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CHILDHOOD BURKITT LYMPHOMA and Tumour Lysis Syndrome

CHILDHOOD BURKITT LYMPHOMA and Tumour Lysis Syndrome. NITMED TUTORIALS. NORMAL LYMPHOID TISSUES. — Lymphoid tissues are subdivided into primary and secondary lymphoid organs.

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CHILDHOOD BURKITT LYMPHOMA and Tumour Lysis Syndrome

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  1. CHILDHOODBURKITT LYMPHOMA and Tumour Lysis Syndrome NITMED TUTORIALS

  2. NORMALLYMPHOID 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 largelysegregated. • Specifically, B cells mainly localize to follicles, whereas T cells mainly localize to interfollicularareas.

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

  4. INTRODUCTION • — Non-Hodgkin lymphoma (NHL) consists of a diverse group of malignant neoplasms ofthe 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-MYCgene on chromosome8. • Three distinct clinical forms of BL arerecognized: Endemic(African) • Sporadic(non-endemic) • Immunodeficiency-associated. • Although they are histologically identical andhave similar clinical behavior, there are differences in epidemiology, clinical presentation, and genetic features between the threeforms.

  6. EPIDEMIOLOGY • Endemic— equatorial Africa and NewGuinea The incidence of BL in Africa is approximately 50-foldhigher • BL accounts for 30 to 50 percent of all childhood cancer in equatorial Africa withan estimated incidence of 3 to 6 cases per 100,000 children per year. • The peak incidence occurs in children age 4to 7 years, andthe m:f approximately2:1.

  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 opportunisticinfections • . • 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 USand • 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 andadults. • In Europe, the incidence is approximately 2.2 casesper • 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 yearsofage . Sporadic BL is more common among Caucasians than inAfrican. • In all groups, the majority of patients are male with a 3 or 4:1 m:f

  9. Epidemiology ofBL 10 • eBL(endemic) Correspondsto areas of high malarial transmission in Africa. • peak age 5 years (most 4-9)years • sBL(sporadic) in fairly older children(peaks at 7years) ChildhoodBurkittLymMpho:mFa =2:1.

  10. CLINICALFEATURES • — 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 acidlevels. • The tumor doubling time is very short (eg,25 hours).

  11. Disease sites at presentationin endemic and sporadicBurkitt lymphom

  12. CNS • presents as paraplegia, sphincterabnormalities, CSF pleocytosis and Cranial nervepalsies

  13. Orbit: 14 The maxillary tumor often spreads to involve the presents as orbit, and proptosis(exo, vision, disfigurement. altered and Childhood BurkittLymphoma Thursday, December 14,2017

  14. JAW: mostaffected maxilla moreaffected than themandible. Oftenpainless. Mainly the 4-5years age-group Associated disfigurement, loosening and loss of teeth,halitosis(A foul odor from themouth), difficulty feedingand speech

  15. Abdominal 16 • Involves the spleen,liver, ovaries, kidneys, lymphnodes • Presents with masses, distention, pain, constipation, diarrhea, difficulty breathing. • Median age of 7years. Childhood BurkittLymphoma Thursday, December 14,2017

  16. immunodeficiency-relatedBL • is often accompanied by signs orsymptoms related to the underlyingimmunodeficiency • Immunodeficiency-related cases more often involve lymph nodes, bone marrow, andCNS.

  17. PATHOGENESIS • Overview — The development of BL is dependent upon the constitutive expression of the c-MYC proto- oncogene located at chromosome8q24 • which encodes the MYC protein transcriptionfactor. • This transcription factor modulates the expression of target genes that regulate many cellular processes, including cell growth, division, death, metabolism, adhesion, andmotility. • Cells can generate high levels of c-MYC protein through various mechanisms. • The vast majority of tumors have c-MYC rearrangements typical of BL lackc-MYC rearrangements.

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

  19. c-MYCoverexpression • — 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 sequencesfor • c-MYC under the control of immunoglobulin gene enhancers that are constitutively active in mature Bcells. • 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 increasingits • half-life. • the expression of a c-MYC oncogene in Epstein Barr virus (EBV)-immortalized human B cells leads to their malignant transformation

  20. Chromosomaltranslocations • — 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 % ofBL. • The kappa light chain gene on chromosome 2 — resulting in the t(2;8)(p11;q24) found in 15 %ofBL. • The lambda light chain gene on chromosome 22 — resulting in the t(8;22)(q24;q11) found in 5 % ofBL. • 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 Bcells

  21. these translocations display a high degree ofmolecular heterogeneity. • The specific gene breakpoint sites vary not only bytranslocation but also by clinical context (ie, endemic versus sporadiccases): • The breakpoint sites on chromosome 8 found in t(8;14) arelocated 5' and centromeric to c-MYC, whereas the sites found in t(2;8) and t(8;22) map 3' toc-MYC. • In endemic (African) cases, the breakpoint on chromosome14 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 intron1 within thegene. • This molecular heterogeneity precludes the development of sensitive polymerase chain reaction (PCR) based testing forthese translocations. • Instead, these translocations are identified either by karyotypingof metaphase chromosomes or by fluorescent in situhybridization

