Burkitt lymphoma | |
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Other names | Burkitt's tumor, Burkitt's lymphoma, malignant lymphoma Burkitt's type |
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Burkitt lymphoma, touch prep, Wright stain | |
Specialty | Hematology and oncology |
Causes | Idiopathic; HIV; 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 cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa. [1] [2] It is a highly aggressive form of cancer which often, but not always, manifests after a person develops acquired immunodeficiency from infection with Epstein-Barr Virus or Human Immunodeficiency Virus (HIV). [3] [4]
The overall cure rate for Burkitt lymphoma in developed countries is about 90%. Burkitt lymphoma is uncommon in adults, in whom it has a worse prognosis. [5]
Burkitt lymphoma can be divided into three main clinical variants: the endemic, the sporadic, and the immunodeficiency-associated variants. [5] By morphology (i.e., microscopic appearance), immunophenotype, and genetics, the variants of Burkitt lymphoma are alike. [5]
Burkitt lymphoma is commonly associated with the infection of B cell lymphocytes with the EBV and in these cases is considered to be one form of the Epstein–Barr virus-associated lymphoproliferative diseases. [8] The endemic variant of Burkitt lymphoma is in almost all cases associated with EBV infection. [9] The fact that some Burkitt lymphoma cases do not involve EBV allows that many cases of the disease are not caused and/or promoted by EBV, i.e. the virus may be an innocent passenger virus in these cases. However, the almost ubiquitous presence of the virus in the endemic variant of Burkitt lymphoma suggests that it contributes to the development and/or progression of this variant. [10] The mutational landscape in Burkitt lymphoma has recently been found to differ between tumors with and without EBV infection, further strengthening the role of the virus in disease origin. [11]
Almost all cases of Burkitt lymphoma are characterized by dysregulation of the c-myc gene by one of three chromosomal translocations which place the myc gene under the control of an immunoglobulin gene enhancer. [4] [12] The MYC gene is found at 8q24.
The c-myc gene found on chromosome 8 is part of the MYC family of genes that serve as regulators of cellular transcription and is associated with Burkitt lymphoma. [15] [16] Expression of the c-myc gene results in the synthesis of transcriptional factors that increase the expression of other genes involved in aerobic glycolysis. [15] Ultimately, an increase in aerobic glycolysis plays a role in providing the necessary energy for cellular growth to occur. [15] The translocation of the c-myc gene to the IGH, IGK, or IGL region moves the gene to a location in the genome near immunoglobulin enhancers which increases the expression of the c-myc gene. [15] Overall, this translocation leads to increased cellular proliferation that is found in Burkitt lymphoma. [15] Point mutations can also be present in the translocated c-myc gene resulting in the expressed c-myc protein being overactive. [15]
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. [3] These additional mutations include mutations of the tumor suppressor TP53, which interacts with the tumor suppressor p53 (which usually causes apoptosis in B cells carrying the disordered MYC oncoprotein). But with TP53 and p53 mutated, apoptosis is blocked, and the oncogenic B-cells are allowed to proliferate unchecked. [3] The tumor suppressors ARF and USP7 are also frequently mutated in Burkitt lymphoma leading to MDM2 inhibition of the tumor suppressor p53 which then leads to enhanced oncogenesis. [3] SIN3A, a regulator of MYC, that acts to inhibit MYC by deacetylating it, is often inactivated in Burkitt lymphoma. [3] Also, sequential mutations of the RNA helicases (involved in RNA synthesis) DDX3X (found on the x chromosome) and DDX3Y (found on the y chromosome) lead to MYC oncogenesis in Burkitt lymphoma. [17] Early in the pathogenesis process, DDX3X mutations limit translation (protein synthesis) allowing lymphoma cells to escape MYC induced proteotoxic stress and apoptosis, then later, DDX3Y mutations restore high level protein synthesis (by producing the translational machinery) and leading to increased proliferation of tumor cells. [17] These sequential DDX3X and DDX3Y mutations are thought to partially explain why Burkitt lymphoma is more common in males as the DDX3Y RNA helicase is only found on the Y chromosome. [3]
Mutations affecting the transcription factor TCF3 and its negative regulator ID3 are found in about 70% of cases of Burkitt lymphoma. [3] [4] These mutations prevent ID3 from binding to and inhibiting TCF3; thus the hyperactive TCF3 then activates B cell receptors which activate PI3K and mTOR, as well as Ig heavy and light chain genes, which contribute to oncogenesis. [15] [3] TCF3 and ID3 mutations lead to continuously active B-cell receptors, explaining the high level of proliferation seen in Burkitt lymphoma. [3] Mutations of ID3 and TCF3 are rarely seen in other aggressive B-cell lymphomas; as a result, they can be used to direct further diagnostic workup if identified. [4]
