Chronic lymphocytic leukemia pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Shalinder Singh, M.B.B.S.[2] Haytham Allaham, M.D. [3]
Overview
Chronic lymphocytic leukemia arises from pre-follicular center B cells, that are normally involved in the process of human immunoglobulin production. Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells. Structural genetic mutations involved in the pathogenesis of chronic lymphocytic leukemia include chromosome 13q deletion, chromosome 17p deletion, and chromosome 11q deletion. On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include small lymphoid cells, thin cytoplasmic border, lack of nucleolus, and the presence of smudge cells.
Pathogenesis
- Chronic lymphocytic leukemia is defined as clonal proliferation of incompetent B-cells.[1]
- Chronic lymphocytic leukemia arises from pre-follicular center B cells that are normally involved in the process of human immunoglobulins production.
- Chronic lymphocytic leukemia cells are clonal B cells and their differentiation is halted between the pre-B cells and mature B cells.[2]
- Pre-malignant B cell proliferation precedes chronic lymphocytic leukemia/small lymphocytic leukemia and is known as monoclonal B cell lymphocytosis (MBL).[3]
- There are multiple factors leading to production of MBL, which involves antigen stimulation, gene mutation, environment factors, immunologic and cytogenetic modifications.
- Repeated results from these factors leads to advancement of MBL to chronic lymphocytic leukemia.
- Most of the patients of chronic lymphocytic leukemia are asymptomatic, until the incomptent lymphocytes start to accumulate and infiltrate organ systems.
- Malignant lymphocytic cells infiltrate hematopoietic sites ,such as the bone marrow, where they interfere with the production of red blood cells and platelets.
- Chronic lymphocytic leukemia may also infiltrate the lymph nodes, spleen, and liver.
- Immune deficiency may occur in chronic lymphocytic leukemia as the majority of cases develop hypogammaglobulinemia.
- Warm autoimmune hemolytic anemia may develop due to the production of IgA and IgG autoantibodies among certain cases of chronic lymphocytic anemia.
- Autoimmune thrombocytopenia may develop due to the production of autoantibodies.
- Production of cytokines, angiogenic factors, and chemokines by the surrounding macrophages and T cells provide important stimuli for malignant B cells proliferation in chronic lymphocytic leukemia.
- Richter's transformation represents the conversion of chronic lymphocytic leukemia into a more aggressive and rapidly growing large B cell lymphoma.[4]
- Richter's transformation may occur among 1-5% of chronic lymphocytic leukemia cases.[5]
The pathogenesis of Chronic lymphocytic leukemia can be described as following:
Immunology
- Chronic lymphocytic leukemia cells express B-cell surface antigens such as CD19, CD20, CD21 and CD23 monoclonal antibodies.[6][7]
- They also express CD5, which is a T-cell antibody.[8]
- Chronic lymphocytic leukemia cells also express decreased level of B- cell surface antigens IgM and IgD immunoglobulin.[9]
Cytogenetics
- Development of chronic lymphocytic leukemia is the result of multiple genetic mutations that promote both malignant leukemic proliferation and apoptotic resistance of mature B cells.
- Structural genetic mutations and associated features involved in the pathogenesis of chronic lymphocytic leukemia include:
- Chromosome 11 long arm deletion (11q22-q23): Relapsing disease, refractory to initial therapy, poor prognosis, large-scale lymph node involvement and shorter survival[10][11]
- Chromosome 13 long arm deletion (most common genetic mutation): Better prognosis[12]
- Chromosome 17p13 deletion: Tumor suppressor gene TP53 deletion, relapsing disease and refractory to initial therapy[12][13]
- Trisomy 12 : Increased proliferation and advanced disease.[14]
Molecular Genetics
- Somatic genetic mutations and associated factors involved in the pathogenesis of chronic lymphocytic leukemia include:
- SF3B1 gene located on chromosome 2: Poor prognosis[15][16]
- B cell receptor (BCR) signaling[17]
- FBXW7 gene located on chromosome 4
- MYD88 gene located on chromosome 3
- TP53 gene located on chromosome 7
- NOTCH1 gene located on chromosome 9[18]
- ATM gene located on chromosome 11
- CHD2 gene located on chromosome 15
- MicroRNA
- The type of the genetic mutation is considered one of the important factors that determine the optimal management protocol of chronic lymphocytic leukemia patients.
