Burkitt lymphoma
Burkitt lymphoma | |
---|---|
Other names | Burkitt's tumor, Burkitt's lymphoma, malignant lymphoma Burkitt's type |
Epstein-Barr Virus; MYC gene translocation | |
Differential diagnosis | Diffuse large B-cell lymphoma, high-grade B cell lymphoma, lymphoblastic leukemia, mantle cell lymphoma (blastoid variant) |
Treatment | Chemotherapy |
Burkitt lymphoma is a
The overall
Classification
Burkitt lymphoma can be divided into three main clinical variants: the endemic, the
- The endemic variant (also called "African variant") most commonly occurs in children living in regions where malaria is endemic (such as
- The sporadic type of Burkitt lymphoma (also known as "non-African") is the most common variant found in places where malaria is not endemic such as North America and parts of Europe.[5] The median onset is 10 years of age, but there are also peaks at ages 40 and 75 years old.[3] Males are 3-4 times more likely to be affected as compared to females.[3] The tumor cells have a similar appearance to those of the classical endemic Burkitt lymphoma. Sporadic type Burkitt lymphomas are less commonly associated with the EBV virus as compared to the endemic variant; with 20-30% of cases being attributed to EBV (most commonly in adults older than 50).[3] The jaw is less commonly involved in this variant.[5] The abdominal region is the most common site of involvement, often at the right lower quadrant.[5][3] The bone marrow is involved in 30-35% of cases and the central nervous system is involved in approximately 20% of cases (usually affecting the meninges, or the covering of the brain and spinal cord).[3]
- Immunodeficiency-associated Burkitt lymphoma is usually associated with
Burkitt lymphoma is commonly associated with the infection of
Pathophysiology
Genetics
Almost all cases of Burkitt lymphoma are characterized by dysregulation of the
- The most common variant is t(8;14)(q24;q32), which accounts for about 70 to 80% of cases of cases.c-myc oncogene translocation from chromosome 8 to the Ig heavy chain region of chromosome 14. A variant of this, a three-way translocation, t(8;14;18), has also been identified.[13]
- Another variant is t(2;8)(p12;q24).[14] This involves the myc oncogene being translocated from chromosome 8 to the Ig kappa locus on chromosome 2. This type of translocation is seen in 15% of cases of Burkitt lymphoma.
- A rare variant is t(8;22)(q24;q11).[14] This type involves myc oncogene translocation from chromosome 8 to the Ig lambda locus on chromosome 22. This type of translocation is involved in about 5% of cases of Burkitt lympohoma.
The c-myc gene found on
Bcl-2 translocations, which are frequently seen in follicular lymphomas and other B-cell Non-Hodgkin Lymphomas, do not occur in Burkitt lymphomas.[3]
One of the above described translocations of MYC is seen in 90% of cases of Burkitt lymphoma, but these oncogenic translocations are not usually sufficient to cause lymphoma; other mutations must also be present.
Mutations affecting the transcription factor
The cell cycle regulators Cyclin D3 and p16 may also be activated and deactivated respectively in Burkitt lymphoma; leading to massive tumor cell proliferation.[3]
Some epigenetic mechanisms have been found to play a role in the pathogenesis of Burkitt lymphoma. FBXO11 is a chromatin regulator. By activating ubiquitin ligase, FBXO11 causes ubiquitination of BCL6 which causes it to be targeted for proteasome degradation.[3] BCL6 normally helps B cells mature in the germinal center and produce antibodies specific to encountered antigens. In Burkitt lymphoma, FBXO11 is deactivated, leading to increased BCL6 activation which then leads to increased proliferation and decreased maturation of germinal center B-cells, thus promoting lymphomagenesis.[3]
EBV associated Burkitts has increased expressional activity of activation-induced cytidine deaminase, which is a mutator, this leads to EBV associated Burkitt lymphomas having more mutations than non-EBV types. Non-EBV subtypes of Burkitt lymphoma more commonly have dysregulation of cyclin D3 and mutated, inactivated p53.[3]
Virology
The complete role of
Immunology
