Part I Neoplastic Proliferation Of Wbc


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Part I Neoplastic Proliferation Of Wbc

  3. 3. Acute Myelogenous<br />Immature progenitor cells accumulate in BM<br />Myelodysplastic Syndromes<br />Ineffective Hematopoiesis<br />Peripheral Cytopenias<br />Chronic Myeloproliferative D/O<br />Increased production<br />1 or more terminally differentiated myeloid elements<br />GRANULOCYTES<br />Leads to elevated peripheral blood counts<br />3<br />Granulocytic Lineage<br />
  4. 4. 4<br />Pathogenetic factors<br />
  5. 5. Mutated genes  Produce Negative protein<br />Interfere with its normal function/ or Inapropriate increase in some normal activity ( MALTomas )<br />Translocation of either MALT1 or BCL10 protein  Upregulation of NF-kB<br />Normally Bind to form complex  regulate NF-kB<br />NF-kB has important pro-survival function in normal lymphocytes<br />Oncoprotein created by genomic abberations<br />Often Block normal maturation  Affect rapidly proliferating cells<br />Acute Leukemias<br />Proto-Oncogenes<br />Often activated in lymphocytes by errors that occur during attempted antibody diversification<br />5<br />Chromosomal Translocation & Other Acquired Mutations<br />
  6. 6. 6<br />Pathogenetic factors<br />
  7. 7. 7<br />Pathogenetic factors<br />
  8. 8. 8<br />Pathogenetic factors<br />
  9. 9. 9<br />Pathogenetic factors<br />
  10. 10. 10<br />Smoking<br />
  11. 11. LYMPHOID NEOPLASMS<br />11<br />
  12. 12. CLASSIFICATION:<br />Lymphocytic Leukemia<br />Lymphoma<br />Plasma cell Neoplasm<br />12<br />
  13. 13. Lymphoid neoplasm<br />Widespread Bone Marrow Involvement<br />Usually (+) Large Numbers of Tumor cells in Peripheral smear<br />13<br />Lymphocytic leukemia<br />
  14. 14. Proliferations arising as Discrete tissue masses<br />2 Types<br />1. Non-HodgkinsLmphoma<br />2. HodgkinsLymhoma<br />Many types present with Leukemia<br />Term used – Tissue distribution of the disease at time of clinical presentation<br />14<br />lymphoma<br />
  15. 15. Most commonly arise in Bone Marrow<br />Rarely present as Leukemia<br />R/T Secretion of Antibodies by tumor cells<br />15<br />Plasma cell Neoplasm<br />
  16. 16. Vast majority are B cell in origin<br />Markers recognized by Antibodies help in characterization into 5 categories<br />Often disrupt normal architecture & function of Immune system<br />Susceptibility to infection<br />Autoimmune<br />16<br />FEATURES- Lymphoid Neoplasm<br />
  17. 17. Inherited or acquired Immunedeficiency High risk certain lymphoid neoplasm<br />Particularly caused by oncogenic virus eg. EBV<br />17<br />FEATURES- Lymphoid Neoplasm<br />
  18. 18. Tend to home to a particular tissue sites<br />Follicular Lymphoma – Germinal center<br />T-cell Lymphomas – Skin<br />Some recirculate through the lymphatics & peripheral blood  Distant sites<br />Except Hodgkins, Marginal zone lymphoma ( MALToma )<br />18<br />FEATURES- Lymphoid Neoplasm<br />
  19. 19. Determined by Anatomic distribuation of disease<br />2/3 NHL and 100% of Hodgkin Lymphomas<br />Enlarged Nontender LN<br />Often > 2 cm<br />Remaining 1/3 NHL<br />Symptoms r/t to involvement of Extranodal sites<br />Skin, Stomach, Brain<br />19<br />Clinical PresentationLymphoma<br />
  20. 20. Abrupt stormy onset<br />Present w/in days to few weeks<br />S/S related to Suppression of normal Hematopoiesis by tumor cells in BM<br />Characteristic is Infiltrate in Spleen & Liver<br />20<br />LYMPHOCYTICLEUKEMIA<br />