Microscopic Pathology
- On microscopic histopathological analysis, characteristic findings of chronic lymphocytic leukemia include:
- On immunohistochemistry, characteristic findings of chronic lymphocytic leukemia include:
- Illustrated below is a series of microscopic images observed in chronic lymphocytic leukemia:
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![Chronic lymphocytic leukemia illustrated on low magnification[19]](/images/9/9b/Chronic_lymphocytic_leukemia_-_low_mag.jpg)
Chronic lymphocytic leukemia illustrated on low magnification[19]
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![Chronic lymphocytic leukemia illustrated on intermediate magnification[19]](/images/5/55/Chronic_lymphocytic_leukemia_-_intermed_mag.jpg)
Chronic lymphocytic leukemia illustrated on intermediate magnification[19]
-
![Chronic lymphocytic leukemia illustrated on high magnification[19]](/images/2/24/Chronic_lymphocytic_leukemia_-_high_mag.jpg)
Chronic lymphocytic leukemia illustrated on high magnification[19]
-
![Chronic lymphocytic leukemia illustrated on very high magnification[19]](/images/7/77/Chronic_lymphocytic_leukemia_-_very_high_mag.jpg)
Chronic lymphocytic leukemia illustrated on very high magnification[19]
![Chronic lymphocytic leukemia illustrated on low magnification[19]](/index.php/File:Chronic_lymphocytic_leukemia_-_low_mag.jpg)
![Chronic lymphocytic leukemia illustrated on intermediate magnification[19]](/index.php/File:Chronic_lymphocytic_leukemia_-_intermed_mag.jpg)
![Chronic lymphocytic leukemia illustrated on high magnification[19]](/index.php/File:Chronic_lymphocytic_leukemia_-_high_mag.jpg)
![Chronic lymphocytic leukemia illustrated on very high magnification[19]](/index.php/File:Chronic_lymphocytic_leukemia_-_very_high_mag.jpg)
References
- ↑ Herishanu Y, Katz BZ, Lipsky A, Wiestner A (April 2013). "Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications". Hematol. Oncol. Clin. North Am. 27 (2): 173–206. doi:10.1016/j.hoc.2013.01.002. PMID 23561469.
- ↑ Herishanu Y, Katz BZ, Lipsky A, Wiestner A (April 2013). "Biology of chronic lymphocytic leukemia in different microenvironments: clinical and therapeutic implications". Hematol. Oncol. Clin. North Am. 27 (2): 173–206. doi:10.1016/j.hoc.2013.01.002. PMID 23561469.
- ↑ Strati P, Shanafelt TD (July 2015). "Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification". Blood. 126 (4): 454–62. doi:10.1182/blood-2015-02-585059. PMID 26065657.
- ↑ Jain P, O'Brien S (December 2012). "Richter's transformation in chronic lymphocytic leukemia". Oncology (Williston Park, N.Y.). 26 (12): 1146–52. PMID 23413591.
- ↑ Jain P, O'Brien S (December 2012). "Richter's transformation in chronic lymphocytic leukemia". Oncology (Williston Park, N.Y.). 26 (12): 1146–52. PMID 23413591.
- ↑ Fournier S, Delespesse G, Rubio M, Biron G, Sarfati M (April 1992). "CD23 antigen regulation and signaling in chronic lymphocytic leukemia". J. Clin. Invest. 89 (4): 1312–21. doi:10.1172/JCI115717. PMC 442993. PMID 1532590.
- ↑ Geisler CH, Larsen JK, Hansen NE, Hansen MM, Christensen BE, Lund B, Nielsen H, Plesner T, Thorling K, Andersen E (October 1991). "Prognostic importance of flow cytometric immunophenotyping of 540 consecutive patients with B-cell chronic lymphocytic leukemia". Blood. 78 (7): 1795–802. PMID 1717071.
- ↑ Friedman DR, Guadalupe E, Volkheimer A, Moore JO, Weinberg JB (December 2018). "Clinical outcomes in chronic lymphocytic leukaemia associated with expression of CD5, a negative regulator of B-cell receptor signalling". Br. J. Haematol. 183 (5): 747–754. doi:10.1111/bjh.15632. PMID 30407619.
