Definition BL is a highly aggressive lymphoma, often occurring outside the nodes or presenting as an acute leukemic form. The tumor consists of single, medium-sized B cells with basophilic cytoplasm and frequent nuclear schizophrenic images. There is often ectopic MYC gene and some cases have EBV infection.
Synonyms Rappaport: undifferentiated lymphoma, Burkitt type Lukes-Collins: small anaplastic follicular center cell lymphoma WF: small anaplastic cells, Burkitt type Kiel: Burkitt, Burkitt lymphoma with intracytoplasmic IgREAL: Burkitt lymphoma FAB: L3, ALL epidemiology BL can be divided into three variants, each with different clinical manifestations, morphologic and biological features.
1, Endemic BL This type occurs in the area of Central Africa and is the most common malignancy in children in this region, with peak age of onset at 4-7 years old and a male to female ratio of 2:1. BL is also an endemic disease in Papua New Guinea. In these areas, the occurrence of BL is related to geographical and climatic (rainforest, equator, etc.) factors, which is exactly in line with the geographical distribution of malaria.
2. Sporadic BL This type is seen worldwide and occurs mainly in children and young adults with a low incidence of 1-2% of all lymphomas in Western Europe and the U.S. BL accounts for approximately 30-50% of childhood lymphomas. The average age of adult patients is approximately 30 years. In some parts of the world, such as South America and North Africa, the incidence of BL is intermediate, between endemic and sporadic BL. EBV-positive BL is often associated with factors such as poor socioeconomic conditions and young age at the time of first EBV infection.
3. Immunodeficiency-associated BL is initially found in cases associated with HIV infection, mostly in AIDS patients. BL is less likely to occur in other immunodeficiency disorders.
The site of involvement is outside the nodes, which is the most frequently involved site, and all three variants can involve the central nervous system.
The jaws and facial bones (orbits) are involved in 50% of endemic BL. The jejunum, ileum, omentum, ovaries, kidneys, breast and other organs can also be involved.
Sporadic BL infrequently involves the jaws. Most cases present as abdominal masses. The jejunum and ileum are the most frequently involved sites. Ovaries, kidney and breast are also more frequently involved. Breast involvement often results in bilateral masses, most often during adolescence, pregnancy or lactation. Retroperitoneal masses can compress the spinal cord and cause paraplegia. Lymph node involvement is most often seen in adults; Waldeyer’s ring and mediastinum are rarely involved, and many cases can be seen in leukemia. However, purely acute leukemia (Burkitt leukemia) with bone marrow involvement and the presence of B-lymphoblasts is rare.
Immunodeficiency-associated BL often involves the LN and the bone marrow.
The clinical features are due to the short tumor multiplication time and rapid growth, and the patient has a high tumor load, which causes a series of symptoms. The clinical manifestations vary due to different types and sites of BL involvement. Some patients (mainly males) present with acute leukemia with peripheral blood and bone marrow involvement. Bone marrow involvement is a sign of poor prognosis and suggests a high tumor load in the patient. Patients with acute leukemia or a high tumor load often present with hyperuricemia and high LDH. BL staging is based on the method of Murphy et al. The limited stage (stages I and II) accounts for 30% of cases. Progressive (advanced) stage accounts for 70% of cases.
Tumor lysis syndrome is due to rapid tumor cell death caused by treatment. This is characteristic of BL, but is also seen in other lymphomas that contain many tumor cells. Tumor cell necrosis and release of intracellular purine, uric acid, and potassium phosphate into the blood cause severe renal failure. When dealing with patients at high risk for tumor lysis syndrome, there should be close monitoring in the early stages of treatment.
Etiology EBV plays an important role in BL, and EBV was first identified from BL cell lines. EBV is present in the vast majority of tumor cells in all endemic BL. The regulatory role of T cells is compromised by infection with a variety of bacteria, viruses (EBV, HIV), and parasites (especially malaria), so that EBV-infected B cells undergo long-term clonal changes and may eventually develop into lymphoma.
The rate of EBV infection in sporadic BL is low, less than 30%. Poorer socioeconomic conditions and earlier EBV infection are closely associated with high EBV detection rates in BL. The rate of EBV infection in immunodeficiency-related BL is in the range of 25-40%.
In sporadic BL, antigenic stimulation and abnormal B-cell expansion also play a role in the occurrence and development of BL. Since EBV is not detected at a high rate in sporadic BL, EBV infection is not necessary for the development of BL and EBV may only be a synergistic factor. In EBV-negative cases, other environmental factors (e.g., immunosuppression, antigenic stimulation) may play a role.
Genetic abnormalities associated with the MYC gene at position 8q24 play an essential role in the development of BL.
The gross lesion site presents as a mass with fishy, hemorrhagic necrotic tumor tissue. Adjacent organs are compressed and infiltrated. Lymph node involvement is rare, but the lymph nodes may be surrounded by tumor.
