Part I Neoplastic Proliferation Of Wbc

1. NEOPLASTIC PROLIFERATION OF WBC 1

2. LYMPHOID NEOPLASM MYELOID NEOPLASM - Hematopoietic stem cells MYELOID LINEAGE 1. ERYTHROID 2. GRANULOCYTIC AML MYELODYSPLASTIC CHRONIC MYELOPROLIFERATIVE D/O 3. THROMBOCYTIC HISTIOCYTOSES 2 CATEGORIES:

3. Acute Myelogenous Immature progenitor cells accumulate in BM Myelodysplastic Syndromes Ineffective Hematopoiesis Peripheral Cytopenias Chronic Myeloproliferative D/O Increased production 1 or more terminally differentiated myeloid elements GRANULOCYTES Leads to elevated peripheral blood counts 3 Granulocytic Lineage

4. 4 Pathogenetic factors

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  A ffect 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

6. 6 Pathogenetic factors

7. 7 Pathogenetic factors

8. 8 Pathogenetic factors

9. 9 Pathogenetic factors

10. 10 Smoking

11. LYMPHOID NEOPLASMS 11

12. CLASSIFICATION: Lymphocytic Leukemia Lymphoma Plasma cell Neoplasm 12

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- Hodgkins Lmphoma 2. Hodgkins Lymhoma 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 Presentation Lymphoma

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 LYMPHOCYTIC LEUKEMIA

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. A cute Lymphoblastic Leukemia/Lymphoma Precursor B and T –Cell Neoplasms - Neoplasm of Immature B cells 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 Mediastinal thymic mass Often with LNadenopathy & Splenomegaly 26 Morphology

27. Lymphoblast in PBS Definitve Dx 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

28. 28 Acute Lymphoblastic Leukemia

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

34. 34

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. < 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 Unfavorable Prognostic Factors 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

39. CHRONIC LYMPHOCYTIC LEUKEMIA – CLL and SMALL LYMPHOCYTIC LYMPHOMA- SLL 39

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 mm 3 PERIPHERAL BLOOD WBC counts is High Increased numbers of Small Lymphocytes Smudge cell 41

42. Chronic Lymphocytic Leukemia 42

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

44. Small Cell Lymphoma 44

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