BURKITTS LYMPHOMA

CHILDHOOD BURKITTS LYMPHOMA

1. CHILDHOOD BURKITT LYMPHOMA BY ALIYU USMAN MUHAMMAD KAMPALA INTERNATIONAL UNIVERSITY, UGANDA MBchB STUDENT.

2. NORMAL LYMPHOID TISSUES    —  Lymphoid tissues are subdivided into primary and secondary lymphoid organs. The primary lymphoid tissues responsible for the initial generation of B and T lymphocytes are the bone marrow and thymus, respectively. Secondary lymphoid tissues include lymph nodes, spleen, tonsils, and the aggregations of lymphoid tissue located in the gastrointestinal and respiratory tracts. Within these lymphoid organs, B and T lymphocytes inhabit highly organized tissues containing some areas in which B and T cells are largely segregated . Specifically, B cells mainly localize to follicles, whereas T cells mainly localize to interfollicular areas.

3. In addition to lymphocytes, non-lymphoid cells dendritic cells,  monocytes /macrophages Histiocytes endothelial cells, and follicular dendritic cells) contribute to the formation of distinct microenvironments . Within these areas, specific cell-cell interactions occur that are required for the generation of cellular and humoral immune responses.

4. INTRODUCTION   — Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignant neoplasms of the lymphoid tissues variously derived from B cell progenitors, T cell progenitors, mature B cells, or mature T cells. Unlike in adults where low-grade, clinically indolent NHL subtypes predominate, most pediatric NHL cases are of high grade and have an aggressive clinical behavior

5. INTRODUCTION    —   Burkitt lymphoma (BL) is a highly aggressive B cell non-Hodgkin lymphoma characterized by the translocation and deregulation of the c-MYC gene on chromosome 8. Three distinct clinical forms of BL are recognized: Endemic (African ) Sporadic (non-endemic ) Immunodeficiency-associated . Although they are histologically identical and have similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the three forms.

6. EPIDEMIOLOGY Endemic — equatorial Africa and New Guinea The incidence of BL in Africa is approximately 50-fold higher BL accounts for 30 to 50 percent of all childhood cancer in equatorial Africa with an estimated incidence of 3 to 6 cases per 100,000 children per year . The peak incidence occurs in children age 4 to 7 years, and the m:f approximately 2:1.

7. Immunodeficiency-associated — Is primarily seen in persons with HIV infection, and less commonly in patients with other causes of immunodeficiency ( eg , recipients of organ transplants). In HIV positive patients, BL typically affects those with a relatively high CD4 count ( eg , >200 cells/ microL ) and no opportunistic infections . In comparison to the majority of other HIV-associated lymphomas, the rate of BL in the HIV-positive population has not decreased with the advent of highly active anti-viral therapy (HAART).

8. Sporadic — The sporadic variant is seen in the US and Western Europe . BL comprises 30 percent of pediatric lymphomas and <1 % of adult non-Hodgkin lymphomas in the US . incidence of approximately three cases per million persons per year in both children and adults. In Europe, the incidence is approximately 2.2 cases per million persons per year . The peak incidence occurs in children age 11 years. Among adults, sporadic BL is typically seen in patients less than 35 years of age . Sporadic BL is more common among Caucasians than in African. In all groups, the majority of patients are male with a 3 or 4:1 m:f

9. Epidemiology of BL eBL (endemic) Corresponds to areas of high malarial transmission in Africa. peak age 5 years (most 4-9) years sBL (sporadic) in fairly older children (peaks at 7 years) M : F = 2:1. 10 Childhood Burkitt Lymphoma

10. CLINICAL FEATURES   — Patients with BL present with rapidly growing tumor masses and often have evidence of spontaneous tumor lysis with a very high serum lactate dehydrogenase (LDH) concentration and elevated uric acid levels. The tumor doubling time is very short ( eg , 25 hours).

11. Disease sites at presentation in endemic and sporadic Burkitt lymphoma bdomen 58 91 Pleural effusion 3 19 Bone marrow 7 20 Peripheral nodes 9 13 Bone 8 9 Central nervous system 19 14 Paraspinal 17 2 Testis 2 6 Pharynx 10 Jaw 58 7 Orbit 11 1 Site Patients with involvement  (percent) Endemic Sporadic

12. CNS presents as paraplegia, sphincter abnormalities, CSF pleocytosis and Cranial nerve palsies

13. Orbit: T he maxillary tumor often spreads to involve the orbit, and presents as proptosis ( exo , altered vision, and disfigurement . Friday, December 15, 2017 14 Childhood Burkitt Lymphoma

14. JAW : most affected maxilla more affected than the mandible. Often painless. Mainly the 4-5 years age-group Associated disfigurement, loosening and loss of teeth, halitosis( A foul odor from the mouth) , difficulty feeding and speech

15. Abdominal Involves the spleen, liver, ovaries , kidneys, lymphnodes Presents with m asses, distention, pain, constipation, diarrhea, difficulty breathing. Median age of 7 years. Friday, December 15, 2017 16 Childhood Burkitt Lymphoma

16. immunodeficiency-related BL is often accompanied by signs or symptoms related to the underlying immunodeficiency  Immunodeficiency-related cases more often involve lymph nodes, bone marrow, and CNS.