Morphology ①Classic BL This type is seen in endemic BL and sporadic BL with high morbidity, especially in children. cells are single, medium-sized, and diffusely infiltrating. The cells are sometimes arranged in a pavement or mosaic pattern after fixation. The nucleus is round, with coarse chromatin and relatively clear parachromatin, and the nucleus is medium-sized, centered, and basophilic. The cytoplasm is deeply basophilic and often accompanied by lipid vacuoles. The fine structure of these cells is more easily observed in the prints. The tumor has a high proliferation rate (nuclear division is common) and a high spontaneous cell death rate (apoptosis). The “starburst” phenomenon is common and is the result of macrophages phagocytosis of apoptotic tumor cells. The nuclei of tumor cells are similar in size to the nuclei of the tissue cells in the “starry sky”.
The nuclei of BL cells with variant plasma cell-like differentiation are partially located and have a single median nucleolus. The cytoplasm is basophilic and the cytoplasm contains a single Ig. The size and morphology of the nucleus are pleomorphic, similar to the atypical BL/BL-like variant. This type of BL can be seen in children, but is most often seen in immunodeficient patients.
(iii) Atypical BL/BL-like variant This type of BL consists mainly of moderately large BL cells and exhibits a large number of apoptotic cells and a very high nuclear division index.
The nuclear division index has to be close to 100% to make a diagnosis. However, in contrast to classical BL, this type has a marked polymorphism in size and morphology. Nucleoli are distinct and not numerous. It is important to note that the term “atypical BL/BL-like variant” refers specifically to cases in which ectopic MYC genes have been demonstrated or are suspected to be present.
Immunophenotypic tumor cells express membrane IgM, a single light chain, B cell-associated antigens (e.g., CD19, CD20, CD22), CD10, and bcl-6, but are negative for CD5, CD23, and TdT. No bcl-2 was expressed. expression of CD10 and bcl-6 indicated that the tumor cells originated from the germinal center. Endemic BL expresses CD21 (a receptor for C3d), but sporadic BL is usually not expressed. Plasmacytic differentiated BL may present with a monotypic intracytoplasmic Ig. nuclear proliferation index is very high, with nearly 100% of cells being Ki-67+, and infiltrating T cells are less common compared to DLBCL.
BL mother cells exhibiting leukemia have a mature B-cell immunophenotype, which includes stronger CD45 expression, in contrast to precursor B-ALL/precursor B lymphoblastoid lymphoma. BL is CD34-negative and TdT is usually negative. Expression membrane single light chain, CD19, CD20, CD22, CD79a usually positive.
Genetics are present with Ig heavy chain, light chain rearrangements with Ig gene autosomal mutations (consistent with the genotype of the differentiation stage of the germinal center). All cases had MYC ectopic t(8;14)(q24;q32). In addition, rare ectopics were t(2;8)(2q11) or t(8;22)(22q11). In endemic BL, the breakpoint on chromosome 14 involves the heavy chain gene linkage region (early B cells), whereas in sporadic BL, the ectopic position involves the Ig transformation region (more advanced B cells). continuous MYC gene expression affects the promoters of Ig genes on chromosomes 14, 2 or 22 (these genes encode Ig heavy chain or Lambda, Kappa light chain, respectively). MYC is dysfunctional and drives cells into the cell proliferation cycle, which plays an important role in the development of lymphoma. MYC also activates target genes, especially those related to apoptosis. mutations in the MYC gene further increase its tumorigenicity. Other genetic alterations include TP53 inactivation and secondary mutations, which are seen in 30% of endemic and sporadic BL.
It is noteworthy that MYC gene ectopics are not exclusively specific to BL. For example, MYC ectopics have been reported in precursor B lymphoblastic leukemia/lymphoma secondary to follicular lymphoma.
EBV is seen in almost all endemic BL, 25-40% of immunodeficiency-associated BL, and <30% of sporadic BL. The precise role of EBV in BL development is unclear.
The cellular origin may be germinal center cells.
Prognostic and predictive factors Both endemic and sporadic BL are highly aggressive, but also potentially curable. Because of the short multiplication time and rapid growth of this tumor, treatment should be administered as early as possible.
Tumor staging was based on the Magrath revised protocol drafted by Murphy and Hustu. Staging is closely related to tumor load and helps to clarify whether the lesion is confined or has progressed to extensive thoracoabdominal involvement. The use of surgical resection to reduce the tumor mass has some value in some patients. Poor prognosis is indicated by bone marrow and central nerve involvement, tumor masses >10 cm, and high LDH serum levels, especially in sporadic BL. Endemic BL is highly sensitive to chemotherapy. High-intensity combination chemotherapy can result in treatment rates of 90% in low-stage cases and 60-80% in progressive (advanced) cases. Treatment is better in children than in adults. However, even patients with advanced disease, including cases with bone marrow and central nervous involvement, may be cured with high-dose chemotherapy.
Recurrence often occurs within one year of diagnosis. Patients are considered cured if they do not relapse for 2 years. However, a second BL has been seen to occur in a few patients.
For BL leukemia, very strong and relatively short chemotherapy may be used. This is different from the treatment of acute lymphoblastic leukemia. With this treatment, most patients have a very good prognosis, with 80-90% of patients surviving.