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]
The complete role of EBV in the pathogenesis of endemic Burkitt lymphoma is not completely elucidated, but it has been shown to cause DNA damage, dysfunction of telomeres, and genome instability. [18] [16] B cell infection with EBV is latent, and the virus does not undergo replication. [18] These latently infected B cells can then go on to produce proteins that function to promote cellular growth through modification of normal signaling pathways. [18] EBV promotes the development of malignant B cells via proteins that limit apoptosis in cells that had the c-myc translocation. [16] Apoptosis is limited by EBV through various means such as the EBNA-1 protein, BHF1 protein, EBER transcripts, vIL-10 gene, BZLF1, and LMP1. [16] Malaria has been found to cause genomic instability in endemic Burkitt lymphoma. [19] Malaria can lead to the reactivation of latent EBV and also MYC translocations via activation of the toll-like receptor 9. [16] Malaria also promotes B-cell proliferation by altering the regular immune response. [18] The immune system targets antigens (e.g., EBNA2 and LMP-1) and eliminates most B cells infected with EBV. [16] Downregulation of antigens targeted by the immune system leads to the development of persistent B cells. [16] These B cells can then undergo further mutations (e.g., c-myc translocation) that promote cancer development. [16]
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]
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 ]
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 apoptotic activity. The "starry sky" appearance seen [21] under low power is due to scattered tingible body-laden macrophages (macrophages containing dead apoptotic tumor cells). The old descriptive term of "small non-cleaved cell" is misleading. The tumor cells are mostly medium in size (i.e., tumor nuclei size similar to that of histiocytes or endothelial cells). "Small non-cleaved cells" are compared to "large non-cleaved cells" of normal germinal center lymphocytes. Tumor cells possess small amounts of basophilic cytoplasm with three to four small nucleoli. The cellular outline usually appears squared off.[ citation needed ]
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]
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 immunotherapy, bone marrow transplants, stem cell transplant, surgery to remove the tumor, and radiotherapy.
![]() | 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]
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]
EBV infection is associated with Burkitt lymphoma. [31] EBV is found in virtually all instances of endemic Burkitt lymphoma. [30] The sporadic variant of Burkitt lymphoma is associated with EBV in only 10–20% of cases. [30] Approximately 30% of immunodeficiency-associated Burkitt lymphoma cases were associated with EBV. [32]
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]
The Epstein–Barr virus (EBV), formally called Human gammaherpesvirus 4, is one of the nine known human herpesvirus types in the herpes family, and is one of the most common viruses in humans. EBV is a double-stranded DNA virus. Epstein–Barr virus (EBV) is the first identified oncogenic virus, which establishes permanent infection in humans. EBV causes infectious mononucleosis and is also tightly linked to many malignant diseases. Various vaccine formulations underwent testing in different animals or in humans. However, none of them were able to prevent EBV infection and no vaccine has been approved to date.
Eosinophilia is a condition in which the eosinophil count in the peripheral blood exceeds 5×108/L (500/μL). Hypereosinophilia is an elevation in an individual's circulating blood eosinophil count above 1.5 × 109/L (i.e. 1,500/μL). The hypereosinophilic syndrome is a sustained elevation in this count above 1.5 × 109/L (i.e. 1,500/μL) that is also associated with evidence of eosinophil-based tissue injury.
Tumors of the hematopoietic and lymphoid tissues or tumours of the haematopoietic and lymphoid tissues are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all intimately connected through both the circulatory system and the immune system, a disease affecting one will often affect the others as well, making aplasia, myeloproliferation and lymphoproliferation closely related and often overlapping problems. While uncommon in solid tumors, chromosomal translocations are a common cause of these diseases. This commonly leads to a different approach in diagnosis and treatment of hematological malignancies. Hematological malignancies are malignant neoplasms ("cancer"), and they are generally treated by specialists in hematology and/or oncology. In some centers "hematology/oncology" is a single subspecialty of internal medicine while in others they are considered separate divisions. Not all hematological disorders are malignant ("cancerous"); these other blood conditions may also be managed by a hematologist.
AIDS-related lymphoma describes lymphomas occurring in patients with acquired immunodeficiency syndrome (AIDS).
