Non-Hodgkin lymphoma pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:  Preeti Singh, M.B.B.S.[2]

## Overview

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Non Hodgkin's Lymphoma (NHL) represents a heterogeneous group of diseases with varied clinical presentation and histological appearance.It arises from cell of the lymphoid system, tumors are mainly derived from B lymphocytes, but are also from T lymphocytes, or natural killer cells. Lymphomas rise from different stages of B and T cell differentiation. Aberrations in the tightly controlled steps of B cell development can lead to oncogenesis. These aberrations are mainly seen in form of chromosomal translocation. About 85% of NHL's are of B-cell origin and only 15% are derived from T/NK cells. Two specific lymphomas, follicular lymphoma and diffuse large B cell lymphoma, account for about 65% of all non-Hodgkin lymphomas.

## Pathophysiology

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* Lymphomas can arise from different stages of B cell development:
* B cell development starts in the primary lymphoid tissue, the bone marrow and subsequent maturation takes place in secondary lymphoid tissue (spleen and lymph nodes).
* At the germinal centers of secondary lymphoid tissue B cells encounter antigens via T cells and then undergo affinity maturation to produce immunoglobulins of high affinity.
* It supports rapid B-cell proliferation for immunoglobulin affinity maturation and production of antibody diversity through two processes know as somatic hypermutation (SHM) and immunoglobulin class switching.
* Both of these processes require rapid cell turnover and multiple double stranded DNA breaks, which is error-prone.
* Somatically acquired genetic alterations ( mainly translocations) of these processes is probably the underlying cause of lymphomagenesis.

* The major subtypes of non-hodgkin lymphoma (NHL) include the following:
* Mature B-cell neoplasms:
* Diffuse large B cell lymphoma
* Follicular lymphoma
* Burkitt lymphoma
* Mantle cell lymphoma
* Hairy cell leukemia
* Extranodal marginal zone lymphoma
* Splenic marginal zone lymphoma
* Plasma cell myeloma
* Mature T and NK neoplasms:
* Adult T-cell lymphoma
* Mycosis fungoides
* Sezary syndrome
* Peripheral T cell lymphoma

* About 85% of NHLs are of B-cell origin and only 15% are derived from T/NK cells.[1]
* The small remainder stems from macrophages.
* These tumors are characterized by the level of differentiation, the size of the cell of origin, the origin cell's rate of proliferation, and the histological pattern of growth.
* Lymphomas of small lymphocytes generally have a more indolent course than those of large lymphocytes, which may have intermediate-grade or high-grade aggressiveness.
* Two specific lymphomas, follicular lymphoma and diffuse large B cell lymphoma, account for about 65% of all non-Hodgkin lymphomas.
* The gene-expression profiles of almost all non-Hodgkin lymphomas are a reflection of the equivalent healthy cell of origin from which the lymphoma is derived.[1]
* Follicular lymphoma most commonly results from the t(14;18)(q32;q21) translocation; this translocation places BCL2 (which encodes B-cell CLL/lymphoma 2) under control of the IGH enhancer element, leading to constitutive BCL2 expression.[2]
* BCL-2 is an anti-apoptotic protein, and the t(14;18)(q32;q21) translocation results in markedly elevated expression of BCL-2, which blocks the healthy germinal center default program of apoptotic cell death and represents a defining pathogenic feature of follicular lymphoma.[2][3]
* Similarly, mantle cell lymphoma is characterised by the t(11;14)(q13;q32) translocation, which leads to the deregulated expression of cyclin D1.[4]
* Moreover, burkitt lymphoma overexpresses MYC as a result of the t(8;14)(q24;q32) translocation or variants.
* Recurrent translocations are less common in peripheral T-cell lymphomas than in other types of lymphoma, and examples include the characteristic t(2;5) (p23;q35) translocation seen in anaplastic lymphoma kinase (ALK)-positive anaplastic T-cell lymphoma and the t(5;9)(q33;q22) translocation associated with follicular T-cell lymphoma.[5]
* Recurrent translocations including t(6;7) (p25;q32) and recurrent gene fusions involving the tumour-suppressor gene TP63 are characteristic of ALK-negative anaplastic T-cell lymphoma.[5][6]

## Genetics

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The development of non-Hodgkin lymphoma is the result of multiple genetic mutations such as:[7][8]

* Mutations of the B-cell receptor genes and NFKB pathway.
* RNA splicing mutations in the small lymphocytic lymphoma.
* Genetic mutations in histone formation:[9]
* MLL2
* MEF2B
* EZH2
* CREBBP
* EP300
* MLL2
* KMT2D
* Mutations in CDKN2A alters cell cycle control and affects JAK–STAT signalling.
* Upregulation of key signalling pathways such as CD79B, MYD88, CARD11.
* Block to terminal differentiation such as BCL6 translocations and loss of PRDM1.