Burkitt Lymphoma cells express HLA class I molecules normally, as well as some HLA class II complexes; however, CD4+ T cells are not properly activated. Burkitt lymphoma cells only express EBNA 1, a poorly antigenic EBV-associated antigen, that is able to escape HLA class I presentation, thus evades an immune response. EBNA 1 can be presented via HLA class II molecules, however HLA Class II pathway is unable to activate the CD4+ T cells.[20]
Diagnosis
Malignant B cell characteristics
Normal B cells of a germinal center possess rearranged immunoglobulin heavy and light chain genes, and each isolated B cell possesses a unique IgH gene rearrangement. Since Burkitt lymphoma and other B-cell lymphomas are a clonal proliferative process, all tumor cells from one patient are supposed to possess identical IgH genes. When the DNA of tumor cells is analyzed using electrophoresis, a clonal band can be demonstrated, since identical IgH genes will move to the same position. On the contrary, when a normal or reactive lymph node is analyzed using the same technique, a smear rather than a distinct band will be seen. This technique is useful since sometimes benign reactive processes (e.g. infectious mononucleosis) and malignant lymphoma can be difficult to distinguish.[citation needed]
Microscopy
The tumor consists of sheets of a monotonous (i.e., similar in size and morphology) population of medium-sized lymphoid cells with high proliferative and
Immunohistochemistry
The tumor cells in Burkitt lymphoma generally strongly express markers of B cell differentiation (CD20, CD22, CD19), as well as CD10 and BCL6. The tumor cells are generally negative for BCL2 and TdT. The high mitotic activity of Burkitt lymphoma is confirmed by nearly 100% of the cells staining positive for Ki67.[22]
Treatment
In general, the first line of treatment for Burkitt lymphoma is chemotherapy. A few of these regimens are: the GMALL-B-ALL/NHL2002 protocol, the modified Magrath regimen (R-CODOX-M/IVAC).[23] COPADM,[24] hyper-CVAD,[25] and the Cancer and Leukemia Group B (CALGB) 8811 regimen;[25] these can be associated with rituximab.[25][26] In older patients, treatment may be dose-adjusted EPOCH with rituximab.[27]
The effects of the chemotherapy, as with all cancers, depend on the time of diagnosis. With faster-growing cancers, such as Burkitt, the cancer actually responds faster than with slower-growing cancers. This rapid response to chemotherapy can be hazardous to the patient, as a phenomenon called "tumor lysis syndrome" could occur. Close monitoring of the patient and adequate hydration is essential during the process. Since Burkitt lymphoma has high propensity to spread to the central nervous system (lymphomatous meningitis), intrathecal chemotherapy with methotrexate and/or ARA-C and/or prednisolone is given along with systemic chemotherapy.[citation needed]
Other treatments for Burkitt lymphoma include
Prognosis
This section may be too technical for most readers to understand.(January 2024) |
Burkitt lymphoma is a very aggressive cancer, which can quickly metastasize and spread throughout the body if the cancer is not treated quickly. If the patient is left untreated, or if treatment is initiated too late, Burkitt lymphoma can be fatal.[4] Burkitt lymphoma in children often has a better prognosis than the same cancer in an adult.[29][16] The overall cure rate for sporadic Burkitt lymphoma in developed countries is about 90%.[5]
Burkitt lymphoma is not common in adults, but has worse outcomes than in children.[5] If treatment with an initial chemotherapy regimen of cyclophosphamide, vincristine, prednisolone, and/or other drugs fails to produce meaningful remission or regression, this usually indicates a more severe outcome.[16] Furthermore, failed initial treatment and return of Burkitt lymphoma after a six-month stint of time serve as a poor prognostic indicator.[16] The adequate utilization of therapeutic drugs during initial treatment limits additional treatment options following the return of the disease.[16] Notably, in areas of the world where the initial treatment of Burkitt lymphoma is inadequate further treatment options may remain for cases when the disease returns.[16] Laboratory studies such as lactate dehydrogenase (LDH), CD4 count, and other cytogenetic studies are also prognostic indicators.[16] Unsatisfactory outcomes have been associated with an LDH that is found to be two times above the upper limit of normal.