Burkitt lymphoma

Classification according to ICD-10
C83.7	Burkitt tumor ICD-O 9687/3 (lymphoma) ICD-O 9826/3 (leukemia)
ICD-10 online (WHO version 2019)

The Burkitt's lymphoma ( BL , English Burkitt's lymphoma ) is a malignant lymphoma and the B-cell - non-Hodgkin's lymphoma counted. It is named after the British surgeon Denis Parsons Burkitt, who first described it.

The World Health Organization (WHO) distinguishes three different types:

• the endemic Burkitt lymphoma , which is found mainly in tropical Africa , where it is one of the most common tumors in children,
• the sporadic Burkitt's lymphoma , which occurs in temperate climates, and
• the HIV-related Burkitt's lymphoma , which in HIV can occur infection.

The BL is one of the fastest growing human tumors and accordingly has an extremely high rate of cell division (the so-called Ki-67 index is greater than 95%, i.e. more than 95% of the cells are dividing). However, precisely because of its rapid growth, the tumor is usually very sensitive to chemotherapy and radiation therapy . In the case of pronounced bone marrow involvement by the BL (> 20% cell proportion), one also speaks of Burkitt leukemia or "mature-cell B- ALL " / " L3-ALL ". This is a rare clinical picture (only around 3–5% of all acute lymphoblastic leukemia , i.e. fewer than 100 cases per year in the whole of Germany ).

Clinically, the BL can occur wherever there are lymphocytes . It preferentially occurs in the lymph nodes . For the endemic BL an invasion of are mandible or maxilla (upper and lower jaw bones) typical. When sporadic BL (in Europe and North America ) it is rare to find this manifestation. Instead, the lymph nodes in the abdomen are often affected.

Staging

The stages are divided into stages I to IV according to the Ann-Arbor system . For children and adolescents, staging is based on St. Jude's modification of the Ann Arbor classification.

St. Jude's modification of the Ann Arbor classification for non-Hodgkin lymphomas in childhood and adolescence
stage	definition
Stage I.	a single nodal or extranodal tumor manifestation without local Spread not: mediastinal and abdominal or epidural locations (see stage III)
Stage II	multiple nodal and / or extranodal manifestations on the same side of the diaphragm with or without local expansion not: mediastinal, epidural or extensive, non-resectable abdominal locations (see stage III)
Stage III	Localizations on both sides of the diaphragm all manifestations in the chest (thorax) such as mediastinum, thymus, pleura all extensive, inoperable (respectable) manifestations in the abdominal cavity (abdomen) Involvement of the outer meninges (epidural involvement) multilocular bone involvement (not bone marrow involvement)
Stage IV	Involvement of the bone marrow and / or the central nervous system (brain and spinal cord)

A blast proportion of more than 5% and less than 25% in the cytological examination of the bone marrow (bone marrow smear) is defined as an infestation of the bone marrow . If there are 25% or more blasts in the bone marrow, it is Burkitt leukemia (L3-ALL). Any detection of blasts in the nerve water (liquor) is assessed as an attack on the central nervous system . The central nervous system is also affected if every mass in the central nervous system with confirmed Burkitt's lymphoma in a different location such as the chest, lower jaw and abdomen cannot be reliably traced back to another cause.

Diagnosis

Histological picture of Burkitt's lymphoma (from a lymph node, HE stain ). As typical of the "starry sky" -like aspect at low magnification applies, the interspersed through between the lymphoma cells macrophages comes

When diagnosing a BL, a complete staging must first be carried out . H. a spread diagnosis is carried out. d. H. it must be determined which stage is present, since the therapy is based on it (the more spread the lymphoma, the more intensive and longer the therapy). The following examinations are necessary:

• Bone marrow examination
• Computed tomography (CT) or magnetic resonance imaging (MRI) of the neck , thorax, and abdomen
• Blood tests ( blood count , LDH , uric acid , creatinine , ...)

