5. Mutated genes Produce Negative protein Interfere with its normal function/ or Inapropriate increase in some normal activity ( MALTomas ) Translocation of either MALT1 or BCL10 protein Upregulation of NF-kB Normally Bind to form complex regulate NF-kB NF-kB has important pro-survival function in normal lymphocytes Oncoprotein created by genomic abberations Often Block normal maturation Affect rapidly proliferating cells Acute Leukemias Proto-Oncogenes Often activated in lymphocytes by errors that occur during attempted antibody diversification 5 Chromosomal Translocation & Other Acquired Mutations
13. Lymphoid neoplasm Widespread Bone Marrow Involvement Usually (+) Large Numbers of Tumor cells in Peripheral smear 13 Lymphocytic leukemia
14. Proliferations arising as Discrete tissue masses 2 Types 1. Non-HodgkinsLmphoma 2. HodgkinsLymhoma Many types present with Leukemia Term used – Tissue distribution of the disease at time of clinical presentation 14 lymphoma
15. Most commonly arise in Bone Marrow Rarely present as Leukemia R/T Secretion of Antibodies by tumor cells 15 Plasma cell Neoplasm
16. Vast majority are B cell in origin Markers recognized by Antibodies help in characterization into 5 categories Often disrupt normal architecture & function of Immune system Susceptibility to infection Autoimmune 16 FEATURES- Lymphoid Neoplasm
17. Inherited or acquired Immunedeficiency High risk certain lymphoid neoplasm Particularly caused by oncogenic virus eg. EBV 17 FEATURES- Lymphoid Neoplasm
18. Tend to home to a particular tissue sites Follicular Lymphoma – Germinal center T-cell Lymphomas – Skin Some recirculate through the lymphatics & peripheral blood Distant sites Except Hodgkins, Marginal zone lymphoma ( MALToma ) 18 FEATURES- Lymphoid Neoplasm
19. Determined by Anatomic distribuation of disease 2/3 NHL and 100% of Hodgkin Lymphomas Enlarged Nontender LN Often > 2 cm Remaining 1/3 NHL Symptoms r/t to involvement of Extranodal sites Skin, Stomach, Brain 19 Clinical PresentationLymphoma
20. Abrupt stormy onset Present w/in days to few weeks S/S related to Suppression of normal Hematopoiesis by tumor cells in BM Characteristic is Infiltrate in Spleen & Liver 20 LYMPHOCYTICLEUKEMIA
21. Involve the skeleton Local bone destruction Pain Pathologic Fractures Addendum Secretion of whole Ab or Ig fragments 21 PLASMA CELL NEOPLASM
22. Precursor B cell Neoplasm Immature B cells Peripheral B cell Neoplasms Mature B cells Percursor T-cell Neoplasm Immature T cells Peripheral T-cell & NK cell Neoplasm Mature T cell & NK cells Hodgkin Lymphoma 22 WHO 5 CATEGORIES
23. Precursor B and T –Cell Neoplasms - Neoplasm of Immature B cells Acute Lymphoblastic Leukemia/Lymphoma 23
24. Group of Neoplasm composed of Immature pre-B or Pre-T LYMPHOBLASTS Most common cancer of Children Slightly higher in boys 2 Types: 1. Pre-B cell 2. Pre-T cell Both tumors types are morphologically indistinguishable Features : 24
25. 85% are B-ALLs Manifest as Childhood Acute Leukemia Peak age is 3 y/o Extensive BM involvement Variable Peripheral involvement Uncommonly present as Lymphoma Less common is T-ALLs Adolescent males As Thymic Lymphoma Many evolve to Leukemia Features : 25
26. B-ALL Leukemic Presentation Marrow Hyperplasia and packed with Lymphoblast T-ALL Mediastinalthymic mass Often with LNadenopathy & Splenomegaly 26 Morphology
27. Lymphoblast in PBS DefinitveDx based on Lymphocyte –specific markers with Antibodies Histochemical stain Negative for myeloperoxidase Often (+) PAS in cytoplasmic aggregates Immunophenotype (+) TdT in > 95% of cases DNA polymerase Expressed only in pre-B and pre-T lymphoblast Morphology : 27
29. B-ALL lymphoblast (+) CD19, CD10, CD19, CD20 T-ALL lymphoblast (+) CD1, CD2, CD5, CD7 Arrest in normal Maturation of Lymphoblast Dysregulation in epxression and function of transcription factors 29