## Associated Conditions

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* Several conditions are associated with non-Hodgkin's lymphoma depending on the type. However, Epstein Barr virus, human immunodeficiency virus, and hepatitis C infection are commonly present.

## Gross Pathology

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* For information on gross pathology findings of Follicular lymphoma, click here.
* For information on gross pathology findings of Mantle cell lymphoma, click here.
* For information on gross pathology findings of Hairy cell leukemia, click here.
* For information on gross pathology findings of Splenic marginal zone lymphoma, click here.
* For information on gross pathology findings of Mycosis fungoides, click here.
* For information on gross pathology findings of Peripheral T cell lymphoma, click here.

## Microscopy Pathology

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* For information on microscopic pathology findings of Follicular lymphoma, click here.
* For information on microscopic pathology findings of Mantle cell lymphoma, click here.
* For information on microscopic pathology findings of Hairy cell leukemia, click here.
* For information on microscopic pathology findings of Splenic marginal zone lymphoma, click here.
* For information on microscopic pathology findings of Mycosis fungoides, click here.
* For information on microscopic pathology findings of Peripheral T cell lymphoma, click here.

## References

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1. ↑ 1.0 1.1 Morton LM, Zheng T, Holford TR, Holly EA, Chiu BC, Costantini AS; et al. (2005). "Alcohol consumption and risk of non-Hodgkin lymphoma: a pooled analysis". Lancet Oncol. 6 (7): 469–76. doi:10.1016/S1470-2045(05)70214-X. PMID 15992695.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
2. ↑ 2.0 2.1 Wang SS, Flowers CR, Kadin ME, Chang ET, Hughes AM, Ansell SM; et al. (2014). "Medical history, lifestyle, family history, and occupational risk factors for peripheral T-cell lymphomas: the InterLymph Non-Hodgkin Lymphoma Subtypes Project". J Natl Cancer Inst Monogr. 2014 (48): 66–75. doi:10.1093/jncimonographs/lgu012. PMC 4155466. PMID 25174027.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
3. ↑ Morton LM, Slager SL, Cerhan JR, Wang SS, Vajdic CM, Skibola CF; et al. (2014). "Etiologic heterogeneity among non-Hodgkin lymphoma subtypes: the InterLymph Non-Hodgkin Lymphoma Subtypes Project". J Natl Cancer Inst Monogr. 2014 (48): 130–44. doi:10.1093/jncimonographs/lgu013. PMC 4155467. PMID 25174034.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
4. ↑ Tamaru JI (2017). "2016 revision of the WHO classification of lymphoid neoplasms". Rinsho Ketsueki. 58 (10): 2188–2193. doi:10.11406/rinketsu.58.2188. PMID 28978864.
5. ↑ 5.0 5.1 Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R; et al. (2016). "The 2016 revision of the World Health Organization classification of lymphoid neoplasms". Blood. 127 (20): 2375–90. doi:10.1182/blood-2016-01-643569. PMC 4874220. PMID 26980727.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
6. ↑ Matutes E (2018). "The 2017 WHO update on mature T- and natural killer (NK) cell neoplasms". Int J Lab Hematol. 40 Suppl 1: 97–103. doi:10.1111/ijlh.12817. PMID 29741263.
7. ↑ Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A; et al. (2011). "Analysis of the coding genome of diffuse large B-cell lymphoma". Nat Genet. 43 (9): 830–7. doi:10.1038/ng.892. PMC 3297422. PMID 21804550.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
8. ↑ Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C; et al. (2012). "Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing". Proc Natl Acad Sci U S A. 109 (10): 3879–84. doi:10.1073/pnas.1121343109. PMC 3309757. PMID 22343534.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)
9. ↑ Green MR, Gentles AJ, Nair RV, Irish JM, Kihira S, Liu CL; et al. (2013). "Hierarchy in somatic mutations arising during genomic evolution and progression of follicular lymphoma". Blood. 121 (9): 1604–11. doi:10.1182/blood-2012-09-457283. PMC 3587323. PMID 23297126.CS1 maint: Explicit use of et al. (link) CS1 maint: Multiple names: authors list (link)

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