17. PATHOGENESIS Overview    — The development of BL is dependent upon the constitutive expression of the c-MYC proto-oncogene located at chromosome 8q24 which encodes the MYC protein transcription factor . This transcription factor modulates the expression of target genes that regulate many cellular processes, including cell growth, division, death, metabolism, adhesion, and motility. Cells can generate high levels of c-MYC protein through various mechanisms . The vast majority of tumors have c-MYC rearrangements  typical of BL lack c-MYC rearrangements.

18. c-MYC in normal cells In vivo, c-MYC is found mainly in heterodimeric complexes with the related protein MAX; these heterodimers bind to the "E box consensus sequence" and directly activate transcription . The MYC-MAX interaction is required for cMYC to stimulate transcription and cell pro liferation c-MYC activity is normally regulated by the amount of MAX available to form MYC-MAX heterodimers and by competition from complexes formed by MAX and other proteins. 

19. c-MYC overexpression    — BL tumors are characterized by an inappropriately high expression of the c-MYC transcription factor through at least one of the following mechanisms : Chromosomal translocations place the DNA coding sequences for c-MYC under the control of immunoglobulin gene enhancers that are constitutively active in mature B cells. 5' regulatory regions normally present within the c-MYC DNA sequence are mutated or moved as a direct result of the translocation. Mutations of the c-MYC gene result in amino acid substitutions that stabilize the c-MYC protein and decrease its proteosome -mediated degradation, thereby increasing its half-life .  the expression of a c-MYC oncogene in Epstein Barr virus (EBV)-immortalized human B cells leads to their malignant transformation

20. Chromosomal translocations    — In virtually all cases, BL is associated with a translocation between the long arm of chromosome 8, the site of the c-MYC oncogene (8q24), and one of three locations on Ig genes: The Ig heavy chain gene on chromosome 14 — resulting in the t(8;14)(q24;q32) found in 80 % of BL. The kappa light chain gene on chromosome 2 — resulting in the t(2;8)(p11;q24) found in 15 % of BL. The lambda light chain gene on chromosome 22 — resulting in the t(8;22)(q24;q11) found in 5 % of BL. The common effect of these translocations is that the translocated c-MYC allele is expressed constitutively in tumor cells, as opposed to the tight regulation of c-MYC levels in normal B cells

21. these translocations display a high degree of molecular heterogeneity . The specific gene breakpoint sites vary not only by translocation but also by clinical context ( ie , endemic versus sporadic cases): The breakpoint sites on chromosome 8 found in t(8;14) are located 5' and centromeric to c-MYC, whereas the sites found in t(2;8) and t(8;22) map 3' to c-MYC. In endemic (African) cases, the breakpoint on chromosome 14 involves the heavy chain joining region, while in non-endemic cases, the translocation involves the heavy chain class-switch region . In endemic cases, the breakpoint in chromosome 8 usually lies adjacent to c-MYC, while in sporadic cases it often lies in intron 1 within the gene. This molecular heterogeneity precludes the development of sensitive polymerase chain reaction (PCR) based testing for these translocations . Instead, these translocations are identified either by karyotyping of metaphase chromosomes or by fluorescent in situ hybridization (FISH).

22. Ig Translocations in BL Myc IgL IgH E E 8;14 Variant (2;8, 8;22) Myc P P Telomere Der Chromosome 14 Der Chromosome 8 Telomere

23. Consequences of c-MYC overexpression    — BL may be the fastest growing human cancer, and c-MYC overexpression is believed to be responsible for many of the alterations that support the rapid growth of BL tumors cells

24. Diagnosis CLINICAL: A rapidly growing tumor of the jaws or the abdomen, loose teeth, disfigurement. HISTOLOGY: described as having the ‘STARRY SKY’ appearance

25. “Starry-sky” appearance Friday, December 15, 2017 Childhood Burkitt Lymphoma 26