  21. 21. Involve the skeleton<br />Local bone destruction<br />Pain<br />Pathologic Fractures<br />Addendum<br />Secretion of whole Ab or Ig fragments<br />21<br />PLASMA CELL NEOPLASM<br />
  22. 22. Precursor B cell Neoplasm<br />Immature B cells<br />Peripheral B cell Neoplasms<br />Mature B cells<br />Percursor T-cell Neoplasm<br />Immature T cells<br />Peripheral T-cell & NK cell Neoplasm<br />Mature T cell & NK cells<br />Hodgkin Lymphoma<br />22<br />WHO 5 CATEGORIES<br />
  23. 23. Precursor B and T –Cell Neoplasms<br />- Neoplasm of Immature B cells<br />Acute Lymphoblastic Leukemia/Lymphoma<br />23<br />
  24. 24. Group of Neoplasm composed of Immature pre-B or Pre-T LYMPHOBLASTS <br />Most common cancer of Children<br />Slightly higher in boys<br />2 Types: <br />1. Pre-B cell <br />2. Pre-T cell<br />Both tumors types are morphologically indistinguishable<br />Features :<br />24<br />
  25. 25. 85% are B-ALLs<br />Manifest as Childhood Acute Leukemia<br />Peak age is 3 y/o<br />Extensive BM involvement<br />Variable Peripheral involvement<br />Uncommonly present as Lymphoma<br />Less common is T-ALLs<br />Adolescent males<br />As Thymic Lymphoma<br />Many evolve to Leukemia<br />Features :<br />25<br />
  26. 26. B-ALL<br />Leukemic Presentation<br />Marrow Hyperplasia and packed with Lymphoblast<br />T-ALL<br />Mediastinalthymic mass <br />Often with LNadenopathy & Splenomegaly<br />26<br />Morphology<br />
  27. 27. Lymphoblast in PBS<br />DefinitveDx based on Lymphocyte –specific markers with Antibodies<br />Histochemical stain <br />Negative for myeloperoxidase<br />Often (+) PAS in cytoplasmic aggregates<br />Immunophenotype<br />(+) TdT in > 95% of cases<br />DNA polymerase<br />Expressed only in pre-B and pre-T lymphoblast<br />Morphology :<br />27<br />
  28. 28. 28<br />Acute Lymphoblastic Leukemia<br />
  29. 29. B-ALL lymphoblast (+)<br />CD19, CD10, CD19, CD20<br />T-ALL lymphoblast (+)<br />CD1, CD2, CD5, CD7<br />Arrest in normal Maturation of Lymphoblast<br />Dysregulation in epxression and function of transcription factors<br />29<br />
  30. 30. About 90% ALL have numerical or structural chromosomal changes<br />Most commonly – Hyperploidy<br />> 50 chromosomes<br />Hypoploidy<br />Translocation<br />Hyperploidy & Hypoploidy are seen only in B-ALL<br />B & T ALL are associated wuth completely different sets of translocation<br />30<br />Molecular Pathogenesis<br />
  31. 31. 70% of T-ALL <br />Have gain-of-function mutations in NOTCH1<br />NOTCH1 is essential for T-cell development<br />High Fraction of B-ALL<br />Have loss-of-function mutations in genes for B cell development<br />NET EFFECT:<br />1. Disturb differentiation of Lymphoid precursor<br /> 2. Promote Maturation arrest<br />Single mutations are not sufficient to produce ALL  Must Acquire additional mutation before ALL develop<br />31<br />Molecular Pathogenesis<br />
  32. 32. Abrupt stormy onset<br />Present w/in days to few weeks<br />Symptoms r/t bone marrow suppression<br /> Anemia , Infection, Bleeding episodes<br />Clinical Features :<br />32<br />
  33. 33. Mass Effects<br />Bone pain & tenderness <br />Generalized Lymphadenopathy, Splenomegaly, Hepatomegaly<br />T-ALL<br />Complications R/T complression of large vessels and Airways in mediastinum<br />Both may have CNS manifestation<br />Due to meningeal spread<br />Headache, Vomiting, Nerve palsies<br />Clinical Features :<br />33<br />
