Etiology

Non-Hodgkin lymphoma (NHL) has been associated with viruses and bacteria:[2][8][14][15][16][17][18][19][20][21][22]​​​​​​​[23]

  • HIV with B-cell lymphoma (e.g., Burkitt lymphoma, primary, primary central nervous system lymphoma, diffuse large B-cell lymphoma)

  • Epstein-Barr virus (EBV) with Burkitt lymphoma, primary central nervous system lymphoma, and nasal natural killer/T-cell lymphoma

  • Hepatitis C virus (HCV) with splenic marginal zone lymphoma and diffuse large B-cell lymphoma

  • Human T-cell lymphotrophic virus type 1 (HTLV-1) with T-cell lymphoma

  • Human herpesvirus 8 (Kaposi sarcoma-associated herpesvirus) with primary effusion/body cavity lymphoma in HIV patients

  • Coxiella burnetii with B-cell lymphoma

  • Helicobacter pylori with gastric mucosa-associated lymphoid tissue (MALT) lymphoma

  • Borrelia burgdorferi with MALT lymphoma (cutaneous type)

  • Chlamydia psittaci with MALT lymphoma (ocular adnexa)

  • Campylobacter jejuni with MALT lymphoma (intestinal)

NHL has been associated with other immune system disorders:[24][25][26][27][28][29][30][31][32][33][34][35]

  • Autoimmune disorders (including Sjogren syndrome, rheumatoid arthritis, systemic lupus erythematosus, and celiac disease)

  • Acquired immunodeficiency states (post-organ transplant and common variable immunodeficiency)

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

Environmental and other factors

Pesticides and phenoxyherbicides have been linked to NHL in farmers.[36][37][38]

Use of anti-tumor necrosis factor (anti-TNF) drugs (e.g., infliximab, adalimumab) is associated with an increased risk for NHL.[39]

Breast implants (reconstruction or augmentation) are associated with an increased risk of anaplastic large cell lymphoma (ALCL).​[10][13][40][41][42]​​​ ​​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.​​[11]​ Median time from implant to diagnosis of BIA-ALCL is approximately 8 years.[11]

Pathophysiology

Lymphoid malignancies can originate from B cells, T cells, or natural killer (NK) cells.

B-cell lymphoma

  • B cells originate and mature in the bone marrow (central lymphoid tissue compartment). They leave bone marrow to undergo subsequent differentiation in secondary lymphoid tissues (e.g., lymph nodes, spleen), and go on to perform their function in these tissues (peripheral lymphoid tissue compartment).

  • The malignant phenotype in NHL is due to a multi-step accumulation of genetic abnormalities (e.g., due to chromosomal translocations, infection from oncogenic viruses) that confer a growth advantage to, and expansion of, a monoclonal population of malignant lymphocytes.

  • Genetic abnormalities can occur at the stage of early precursors and lead to corresponding subtypes of acute lymphoblastic leukemia. Similarly, immature B cells, mature antigen-naive B cells, and mature antigen-activated B cells may transform to various types of NHL such as Burkitt lymphoma, diffuse large B-cell lymphoma, and mantle cell lymphoma.

  • In terms of transformation from indolent follicular lymphoma to large cell lymphoma, 84% of transformed follicular lymphoma cells are of the germinal center B-cell-like phenotype, while 16% are of the non-germinal center (activated) B-cell-like phenotype. Activated B-cell-like phenotype arises preferentially from BCL2 translocation-negative follicular lymphomas.[43]

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.[44] Interaction between TCR and peptide/major histocompatibility complex (MHC) leads to a commitment to either the CD4+ or the CD8+ cell lineage. Subsequently, T cells undergo a positive selection (to recognize host MHC, self-MHC restriction) and negative selection (to not bind MHC too strongly, which would lead to autoreactive clone, self-MHC tolerance) and are ready to leave the thymus. Those that do not pass double selection die in the thymus through apoptosis. 