26. Investigations Recommended laboratory and radiologic testing includes: CBC; measurements of electrolytes, uric acid, calcium, phosphorus, blood urea nitrogen, creatinine , bilirubin , alanine aminotransferase , and aspartate aminotransferase ; bone marrow aspiration and biopsy; lumbar puncture with cerebrospinal fluid (CSF) cytology, cell count and protein; chest radiographs; and neck, chest, abdominal, and pelvic CT scans (head CT for suspicion of CNS disease), and PET scan. Tumor tissue (i.e., biopsy, bone marrow, CSF, or pleurocentesis / paracentesis fluid) should be tested by flow cytometry for immunophenotypic origin (T, B, or null) and cytogenetics ( karyotype ). Additional tests might include fluorescent in situ hybridization (FISH) or quantitative reverse transcription polymerase chain reaction (RT-PCR) for specific genetic translocations, T- and B-cell gene rearrangement studies, and molecular profiling by oligonucleotide microarray

27. Staging Friday, December 15, 2017 Childhood Burkitt Lymphoma 28 Cytology of fluid aspirate from ascites , pleural fluid and CSF, etc Chest X-ray: mediastinal , paraspinal , lung, jaw Ultrasound, CT scan of the abdomen, chest. Bone marrow aspiration or biopsy

28. Staging Friday, December 15, 2017 Childhood Burkitt Lymphoma 29 Stage A Single Extra-abdominal tumor site. AR Completely (>90%) resected intra-abdominal tumor B Multiple extra-abdominal tumor sites C Intra-abdominal tumor with or without facial tumor D CNS and Bone-marrow involvement.

29. St Jude's staging Important for RX 1-Local 2-Regional 3-Extensive 4-Disseminated(CNS and / BM)

30. Treatment Friday, December 15, 2017 Childhood Burkitt Lymphoma 31 Pre-treatment management Hydrate Give allopurinol Explain to family and patient Chemotherapy Vincristine , Actinomycin , Methotrexate iv/IT for CNS prophylaxis Second line : Etoposide , Cytarabine , Rituximab , Doxorubicin. Read role: FUOXETINE Surgery : Decompression of spine, debulking tumour

31. Treatment Results Friday, December 15, 2017 Childhood Burkitt Lymphoma 32 Complete Remission

32. Differential diagnosis Dental cysts Jaw abcess Osteomyelitis of jaw Nueroblastoma Rhabdomyosarcoma Nephroblastoma Ameloblastoma Tb spine

33. Prognostic markers Tumour burden (size) BM/CNS involvement/stage of disease Age > 13 years High serum lactate dehydrogenase and uric acid levels .

34. Prognosis and follow up Friday, December 15, 2017 Childhood Burkitt Lymphoma 35 Prognosis depends on extent and stage of the pre-treatment tumor, age at presentation Compliance with and quality of chemotherapy Recurrences after 2 years rare and exceptional after 3 years.

35. Prognosis and follow up Relapses frequent (43 - 50%) Most occur in first year. Relapses often involve the CNS Most relapsers often achieve long term remisssion (4-10 years) Relapses in < 3 mons respond poorly. Those after ,do well and respond to initial Rx regime. Patients generally followed up for 5 years post chemo.

36. TUMOR LYSIS SYNDROME Friday, December 15, 2017 Childhood Burkitt Lymphoma 37 Results from release of intracellular components of malignant cells due to the effect of chemotherapeutic agents or spontaneous activity of the tumor burden . Cellular components include (potassium, phosphate and nucleic acid). Nucleic acids are broken into xanthine and hypoxanthine and then uric acid by xanthine oxidase . Uric acid may precipitate in the renal collecting duct and cause renal failure.

37. Components of the definition: Friday, December 15, 2017 Childhood Burkitt Lymphoma 38 Hyperuricaemia Hyperkalaemia Hyperphosphataemia Secondary Hypocalcaemia Metabolic Acidosis.

38. Presentation Friday, December 15, 2017 Childhood Burkitt Lymphoma 39 Nausea, vomiting, diarrhoea , anorexia, lethargy, hematuria , heart failure, cardiac dysrhythmias , seizures, muscle cramps, tetany , syncope, and sudden death. Commonly associated high-grade NHLs , and Acute Lymphoblastic Leukemia (ALL).

39. TLS Friday, December 15, 2017 Childhood Burkitt Lymphoma 40 Factors associated with higher risk for TLS : High tumor cell proliferation rate Chemosensitivity of the malignancy Bulky disease WBC count >50,000/ microL . A preexisting reduction in renal function Pretreatment oliguria and volume depletion

40. Treatment of Tumor Lysis Syndrome Friday, December 15, 2017 Childhood Burkitt Lymphoma 41 Prevention is the best treatment: HYPER-HYDRATION: 1.5 – 2.0 times the normal maintenance fluid requirement . ALLOPURINOL : should be started early and adequately . Urate oxidase (URICASE): inhibits formation of uric acid crystals that may cause ARF..

41. THANK YOU ALL