Non-Hodgkin lymphoma pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Pathophysiology
- Non-Hodgkin's lymphoma is a group of different types of lymphoid tissue tumors. These lymphoid tumors are derived from B lymphocytes, T lymphocytes, or natural killer cells which are the main immune cells in the body.[1]
- The subtypes of non-hodgkin lymphoma include the following:[2]
- Burkitt lymphoma
- Diffuse large B cell lymphoma
- Mantle cell lymphoma
- Small lymphocytic lymphoma
- Follicular lymphoma
- Extranodal marginal zone lymphoma
- Splenic marginal zone lymphoma
- Lymphoplasmacytic lymphoma
Pathogenesis
- The main pathogenesis mechanism of NHL is genetic mutations of the proto-oncogenes and tumor suppressor genes.
- Unlike the solid tumors, the lymphomas do not have have microsatellite instability which is a DNA mismatch repair defect. Microsatellite instability is incorporated in the pathogenesis of many solid tumors.
- In NHL, there is mostly single or few chromosomal abnormalities in the genes causing lymphoma and it is caused by chromosomal translocation. The unbalanced translocations has been shown to be the cause of the disease progression.[3]
- At the molecular level, the genetic lesions identified thus far in the lymphomas include the activation of oncogenes by chromosomal translocations, as well as the inactivation of tumor suppressor loci by chromosomal deletion or mutation. Of importance, the genome in certain lymphoma subtypes has been altered by the introduction of exogenous genes via a number of oncogenic viruses. Point mutations may also result in the changes in the epigenetic control of transcription (eg, TET mutations, DNMT3A mutations) or process of translation (eg, spliceosome mutations) [11,12,19,20]. The full spectrum of somatic mutations has yet to be defined. (See 'Viral genome integration' below.) Deletions and mutations of the p53 tumor suppressor gene, which may represent the most common genetic alteration in human cancer, are relatively restricted to specific subsets of NHL, including late stages of follicular lymphoma, CLL/SLL,mantle cell NHL, and Burkitt lymphoma [21-23]. The mechanisms of p53 inactivation in NHL are similar to those detected in human neoplasia in general, occurring through point mutation of one allele and/or chromosomal deletion of the second allele [21]. The occurrence of NHL variants associated with specific chromosomal deletions also suggests the loss of currently unknown tumor suppressor genes [6]. The most frequent of these deletions involves the long arm of chromosome 6 (6q) [24]. The observations that 6q deletions may occur as the sole cytogenetic abnormality in some NHL cases, and are associated with poor prognosis [5], strongly support a pathogenetic role for these alterations. Deletions of chromosome 13q14 represent the most frequent lesion in CLL/SLL, occurring in more than 50 percent of cases [25]. Mapping studies have determined that the minimal region of deletion does not include the retinoblastoma tumor suppressor gene, which is also located on chromosome 13q14, but rather is focused on MIR15-16 [25]. These micro-RNA genes, such as miR-15a or miR-16-1, may also act as tumor suppressors [26,27]. MicroRNAs are small conserved noncoding RNAs that downregulate their target genes by specifically decreasing their mRNA levels [28]. The B cell leukemia/lymphoma 2 (Bcl-2) gene is thought to be a target of miR-15a/miR16-1. (See "Pathophysiology and genetic features of chronic lymphocytic leukemia", section on 'del(13q14)'.)
Genetics
The development of Non-Hodgkin lymphoma is the result of multiple genetic mutations such as:[4][5]
- Mutations of the B-cell receptor genes and NFKB pathway
- RNA splicing mutations in the small lymphocytic lymphoma
- Genetic mutations in histone formation:[6]
- MLL2
- MEF2B
- EZH2
- CREBBP
- EP300
- MLL2
Gross Pathology
On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
Microscopic Pathology
On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name].
References
- ↑ Farrell K, Jarrett RF (2011). "The molecular pathogenesis of Hodgkin lymphoma". Histopathology. 58 (1): 15–25. doi:10.1111/j.1365-2559.2010.03705.x. PMID 21261680.
- ↑ Coupland SE (2011). "The challenge of the microenvironment in B-cell lymphomas". Histopathology. 58 (1): 69–80. doi:10.1111/j.1365-2559.2010.03706.x. PMID 21261684.
- ↑ Johansson B, Mertens F, Mitelman F (1995). "Cytogenetic evolution patterns in non-Hodgkin's lymphoma". Blood. 86 (10): 3905–14. PMID 7579360.
- ↑ 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.