[16] Specifically, there is a poor prognosis associated with a CD4 count that is decreased in the immunodeficiency-associated variant of Burkitt lymphoma.[16] Genetic mutations extending beyond the previously described MYC translocation may also serve as negative prognostic indicators.[16] Some notable genetic findings that may be associated with poor outcomes include: 13q deletion, 7q gain, ID3 and CCND3 double-hit mutations, and 18q21 CN-LOH mutations.[16] The prognosis for Burkitt lymphoma can be better determined following staging utilizing imaging modalities such as positron emission tomography and computed tomography scans where tumor burden and invasion of the central nervous system have been found to indicate a poor prognosis.[29][16]
Epidemiology
As a non-Hodgkin lymphoma (NHL), Burkitt lymphoma makes up 1-5% of cases, and it is more common in males than females with a 3–4 to 1 ratio.[16] The endemic variant mainly impacts areas with an increased prevalence of malaria and EBV in Africa and Papua New Guinea.[16][30] For children less than 18 years of age from equatorial Africa, the annual incidence of Burkitt lymphoma is 4–5/100,000.[30] Additionally, in equatorial Africa, 50% of tumors that are diagnosed during childhood as well as 90% of lymphoma cases can be attributed to Burkitt lymphoma.[30] The peak incidence for endemic Burkitt lymphoma is from ages 4 to 7 with an average age of 6 years.[16][30] The sporadic variant with an annual incidence 2-3/million is more commonly found in North America and Europe comprising 1-2% of adult lymphomas and 30–40% of NHL cases.[16][30] This variant is 3.5 times more commonly found in males compared to females and it is more frequent in younger individuals.[30] The sporadic variant has a peak incidence at 11 years of age in children, and diagnosis typically occurs from 3–12 years of age on average.[16][30] For adults, 45 years was the median age that the sporadic Burkitt lymphoma was diagnosed.[16] The immunodeficiency-associated variant predominantly impacts the HIV-infected population.[30] For those in the United States and with AIDS, the incidence of this variant was found to be 22/100,000 person-years.[16][30] There is also an increased risk of developing this variant of Burkitt lymphoma for individuals that have received an organ transplant after 4–5 years.[30]
Research
Gene targets
Unique genetic alterations promote cell survival in Burkitt lymphoma, distinct from other types of lymphoma.[33] These TCF3 and ID3 gene mutations in Burkitt correspond to a cell survival pathway that may be found to be amenable to targeted therapy.[34]
References
- Who Named It?
- S2CID 46452308.
- ^ S2CID 252437964.
- ^ a b c d e Gonzales, Blanca; Wang, Luojun; Campo, Elias (2021). "Chapter 95: Pathology of Lymphomas". Williams Hematology (10th ed.). New York: McGraw Hill.
- ^ S2CID 39960470.
- ^ PMID 29518976.
- PMID 12610094.
- S2CID 22313509.
- S2CID 21258747.
- S2CID 47010934.
- PMID 30617194.
- ISBN 978-0-443-06715-0.
- PMID 17547754.
- ^ PMID 18813817.
- ^ OCLC 1191840836.)
{{cite book}}
: CS1 maint: location missing publisher (link) CS1 maint: others (link - ^ PMID 30844175, retrieved 2022-01-20
- ^ S2CID 237327258.
- ^ OCLC 1161987164.)
{{cite book}}
: CS1 maint: location missing publisher (link) CS1 maint: others (link - OCLC 1001961209.)
{{cite book}}
: CS1 maint: location missing publisher (link) CS1 maint: others (link - PMID 20953370.
- PMID 15086279.
- ISBN 978-92-832-2431-0.
- PMID 21339382.)
{{cite journal}}
: CS1 maint: numeric names: authors list (link - S2CID 6418151.
- ^ a b c "Burkitt Lymphoma and Burkitt-like Lymphoma: Practice Essentials, Background, Etiology and Pathophysiology". 29 June 2017. Retrieved 19 March 2018 – via eMedicine.
{{cite journal}}
: Cite journal requires|journal=
(help) - ^ "BHS Guidelines for the treatment of Burkitt's lymphoma" (PDF). Bhs.be. Retrieved 17 March 2022.
- PMID 18378569.
- S2CID 8778208.
- ^ OCLC 1001961209.)
{{cite book}}
: CS1 maint: location missing publisher (link) CS1 maint: others (link - ^ S2CID 212420935.
- PMID 25364378.
- PMID 26113842.
- ^ "NIH study shows Burkitt lymphoma is molecularly distinct from other lymphomas". National Cancer Institute. Archived from the original on 2012-08-16. Retrieved 2012-10-19.
- PMID 22885699.