Non-Hodgkin lymphoma pathophysiology: Difference between revisions
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{{Non-Hodgkin lymphoma}} | {{Non-Hodgkin lymphoma}} | ||
{{CMG}}; {{AE}} | {{CMG}}; {{AE}} {{Preeti}} | ||
==Overview== | ==Overview== | ||
Non Hodgkin's Lymphoma 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. | Non Hodgkin's Lymphoma 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. | ||
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*Somatically acquired genetic alterations ( mainly [[Chromosomal translocation|translocations]]) of these processes is probably the underlying cause of lymphomagenesis. | *Somatically acquired genetic alterations ( mainly [[Chromosomal translocation|translocations]]) of these processes is probably the underlying cause of lymphomagenesis. | ||
* The major subtypes of non-hodgkin lymphoma include the following: | * The major subtypes of non-hodgkin lymphoma (NHL) include the following: | ||
** Mature B-cell neoplasms: | ** Mature B-cell neoplasms: | ||
*** [[Diffuse large B cell lymphoma]] | *** [[Diffuse large B cell lymphoma]] | ||
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*** [[Peripheral T cell lymphoma]] | *** [[Peripheral T cell lymphoma]] | ||
*About 85% of NHLs are of B-cell origin | |||
*Only 15% are derived from T/NK cells | |||
*The small remainder stem 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 histologic 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 DLBCL, account for about 65% of all non-Hodgkin lymphomas, and thus a thorough knowledge of these two entities is essential. | |||
*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. | |||
*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. | |||
*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 programme of apoptotic cell death and represents a defi ning pathogenic feature of follicular lymphoma. | |||
*Similarly, mantle cell lymphoma is characterised by the t(11;14)(q13;q32) translocation, which leads to the deregulated expression of cyclin D1. | |||
*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. | |||
==Genetics== | ==Genetics== | ||
The development of Non-Hodgkin lymphoma is the result of multiple genetic mutations such as:<ref name="pmid21804550">{{cite journal| author=Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A et al.| title=Analysis of the coding genome of diffuse large B-cell lymphoma. | journal=Nat Genet | year= 2011 | volume= 43 | issue= 9 | pages= 830-7 | pmid=21804550 | doi=10.1038/ng.892 | pmc=3297422 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21804550 }}</ref><ref name="pmid22343534">{{cite journal| author=Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C et al.| title=Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. | journal=Proc Natl Acad Sci U S A | year= 2012 | volume= 109 | issue= 10 | pages= 3879-84 | pmid=22343534 | doi=10.1073/pnas.1121343109 | pmc=3309757 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22343534 }}</ref> | The development of Non-Hodgkin lymphoma is the result of multiple genetic mutations such as:<ref name="pmid21804550">{{cite journal| author=Pasqualucci L, Trifonov V, Fabbri G, Ma J, Rossi D, Chiarenza A et al.| title=Analysis of the coding genome of diffuse large B-cell lymphoma. | journal=Nat Genet | year= 2011 | volume= 43 | issue= 9 | pages= 830-7 | pmid=21804550 | doi=10.1038/ng.892 | pmc=3297422 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21804550 }}</ref><ref name="pmid22343534">{{cite journal| author=Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C et al.| title=Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. | journal=Proc Natl Acad Sci U S A | year= 2012 | volume= 109 | issue= 10 | pages= 3879-84 | pmid=22343534 | doi=10.1073/pnas.1121343109 | pmc=3309757 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22343534 }}</ref> | ||
Revision as of 21:21, 19 January 2019
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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
Non Hodgkin's Lymphoma 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.
Pathophysiology
- 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:
- Mature B-cell neoplasms:
- About 85% of NHLs are of B-cell origin
- Only 15% are derived from T/NK cells
- The small remainder stem 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 histologic 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 DLBCL, account for about 65% of all non-Hodgkin lymphomas, and thus a thorough knowledge of these two entities is essential.
- 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.
- 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.
- 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 programme of apoptotic cell death and represents a defi ning pathogenic feature of follicular lymphoma.
- Similarly, mantle cell lymphoma is characterised by the t(11;14)(q13;q32) translocation, which leads to the deregulated expression of cyclin D1.
- 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.
Genetics
The development of Non-Hodgkin lymphoma is the result of multiple genetic mutations such as:[1][2]
- Mutations of the B-cell receptor genes and NFKB pathway
- RNA splicing mutations in the small lymphocytic lymphoma
- Genetic mutations in histone formation:[3]
- MLL2
- MEF2B
- EZH2
- CREBBP
- EP300
- MLL2
References
- ↑ 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.
- ↑ 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.
- ↑ 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.