  • Genetic abnormalities can occur at different stages of T-cell development and can lead to different malignant phenotypes.

Classification

The 5th edition of the World Health Organization classification of hematolymphoid tumors: lymphoid neoplasms[2]

Mature B-cell neoplasms

  • Pre-neoplastic and neoplastic small lymphocytic proliferations

    • Monoclonal B-cell lymphocytosis

    • Chronic lymphocytic leukemia/small lymphocytic lymphoma

  • Splenic B-cell lymphomas and leukemias

    • Hairy cell leukemia

    • Splenic marginal zone lymphoma

    • Splenic diffuse red pulp small B-cell lymphoma

    • Splenic B-cell lymphoma/leukemia with prominent nucleoli

  • Lymphoplasmacytic lymphoma

    • IgM-lymphoplasmacytic lymphoma (Waldenström macroglobulinemia)

    • Non-Waldenström macroglobulinemia type lymphoplasmacytic lymphoma

  • Marginal zone lymphoma

    • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue

    • Primary cutaneous marginal zone lymphoma

    • Nodal marginal zone lymphoma

    • Pediatric 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 cytologic features; or predominantly diffuse growth pattern)

    • Pediatric-type follicular lymphoma

    • Duodenal-type follicular lymphoma

  • Cutaneous follicle center lymphoma

    • Primary cutaneous follicle center lymphoma

  • Mantle cell lymphoma

    • In situ mantle cell neoplasm

    • Mantle cell lymphoma

    • Leukemic non-nodal mantle cell lymphoma

  • Transformations of indolent B-cell lymphomas

  • Large B-cell lymphomas

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

    • 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 grey zone lymphoma

    • High-grade B-cell lymphoma, NOS

  • Burkitt lymphoma

  • Kaposi 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 leukemias

    • T-prolymphocytic leukemia

    • T-large granular lymphocytic leukemia

    • NK-large granular lymphocytic leukemia

    • Adult T-cell leukemia/lymphoma

    • Sézary syndrome

    • Aggressive NK-cell leukemia

  • 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[3]

Mature B-cell neoplasms

  • Chronic lymphocytic leukemia/small lymphocytic lymphoma

  • Monoclonal B-cell lymphocytosis

    • Chronic lymphocytic leukemia type

    • Nonchronic lymphocytic leukemia type

  • B-cell prolymphocytic leukemia

  • Splenic marginal zone lymphoma

  • Hairy cell leukemia

  • Splenic B-cell lymphoma/leukemia, unclassifiable

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

    • Hairy cell leukemia-variant (provisional)

  • Lymphoplasmacytic lymphoma

    • Waldenström macroglobulinemia

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

  • Primary cutaneous marginal zone lymphoproliferative disorder

  • Nodal marginal zone lymphoma

    • Pediatric nodal marginal zone lymphoma (provisional)

  • Follicular lymphoma

    • In situ follicular neoplasia

    • Duodenal-type follicular lymphoma

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

  • Primary cutaneous follicle center lymphoma

  • Pediatric-type follicular lymphoma

  • Testicular follicular lymphoma

  • Large B-cell lymphoma with IRF4 rearrangement

  • Mantle cell lymphoma

    • In situ mantle cell neoplasia

    • Leukemic non-nodal mantle cell lymphoma

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

    • Germinal center 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 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 leukemia

  • T-cell large granular lymphocytic leukemia

  • Chronic lymphoproliferative disorder of NK cells (provisional)

  • Adult T-cell leukemia/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 leukemia

  • 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/body cavity lymphoma

  • Burkitt lymphoma

  • Mantle cell lymphoma

  • High-grade B-cell lymphoma

  • B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin 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 leukemia/small lymphocytic lymphoma

  • Lymphoplasmacytic lymphoma

    • Waldenström macroglobulinemia

Indolent T-cell lymphomas

  • Mycosis fungoides/Sézary syndrome

  • Primary cutaneous anaplastic large cell lymphoma

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

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