  22. Ig Translocations inBL 8;14 Der Chromosome14 Variant (2;8,8;22) Der Chromosome8

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

  24. Diagnosis • CLINICAL: • Arapidlygrowingtumorofthejawsorthe abdomen, loose teeth,disfigurement. • HISTOLOGY: • described as having the ‘STARRY SKY’appearance

  25. “Starry-sky”appearance 26 Childhood BurkittLymphoma Thursday, December 14,2017

  26. Investigations • Recommended laboratory and radiologic testingincludes: • CBC; • measurements ofelectrolytes, • uric acid, calcium,phosphorus, • blood urea nitrogen, creatinine,bilirubin, • alanine aminotransferase, and aspartateaminotransferase; • bone marrow aspiration andbiopsy; • lumbar puncture with cerebrospinal fluid (CSF)cytology, • cell count andprotein; • chest radiographs; andneck, • chest,abdominal,andpelvic CTscans(headCTforsuspicionofCNSdisease), • and PETscan. • 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 rearrangementstudies, • and molecular profiling by oligonucleotidemicroarray

  27. Staging 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 orbiopsy Childhood BurkittLymphoma Thursday, December 14,2017

  28. Staging 29 ChildhoodBurkittLymphoma Thursday, December 14,2017

  29. St Jude'sstaging • Important forRX • 1-Local • 2-Regional • 3-Extensive • 4-Disseminated(CNS and /BM)

  30. Treatment 31 • Pre-treatmentmanagement • Hydrate • Giveallopurinol • Explain to family andpatient • Chemotherapy • Vincristine, Actinomycin , Methotrexate iv/ITfor CNSprophylaxis • Second line: Etoposide, Cytarabine, Rituximab, Doxorubicin. Read role:FUOXETINE • Surgery: • Decompression of spine, debulkingtumour Childhood BurkittLymphoma Thursday, December 14,2017

  31. TreatmentResults 32 Complete Remission Childhood BurkittLymphoma Thursday, December 14,2017

  32. Differentialdiagnosis • Dentalcysts • Jawabcess • Osteomyelitis ofjaw • Nueroblastoma • Rhabdomyosarcom a • Nephroblastoma • Ameloblastoma • Tbspine

  33. Prognosticmarkers • Tumour burden(size) • BM/CNS involvement/stage ofdisease • Age > 13years • High serum lactate dehydrogenase anduric acid levels.

  34. Prognosis and followup 35 • Prognosis dependson • extent and stage of the pre-treatmenttumor, • age at presentation • Compliance with and quality ofchemotherapy • Recurrences after 2 years rare andexceptional after 3years. Childhood BurkittLymphoma Thursday, December 14,2017

  35. Prognosis and followup • Relapses frequent (43 -50%) • Most occur in firstyear. • Relapses often involve theCNS • Most relapsers often achieve longterm remisssion (4-10years) • Relapses in < 3 mons respondpoorly. • Those after ,do well and respond to initialRx regime. • Patients generally followed up for 5 years post chemo.

  36. TUMOR LYSISSYNDROME 37 • Results from release of intracellular components of malignant cells due to the effect of chemotherapeutic agents or spontaneous activity of the tumorburden. • Cellular components include (potassium, phosphate and nucleicacid). • Nucleic acids are broken into xanthineand • hypoxanthine and then uric acid byxanthine oxidase. • Uric acid may precipitate in the renalcollecting duct and cause renalfailure. Childhood BurkittLymphoma Thursday, December 14,2017

  37. Components of thedefinition: 38 • Hyperuricaemia • Hyperkalaemia • Hyperphosphataemia • SecondaryHypocalcaemia • MetabolicAcidosis. Childhood BurkittLymphoma Thursday, December 14,2017

  38. Presentation 39 Nausea, vomiting, diarrhoea, anorexia, lethargy, hematuria, heart failure,cardiac dysrhythmias, seizures, muscle cramps, tetany, syncope, and suddendeath. Commonly associated high-grade NHLs , and Acute Lymphoblastic Leukemia(ALL). Childhood BurkittLymphoma Thursday, December 14,2017

  39. TLS 40 • Factors associated with higher risk forTLS: • High tumor cell proliferationrate • Chemosensitivity of themalignancy • Bulkydisease • WBC count>50,000/microL. • A preexisting reduction in renalfunction • Pretreatment oliguria andvolume depletion Childhood BurkittLymphoma Thursday, December 14,2017

  40. Treatment of Tumor LysisSyndrome 41 • Prevention is the besttreatment: • HYPER-HYDRATION: 1.5 – 2.0 times the normal maintenance fluidrequirement. • ALLOPURINOL : should be started earlyand adequately. • Urate oxidase (URICASE): inhibits formation ofuric acid crystals that may causeARF.. Childhood BurkittLymphoma Thursday, December 14,2017

  41. THANK  YOU  ALL 

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