Follicular lymphoma (FL) is a cancer that involves certain types of white blood cells known as lymphocytes. The cancer originates from the uncontrolled division of specific types of B-cells known as centrocytes and centroblasts. These cells normally occupy the follicles in the germinal centers of lymphoid tissues such as lymph nodes. The cancerous cells in FL typically form follicular or follicle-like structures in the tissues they invade. These structures are usually the dominant histological feature of this cancer.
Lymphoproliferative disorders (LPDs) refer to a specific class of diagnoses, comprising a group of several conditions, in which lymphocytes are produced in excessive quantities. These disorders primarily present in patients who have a compromised immune system. Due to this factor, there are instances of these conditions being equated with "immunoproliferative disorders"; although, in terms of nomenclature, lymphoproliferative disorders are a subclass of immunoproliferative disorders—along with hypergammaglobulinemia and paraproteinemias.
Primary effusion lymphoma (PEL) is classified as a diffuse large B cell lymphoma. It is a rare malignancy of plasmablastic cells that occurs in individuals that are infected with the Kaposi's sarcoma-associated herpesvirus. Plasmablasts are immature plasma cells, i.e. lymphocytes of the B-cell type that have differentiated into plasmablasts but because of their malignant nature do not differentiate into mature plasma cells but rather proliferate excessively and thereby cause life-threatening disease. In PEL, the proliferating plasmablastoid cells commonly accumulate within body cavities to produce effusions, primarily in the pleural, pericardial, or peritoneal cavities, without forming a contiguous tumor mass. In rare cases of these cavitary forms of PEL, the effusions develop in joints, the epidural space surrounding the brain and spinal cord, and underneath the capsule which forms around breast implants. Less frequently, individuals present with extracavitary primary effusion lymphomas, i.e., solid tumor masses not accompanied by effusions. The extracavitary tumors may develop in lymph nodes, bone, bone marrow, the gastrointestinal tract, skin, spleen, liver, lungs, central nervous system, testes, paranasal sinuses, muscle, and, rarely, inside the vasculature and sinuses of lymph nodes. As their disease progresses, however, individuals with the classical effusion-form of PEL may develop extracavitary tumors and individuals with extracavitary PEL may develop cavitary effusions.
The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals.
Intravascular lymphomas (IVL) are rare cancers in which malignant lymphocytes proliferate and accumulate within blood vessels. Almost all other types of lymphoma involve the proliferation and accumulation of malignant lymphocytes in lymph nodes, other parts of the lymphatic system, and various non-lymphatic organs but not in blood vessels.
Diffuse large B-cell lymphoma (DLBCL) is a cancer of B cells, a type of lymphocyte that is responsible for producing antibodies. It is the most common form of non-Hodgkin lymphoma among adults, with an annual incidence of 7–8 cases per 100,000 people per year in the US and UK. This cancer occurs primarily in older individuals, with a median age of diagnosis at ~70 years, although it can occur in young adults and, in rare cases, children. DLBCL can arise in virtually any part of the body and, depending on various factors, is often a very aggressive malignancy. The first sign of this illness is typically the observation of a rapidly growing mass or tissue infiltration that is sometimes associated with systemic B symptoms, e.g. fever, weight loss, and night sweats.
Angioimmunoblastic T-cell lymphoma is a mature T-cell lymphoma of blood or lymph vessel immunoblasts characterized by a polymorphous lymph node infiltrate showing a marked increase in follicular dendritic cells (FDCs) and high endothelial venules (HEVs) and systemic involvement.
MYC proto-oncogene, bHLH transcription factor is a protein that in humans is encoded by the MYC gene which is a member of the Myc family of transcription factors. The protein contains basic helix-loop-helix (bHLH) structural motif.
Pvt1 oncogene, also known as PVT1 or Plasmacytoma Variant Translocation 1 is a long non-coding RNA gene. In mice, this gene was identified as a breakpoint site in chromosome 6;15 translocations. These translocations are associated with murine plasmacytomas. The equivalent translocation in humans is t(2;8), which is associated with a rare variant of Burkitt's lymphoma. In rats, this breakpoint was shown to be a common site of proviral integration in retrovirally induced T lymphomas. Transcription of PVT1 is regulated by Myc.
There are several forms of Epstein–Barr virus (EBV) infection. These include asymptomatic infections, the primary infection, infectious mononucleosis, and the progression of asymptomatic or primary infections to: 1) any one of various Epstein–Barr virus-associated lymphoproliferative diseases such as chronic active EBV infection, EBV+ hemophagocytic lymphohistiocytosis, Burkitt's lymphoma, and Epstein–Barr virus positive diffuse large B-cell lymphoma, not otherwise specified); 2) non-lymphoid cancers such as Epstein–Barr virus associated gastric cancer, soft tissue sarcomas, leiomyosarcoma, and nasopharyngeal cancers; and 3) Epstein–Barr virus-associated non-lymphoproliferative diseases such as some cases of the immune disorders of multiple sclerosis and systemic lupus erythematosis and the childhood disorders of Alice in Wonderland Syndrome and acute cerebellar ataxia.