- ↑ Haerzschel A, Catusse J, Hutterer E, Paunovic M, Zirlik K, Eibel H, Krenn PW, Hartmann TN, Burger M (December 2016). "BCR and chemokine responses upon anti-IgM and anti-IgD stimulation in chronic lymphocytic leukaemia". Ann. Hematol. 95 (12): 1979–1988. doi:10.1007/s00277-016-2788-6. PMC 5093209. PMID 27542958.
- ↑ Döhner H, Stilgenbauer S, James MR, Benner A, Weilguni T, Bentz M, Fischer K, Hunstein W, Lichter P (April 1997). "11q deletions identify a new subset of B-cell chronic lymphocytic leukemia characterized by extensive nodal involvement and inferior prognosis". Blood. 89 (7): 2516–22. PMID 9116297.
- ↑ Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P (December 2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". N. Engl. J. Med. 343 (26): 1910–6. doi:10.1056/NEJM200012283432602. PMID 11136261.
- ↑ 12.0 12.1 Döhner H, Stilgenbauer S, Benner A, Leupolt E, Kröber A, Bullinger L, Döhner K, Bentz M, Lichter P (December 2000). "Genomic aberrations and survival in chronic lymphocytic leukemia". N. Engl. J. Med. 343 (26): 1910–6. doi:10.1056/NEJM200012283432602. PMID 11136261.
- ↑ Guièze R, Robbe P, Clifford R, de Guibert S, Pereira B, Timbs A, Dilhuydy MS, Cabes M, Ysebaert L, Burns A, Nguyen-Khac F, Davi F, Véronèse L, Combes P, Le Garff-Tavernier M, Leblond V, Merle-Béral H, Alsolami R, Hamblin A, Mason J, Pettitt A, Hillmen P, Taylor J, Knight SJ, Tournilhac O, Schuh A (October 2015). "Presence of multiple recurrent mutations confers poor trial outcome of relapsed/refractory CLL". Blood. 126 (18): 2110–7. doi:10.1182/blood-2015-05-647578. PMID 26316624.
- ↑ Garcìa-Marco JA, Price CM, Ellis J, Morey M, Matutes E, Lens D, Colman S, Catovsky D (November 1996). "Correlation of trisomy 12 with proliferating cells by combined immunocytochemistry and fluorescence in situ hybridization in chronic lymphocytic leukemia". Leukemia. 10 (11): 1705–11. PMID 8892671.
- ↑ Wang L, Lawrence MS, Wan Y, Stojanov P, Sougnez C, Stevenson K, Werner L, Sivachenko A, DeLuca DS, Zhang L, Zhang W, Vartanov AR, Fernandes SM, Goldstein NR, Folco EG, Cibulskis K, Tesar B, Sievers QL, Shefler E, Gabriel S, Hacohen N, Reed R, Meyerson M, Golub TR, Lander ES, Neuberg D, Brown JR, Getz G, Wu CJ (December 2011). "SF3B1 and other novel cancer genes in chronic lymphocytic leukemia". N. Engl. J. Med. 365 (26): 2497–506. doi:10.1056/NEJMoa1109016. PMC 3685413. PMID 22150006.
- ↑ Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC (January 2013). "The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial". Blood. 121 (3): 468–75. doi:10.1182/blood-2012-05-429282. PMID 23086750.
- ↑ Woyach JA, Johnson AJ, Byrd JC (August 2012). "The B-cell receptor signaling pathway as a therapeutic target in CLL". Blood. 120 (6): 1175–84. doi:10.1182/blood-2012-02-362624. PMID 22715122.
- ↑ Oscier DG, Rose-Zerilli MJ, Winkelmann N, Gonzalez de Castro D, Gomez B, Forster J, Parker H, Parker A, Gardiner A, Collins A, Else M, Cross NC, Catovsky D, Strefford JC (January 2013). "The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial". Blood. 121 (3): 468–75. doi:10.1182/blood-2012-05-429282. PMID 23086750.
- ↑ 19.0 19.1 19.2 19.3 Chronic Lymphocytic Leukemia. Libre Pathology (2015) http://librepathology.org/wiki/index.php/B_cell_small_lymphocytic_lymphoma/chronic_lymphocytic_leukemia Accessed on October, 12 2015