Lactate dehydrogenase (LDH) in serum or plasma is of particular importance in Burkitt's lymphoma in children and adolescents, since the LDH value helps determine the risk group at the time of diagnosis (more than 500 U / L LDH in serum or plasma corresponds to a higher one Risk group). The co-determination of the LDH in the risk group allocation is mainly used in therapy optimization studies in the German-speaking area and now also in Europe.

therapy

The mortality of affected patients has improved very significantly since chemotherapy was introduced ( Joseph H. Burchenal and others in the 1960s); before that, those affected died quickly. The tumor is extremely sensitive to chemicals and radiation. The more localized the tumor, the better the chances of complete cure.

If the disease is more widespread or affects the bone marrow or central nervous system (CNS), it worsens. Even so, the curative outlook is often over 50% these days. Affected adults have a worse prognosis than children. Have been proven chemotherapeutic the CHOP scheme (if possible in a 14-day intervals), and in particular treatment regimens with high-dose methotrexate (MTX), as z. B. in the context of the German multicenter therapy study of acute lymphoblastic leukemia in adults (GMALL) are common. In addition, all newer schemes contain the recombinant monoclonal antibody rituximab . CNS prophylaxis / therapy is indicated in most cases, in which case methotrexate is administered intrathecally . A surgical or radiation therapy procedure alone does not generally make sense and is a malpractice (of course, exceptions are diagnostic interventions to gain tumor tissue, e.g. removal of lymph nodes). Because of the rapidly growing tumor, there is a risk of tumor lysis syndrome in all patients , which must be prevented.

In children and adolescents, Burkitt's lymphoma is treated following therapy optimization studies for highly malignant (lymphoblastic) B-cell non-Hodgkin lymphomas . These include a stratified (stage and risk factor-controlled) therapy. This usually consists of a combination chemotherapy . Important cytostatics are methotrexate (in high doses: more than 1000 mg / m² BSA per single dose), adriamycin ( doxorubicin ), cyclophosphamide or ifosfamide , cytarabine , dexamethasone , etoposide and vincristine . In addition to the systemic administration of cytostatic drugs, intrathecal therapy (in the event of infestation) or prophylaxis must also be carried out: this is usually carried out as a regular intrathecal injection of a combination of the three cytostatic drugs methotrexate, cytarabine and prednisone (so-called triple LP ). For refractory Burkitt lymphomas, the standard chemotherapy described above is usually followed by high-dose myeloablative (bone marrow-eliminating) chemotherapy followed by autologous stem cell transplantation . The treatment of Burkitt's lymphoma with rituximab is currently not a standard in children and adolescents. The Radiotherapy plays due to the good to very good treatability of Burkitt's lymphoma by combination chemotherapy in childhood and adolescence significantly minor role in the treatment optimization studies (standard) in German-speaking radiation therapy is used only in exceptional cases.

Pathophysiology, genetic characteristics

Genetic changes that affect the Myc gene on chromosome 8 are typical of Burkitt's lymphoma . However, these are rarely found in other malignant lymphomas, especially in diffuse large-cell B-NHL , so that they are not 100% specific for the BL. Cytogenetically , one of the following chromosome translocations is found in the vast majority of cases :

• t (8; 14) (q24; q32) - in approx. 85% of the cases
• t (8.22) (q24; q11) - in about 10% of cases.
• t (2; 8) (p11; q24) - in about 5% of cases

All 3 translocations have in common that the MYC gene comes close to immunoglobulin ( IG ) genes, namely in the area of ​​the immunoglobulin heavy chain on chromosome 14 or the kappa light chain on chromosome 2 or lambda on chromosome 22 . The last two translocations mentioned are also referred to as variant translocations . Chromosome translocations of MYC into non- IG gene areas are also rarely found.