  34. 34. 34<br />
  35. 35. Aggressive ChemoTx often w/ prophylactic CNS treatment<br />> 95% of children achieve complete remission<br />75-85% of choldren are Cured<br />Still the leading cause of cancer death in children<br />Treatment & Prognosis :<br />35<br />
  36. 36. Unfavorable Prognostic Factors<br />< 2y/o<br />Presentation in adolescence or childhood<br />Peripheral blast count > 100,000<br />Presence of Ph’ chromosome<br />T(9;22)<br />Commonly seen in adult patients<br />ALLOGENIC BM TRANSPLANT – POOR PROGNOSTIC CATEGORIES<br />36<br />
  37. 37. Age 2-10 y/o<br />Low WBC count<br />Early pre-B phenotype<br />Hyperploidy or t(12;21)<br />Favorable Prognostic Factor<br />37<br />
  38. 38. Peripheral B cell Neoplasm- Neoplasm of Mature B cells<br />38<br />Chronic Lymphocytic Leukemia & Small Lymphocytic Lymphoma<br />2. Follicular Lymphoma<br />3. Diffuse Large Cell Lymphoma<br />4. Extranodal marginal zone Lymphoma<br />5. Burkitts Lymphoma <br />
  40. 40. Features<br />Similar - Morphological, Phenotype, Genotype<br />Differ only in degree of peripheral blood Lymphocytosis<br />40<br />
  41. 41. Features<br />CLL – Chronic Lymphocytic Leukemia<br />Most common leukemia of Adults in Western countries<br />Median age 60 y/o<br />2:1 male preponderance<br />Diagnostic Criteria<br />Absolute Lymphocytosis > 4000 per mm3<br />PERIPHERAL BLOOD <br />WBC counts is High<br />Increased numbers of Small Lymphocytes<br />Smudge cell <br />41<br />
  42. 42. Chronic Lymphocytic Leukemia<br />42<br />
  43. 43. Features<br />SLL – Small Lymphocytic Lymphoma.<br />Represent 4% of Non-Hodgkin Lymphoma<br />Total WBC count is Variable<br />If w/ Bone Marrow Involvement can present as Leukopenia<br />LYMPH NODE<br />Diffusely Effaced , Predominant Small Lymphocytes<br />Variable large Prolymphocytes<br />CREATE PROLIFERATION CENTERS <br />PATHOGNOMONIC FOR CLL/SLL<br />43<br />
  44. 44. Small Cell Lymphoma<br />44<br />
  45. 45. Immunophenotype/ Molecular Genetics<br />CD5 – present in tumor cells<br />T-cell marker <br />Expressed by small subset of normal B lymphos<br />Chromosomal translocation is rare<br />Most are Deletions <br />13q14<br />11q<br />17p<br />45<br />
  46. 46. Clinical Features<br />Mostly over 50 y/o<br />Male > Female 2:1<br />Often Asymptomatic<br />Nonspecific symptoms when manifest<br />BONE MARROW INVOLVEMENT<br />All cases of CLL<br />Most cases of SLL<br />46<br />
  47. 47. Clinical Features<br />50-60% show<br />Generalized Lymphadenopathy<br />Hepatosplenomegaly<br />VARIABLE INVOLVEMENT OF SPLEEN & HEPATIC PORTAL TRATS<br />47<br />
  48. 48. Clinical Features<br />Disrupts Immune function<br />Hypogammaglobulinemia – Susceptible to INFXN<br />Autoimmune <br />Auto-Antibodies produced by non-neoplastic B cells<br /> 10-15% develop Hemolytic anemia /Thrombocytopenia<br />48<br />
  49. 49. Prognosis<br />Extremely Variable<br />Depend mostly on Stage<br />Overall Median is 4-6 years<br />Minimal Tumor burden  10 years<br />49<br />
  50. 50. Poor Prognostic Factors<br />Presence of Deletions 11q & 17p<br />Usually higher stage<br />Transformation to higher grades<br />Prolymphocytic 15%-30%<br />Worsening cytopenias<br />Increasing Splenomegaly<br />Diffuse Large cell 5%-10%<br />Rapidly enlarging mass w/in LN or spleen<br />Richter syndrome<br />Survival < 1 year<br />50<br />