30. About 90% ALL have numerical or structural chromosomal changes Most commonly – Hyperploidy > 50 chromosomes Hypoploidy Translocation Hyperploidy & Hypoploidy are seen only in B-ALL B & T ALL are associated wuth completely different sets of translocation 30 Molecular Pathogenesis
31. 70% of T-ALL Have gain-of-function mutations in NOTCH1 NOTCH1 is essential for T-cell development High Fraction of B-ALL Have loss-of-function mutations in genes for B cell development NET EFFECT: 1. Disturb differentiation of Lymphoid precursor 2. Promote Maturation arrest Single mutations are not sufficient to produce ALL Must Acquire additional mutation before ALL develop 31 Molecular Pathogenesis
32. Abrupt stormy onset Present w/in days to few weeks Symptoms r/t bone marrow suppression Anemia , Infection, Bleeding episodes Clinical Features : 32
33. Mass Effects Bone pain & tenderness Generalized Lymphadenopathy, Splenomegaly, Hepatomegaly T-ALL Complications R/T complression of large vessels and Airways in mediastinum Both may have CNS manifestation Due to meningeal spread Headache, Vomiting, Nerve palsies Clinical Features : 33
35. Aggressive ChemoTx often w/ prophylactic CNS treatment > 95% of children achieve complete remission 75-85% of choldren are Cured Still the leading cause of cancer death in children Treatment & Prognosis : 35
36. Unfavorable Prognostic Factors < 2y/o Presentation in adolescence or childhood Peripheral blast count > 100,000 Presence of Ph’ chromosome T(9;22) Commonly seen in adult patients ALLOGENIC BM TRANSPLANT – POOR PROGNOSTIC CATEGORIES 36
37. Age 2-10 y/o Low WBC count Early pre-B phenotype Hyperploidy or t(12;21) Favorable Prognostic Factor 37
38. Peripheral B cell Neoplasm- Neoplasm of Mature B cells 38 Chronic Lymphocytic Leukemia & Small Lymphocytic Lymphoma 2. Follicular Lymphoma 3. Diffuse Large Cell Lymphoma 4. Extranodal marginal zone Lymphoma 5. Burkitts Lymphoma
40. Features Similar - Morphological, Phenotype, Genotype Differ only in degree of peripheral blood Lymphocytosis 40
41. Features CLL – Chronic Lymphocytic Leukemia Most common leukemia of Adults in Western countries Median age 60 y/o 2:1 male preponderance Diagnostic Criteria Absolute Lymphocytosis > 4000 per mm3 PERIPHERAL BLOOD WBC counts is High Increased numbers of Small Lymphocytes Smudge cell 41
43. Features SLL – Small Lymphocytic Lymphoma. Represent 4% of Non-Hodgkin Lymphoma Total WBC count is Variable If w/ Bone Marrow Involvement can present as Leukopenia LYMPH NODE Diffusely Effaced , Predominant Small Lymphocytes Variable large Prolymphocytes CREATE PROLIFERATION CENTERS PATHOGNOMONIC FOR CLL/SLL 43
45. Immunophenotype/ Molecular Genetics CD5 – present in tumor cells T-cell marker Expressed by small subset of normal B lymphos Chromosomal translocation is rare Most are Deletions 13q14 11q 17p 45
46. Clinical Features Mostly over 50 y/o Male > Female 2:1 Often Asymptomatic Nonspecific symptoms when manifest BONE MARROW INVOLVEMENT All cases of CLL Most cases of SLL 46
47. Clinical Features 50-60% show Generalized Lymphadenopathy Hepatosplenomegaly VARIABLE INVOLVEMENT OF SPLEEN & HEPATIC PORTAL TRATS 47
48. Clinical Features Disrupts Immune function Hypogammaglobulinemia – Susceptible to INFXN Autoimmune Auto-Antibodies produced by non-neoplastic B cells 10-15% develop Hemolytic anemia /Thrombocytopenia 48
49. Prognosis Extremely Variable Depend mostly on Stage Overall Median is 4-6 years Minimal Tumor burden 10 years 49
50. Poor Prognostic Factors Presence of Deletions 11q & 17p Usually higher stage Transformation to higher grades Prolymphocytic 15%-30% Worsening cytopenias Increasing Splenomegaly Diffuse Large cell 5%-10% Rapidly enlarging mass w/in LN or spleen Richter syndrome Survival < 1 year 50