The translocation leads to a dysregulation of the MYC gene, which has a control function in cell division and influences a large number of other genes. In the event of a translocation, the expression of the MYC gene is no longer controlled by its normal DNA control sequences ( promoter , inhibitors) on chromosome 8, but by the DNA control sequences of the immunoglobulin light or heavy chains. In addition, the MYC gene itself can also be damaged. Since the light and heavy chains of immunoglobulins in B cells are read and expressed almost continuously during antibody production, this also happens for the MYC gene and MYC protein. This severely disrupts the control of cell division; The overexpression of MYC protein leads to a significantly increased to (in the case of Burkitt's lymphoma) uninhibited cell division from a single genetically modified cell ( malignant transformation with monoclonal proliferation ), whereby the dysregulation of the MYC gene alone is not sufficient. Over-expression of MYC alone would lead to an increase in the rate of proliferation and an increase in MYC-dependent apoptosis mechanisms (for example via the CD95 antigen). Thus, in addition to a dysregulation of the MYC gene, further genetic changes are necessary to complete a malignant transformation to Burkitt's lymphoma. A possible cause could be the occurrence of a translocation of MYC at the same time as the so-called immunoglobulin gene rearrangement in B cells, which circumvents the apoptosis induction of MYC overexpression.

The geographically different forms ( endemic vs. sporadic ) are also reflected in the genetics: The breakpoint location of the c-myc gene on chromosome 8 varies according to the location, but is only specific to the type of disease with restrictions ( endemic vs. sporadic ).

In addition to the genetic changes in the MYC gene, mutations in the protein 53 (p53) gene have also been described in about 40% of Burkitt's lymphomas. Mutations in the retinoblastoma (Rb) gene and its products protein 107 (p107) and protein 130 (p130) have also been identified.

The reason for the emergence of the endemic form in Africa can be seen as a step-by-step carcinogenesis (cancer development), in which various factors are responsible for the individual steps. The first step is the infection of B cells by EBV ( Epstein-Barr virus ), which leads to polyclonal growth of the B lymphocytes . In vitro , normal B cells can be immortalized (made immortal) by infection with EBV. In the areas of Equatorial Africa where Burkitt's lymphoma is endemic, around 80% of children are infected with EBV. In the second step, the infection with malaria is added. This is also endemic there and causes additional immunosuppression. This disrupts the T-cell population in such a way that it can no longer control the proliferation of B-cell clones and thus increases the proportion of B-cells that are susceptible to translocations. The third step is in a dysregulation of MYC - oncogene by the above chromosome translocations . This process is like breaking a dam. The cells now grow indefinitely and very quickly, the BL is developing inexorably.

In Europe and North America, EBV infections and childhood malaria are much less common. The sporadic BL show an association with EBV in less than 20%. What's all BL in common is the translocation of IG - and MYC - genes .

literature

• PA Pizzo, DG Poplack: Principles and Practice of Pediatric Oncology . 4th edition. Lippincott Williams & Wilkins Publishers, Philadelphia / Baltimore / New York, 2001, ISBN 0-7817-2658-1

Web links

Commons : Burkitt Lymphoma  - Collection of Pictures, Videos, and Audio Files

• S1 guideline for non-Hodgkin lymphomas of the German Cancer Society and Society for Pediatric Oncology and Hematology. In: AWMF online (as of January 2009)
• Guideline for malignant lymphomas . (PDF) German Society for Hematology and Oncology (February 2007)

Individual evidence

1. ^ D Burkitt: A sarcoma involving the jaws in African children . In: British Journal of Surgery . 46, No. 197, 1958, pp. 218-23. doi : 10.1002 / bjs.18004619704 . PMID 13628987 .
2. ↑ P Bertrand, C Bastard, C Maingonnat, F Jardin, C Maisonneuve, MN Courel, P Ruminy, JM Picquenot, H Tilly: Mapping of MYC breakpoints in 8q24 rearrangements involving non-immunoglobulin partners in B-cell lymphomas . In: Leukemia , 2007, 21 (3), pp. 515-523, PMID 17230227

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