cell subtype

  • Large B-cell lymphoma with 11q aberration (provisional)

  • Nodular lymphocyte predominant B-cell lymphoma

  • T cell/histiocyte-rich large B-cell lymphoma

  • Primary diffuse large B-cell lymphoma of the CNS

  • Primary diffuse large B-cell lymphoma of the testis

  • Primary cutaneous diffuse large B-cell lymphoma, leg type

  • Intravascular large B-cell lymphoma

  • Human herpesvirus (HHV)-8 and Epstein-Barr virus-negative primary effusion-based lymphoma (provisional)

  • Epstein-Barr virus-positive mucocutaneous ulcer

  • Epstein-Barr virus-positive diffuse large B-cell lymphoma, NOS

  • Diffuse large B-cell lymphoma associated with chronic inflammation

    • Fibrin-associated diffuse large B-cell lymphoma

  • Lymphomatoid granulomatosis

  • Epstein-Barr virus-positive polymorphic B-cell lymphoproliferative disorder, NOS

  • ALK-positive large B-cell lymphoma

  • Plasmablastic lymphoma

  • HHV-8-associated lymphoproliferative disorders

    • Multicentric Castleman disease

    • HHV-8-positive germinotropic lymphoproliferative disorder

    • HHV-8-positive diffuse large B-cell lymphoma, NOS

    • Primary effusion lymphoma

  • Burkitt's lymphoma

  • High-grade B-cell lymphoma, with MYC and BCL2 rearrangements

  • High-grade B-cell lymphoma with MYC and BCL6 rearrangements (provisional)

  • High-grade B-cell lymphoma, NOS

  • Primary mediastinal large B-cell lymphoma

  • Mediastinal gray-zone lymphoma

Mature T-cell and NK-cell neoplasms

  • T-cell prolymphocytic leukaemia

  • T-cell large granular lymphocytic leukaemia

  • Chronic lymphoproliferative disorder of NK cells (provisional)

  • Adult T-cell leukaemia/lymphoma

  • Epstein-Barr virus-positive T-cell/NK-cell lymphoproliferative disorders of childhood

    • Hydroa vacciniforme lymphoproliferative disorder

      • Classic

      • Systemic

    • Severe mosquito bite allergy

    • Chronic active Epstein-Barr virus disease, systemic (T-cell and NK-cell phenotype)

    • Systemic Epstein-Barr virus-positive T-cell lymphoma of childhood

  • Extranodal NK/T-cell lymphoma, nasal type

  • Aggressive NK-cell leukaemia

  • Primary nodal Epstein-Barr virus-positive T-cell/NK-cell lymphoma (provisional)

  • Enteropathy-associated T-cell lymphoma

    • Type II refractory celiac disease

  • Monomorphic epitheliotropic intestinal T-cell lymphoma

  • Intestinal T-cell lymphoma, NOS

  • Indolent clonal T-cell lymphoproliferative disorder of the gastrointestinal tract

  • Indolent NK-cell lymphoproliferative disorder of the gastrointestinal tract

  • Hepatosplenic T-cell lymphoma

  • Mycosis fungoides

  • Sézary syndrome

  • Primary cutaneous CD30+ T-cell lymphoproliferative disorders

    • Lymphomatoid papulosis

    • Primary cutaneous anaplastic large cell lymphoma

  • Primary cutaneous small/medium CD4+ T-cell lymphoproliferative disorder

  • Subcutaneous panniculitis-like T-cell lymphoma

  • Primary cutaneous gamma-delta T-cell lymphoma

  • Primary cutaneous acral CD8+ T-cell lymphoproliferative disorder

  • Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma

  • Peripheral T-cell lymphoma, NOS

  • Follicular helper T-cell lymphoma

    • Follicular helper T-cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma)

    • Follicular helper T-cell lymphoma, follicular type

    • Follicular helper T-cell lymphoma, NOS

  • Anaplastic large cell lymphoma, ALK positive

  • Anaplastic large cell lymphoma, ALK negative

  • Breast implant-associated anaplastic large cell lymphoma

Clinical classification

Aggressive B-cell lymphomas

  • Diffuse large B-cell lymphoma (DLBCL)

  • Primary mediastinal large B-cell lymphoma

  • Primary CNS lymphoma (95% are DLBCL)

  • Primary effusion lymphoma

  • Burkitt's lymphoma

  • Mantle cell lymphoma

  • High-grade B-cell lymphoma

  • Mediastinal gray zone lymphoma

Aggressive T-cell lymphomas

  • Enteropathy-associated T-cell lymphoma/intestinal T-cell lymphoma

  • Peripheral T-cell lymphoma, NOS

  • Subcutaneous panniculitis-like T-cell lymphoma

  • Systemic anaplastic large cell lymphoma

  • Angioimmunoblastic T-cell lymphoma

Indolent B-cell lymphomas

  • Follicular lymphoma

  • Marginal zone lymphoma

  • Chronic lymphocytic leukaemia/small lymphocytic lymphoma

  • Lymphoplasmacytic lymphoma

    • Waldenström's macroglobulinaemia

Indolent T-cell lymphomas

  • Mycosis fungoides/Sézary syndrome*

  • Primary cutaneous anaplastic large cell lymphoma

  • Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL)

*These subtypes are covered in separate topics in BMJ Best Practice, and are not discussed in this topic.

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