Extranodal NK/T-cell lymphoma, nasal type (ENKTCL-NT) is a rare type of lymphoma that commonly involves midline areas of the nasal cavity, oral cavity, and/or pharynx At these sites, the disease often takes the form of massive, necrotic, and extremely disfiguring lesions. However, ENKTCL-NT can also involve the eye, larynx, lung, gastrointestinal tract, skin, and various other tissues. ENKTCL-NT mainly affects adults; it is relatively common in Asia and to lesser extents Mexico, Central America, and South America but is rare in Europe and North America. In Korea, ENKTCL-NT often involves the skin and is reported to be the most common form of cutaneous lymphoma after mycosis fungoides.
Plasmablastic lymphoma (PBL) is a type of large B-cell lymphoma recognized by the World Health Organization (WHO) in 2017 as belonging to a subgroup of lymphomas termed lymphoid neoplasms with plasmablastic differentiation. The other lymphoid neoplasms within this subgroup are: plasmablastic plasma cell lymphoma ; primary effusion lymphoma that is Kaposi's sarcoma-associated herpesvirus positive or Kaposi's sarcoma-associated Herpesvirus negative; anaplastic lymphoma kinase-positive large B-cell lymphoma; and human herpesvirus 8-positive diffuse large B-cell lymphoma, not otherwise specified. All of these lymphomas are malignancies of plasmablasts, i.e. B-cells that have differentiated into plasmablasts but because of their malignant nature: fail to differentiate further into mature plasma cells; proliferate excessively; and accumulate in and injure various tissues and organs.
Epstein–Barr virus–associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells, i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV). This causes the infected cells to divide excessively, and is associated with the development of various non-cancerous, pre-cancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, and the large number of subsequent disorders that may occur thereafter. The virus is usually involved in the development and/or progression of these LPDs although in some cases it may be an "innocent" bystander, i.e. present in, but not contributing to, the disease.
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a malignancy of B cells. B-cells are lymphocytes that normally function in the humoral immunity component of the adaptive immune system by secreting antibodies that, for example, bind to and neutralize invasive pathogens. Among the various forms of B-cell lymphomas, THRLBCL is a rarely occurring subtype of the diffuse large B-cell lymphomas (DLBCL). DLBCL are a large group of lymphomas that account for ~25% of all non-Hodgkin lymphomas worldwide. THRLBCL is distinguished from the other DLBCL subtypes by the predominance of non-malignant T-cell lymphocytes and histiocytes over malignant B-cells in its tumors and tissue infiltrates.
Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a cutaneous lymphoma skin disease that occurs mostly in elderly females. In this disease, B cells become malignant, accumulate in the dermis and subcutaneous tissue below the dermis to form red and violaceous skin nodules and tumors. These lesions typically occur on the lower extremities but in uncommon cases may develop on the skin at virtually any other site. In ~10% of cases, the disease presents with one or more skin lesions none of which are on the lower extremities; the disease in these cases is sometimes regarded as a variant of PCDLBL, LT termed primary cutaneous diffuse large B-cell lymphoma, other (PCDLBC-O). PCDLBCL, LT is a subtype of the diffuse large B-cell lymphomas (DLBCL) and has been thought of as a cutaneous counterpart to them. Like most variants and subtypes of the DLBCL, PCDLBCL, LT is an aggressive malignancy. It has a 5-year overall survival rate of 40–55%, although the PCDLBCL-O variant has a better prognosis than cases in which the legs are involved.
Diffuse large B-cell lymphoma associated with chronic inflammation (DLBCL-CI) is a subtype of the Diffuse large B-cell lymphomas and a rare form of the Epstein–Barr virus-associated lymphoproliferative diseases, i.e. conditions in which lymphocytes infected with the Epstein-Barr virus (EBV) proliferate excessively in one or more tissues. EBV infects ~95% of the world's population to cause no symptoms, minor non-specific symptoms, or infectious mononucleosis. The virus then enters a latency phase in which the infected individual becomes a lifetime asymptomatic carrier of the virus. Some weeks, months, years, or decades thereafter, a very small fraction of these carriers, particularly those with an immunodeficiency, develop any one of various EBV-associated benign or malignant diseases.
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