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Part i neoplastic proliferation of wbc
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Part i neoplastic proliferation of wbc

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  • 1. 1
  • 2. 2
  • 3. STAGE CRITERIA I In one lymph node only II In 2 or more LN on same side of the diaphragm III In the Lymph nodes, Spleen, or Both AND on Both sides of the diaphragm 1 Above the renal vessels (eg. Spleen, splenic, hilar, celiac, portal nodes 2 In the lower abdomen ( periaortic, pelvic, or imguinal nodes ) IV Extranodal involvement ( eg. Bone marrow, Lung, Liver ) A – absence of Systemic manifestation B – presence of Systemic manifestation NIGHT SWEATS, FEVER, WEIGHT LOSS
  • 4.  LYMPHOID NEOPLASM  MYELOID NEOPLASM - Hematopoietic stem cells ◦ MYELOID LINEAGE  1. ERYTHROID  2. GRANULOCYTIC  AML  MYELODYSPLASTIC  CHRONIC MYELOPROLIFERATIVE D/O  3. THROMBOCYTIC  HISTIOCYTOSES 4
  • 5.  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 5
  • 6. •Lymphoid Neoplasms •Oncogenic rearrangement •Mutation in oncogenes r/t inherent genomic instability of germinal B cells •Myeloid Neoplasms •Chromosmal translocation •Unknown mechanism CHROMOSOMAL TRANSLOCATION AND ONCOGENES 6
  • 7.  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 7
  • 8. •Promote genomic instability •Down syndrome •Fanconi anemia Inherent Genetic Factors 8
  • 9. Viruses •HTLV-1 •Adult T cell Leukemia/ Lymphoma • EBV •Burkitts, Hodgkins •Diminsihed T cell dependent Immune surveillance • KSHV/HHV- • Kaposi sarcoma herpes virus/ • Human herpes Virus 8 9
  • 10. Chronic Immune Stimulation •H. pylori- Gastric lymphoma •Gluten enteropathy – Intestinal lymphoma T cell dysregulation  Systemic hyperplasia of germinal center B cells •HIV B cell Lymphoma •Arise w/in virtually any organ Diminsihed T cell dependent Immune surveillance • EBV 10
  • 11. Iatrogenic Factors Mutagenic effects on Progenitor cells •Radiotherapy •Chemotherapy 11
  • 12. Incidence of AML increased 1.3 to 2 fold in smokers Exposure to carcinogens like benzene in tobacco smoke 12
  • 13. STAGE CRITERIA I In one lymph node only II In 2 or more LN on same side of the diaphragm III In the Lymph nodes, Spleen, or Both AND on Both sides of the diaphragm 1 Above the renal vessels (eg. Spleen, splenic, hilar, celiac, portal nodes 2 In the lower abdomen ( periaortic, pelvic, or imguinal nodes ) IV Extranodal involvement ( eg. Bone marrow, Lung, Liver ) A – absence of Systemic manifestation B – presence of Systemic manifestation NIGHT SWEATS, FEVER, WEIGHT LOSS
  • 14. 14
  • 15. 1. Lymphocytic Leukemia 2. Lymphoma 3. Plasma cell Neoplasm 15
  • 16.  Lymphoid neoplasm  Widespread Bone Marrow Involvement  Usually (+) Large Numbers of Tumor cells in Peripheral smear 16
  • 17.  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 17
  • 18.  Most commonly arise in Bone Marrow  Rarely present as Leukemia  R/T Secretion of Antibodies by tumor cells 18
  • 19.  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 19
  • 20.  Inherited or acquired Immunedeficiency  High risk certain lymphoid neoplasm ◦ Particularly caused by oncogenic virus eg. EBV 20
  • 21.  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 ) 21
  • 22.  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 22
  • 23.  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 23
  • 24.  Involve the skeleton ◦Local bone destruction ◦Pain ◦Pathologic Fractures  Addendum ◦Secretion of whole Ab or Ig fragments 24
  • 25.  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 25
  • 26. Precursor B and T –Cell Neoplasms -Neoplasm of Immature B & T cells -lymphoblast 26
  • 27.  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 27
  • 28.  85% Childhood Acute Leukemia ◦ Are pre B cells ◦ Affect children ◦ Peak age is 3 y/o ◦ Extensive BM involvement ◦ Variable Peripheral involvement ◦ Uncommonly present as Lymphoma  Less common As Thymic Lymphoma ◦ Are pre-T cells ◦ Adolescent males ◦ Many evolve to Leukemia 28
  • 29.  B-ALL ◦ Leukemic Presentation ◦ Marrow Hyperplasia and packed with Lymphoblast  T-ALL ◦ Mediastinal thymic mass ◦ Often with LNadenopathy & Splenomegaly 29
  • 30.  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 30
  • 31. 31
  • 32.  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 32
  • 33.  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 33
  • 34.  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 34
  • 35.  Abrupt stormy onset  Present w/in days to few weeks  Symptoms r/t bone marrow suppression ◦ Anemia , Infection, Bleeding episodes 35
  • 36.  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 36
  • 37. 37
  • 38.  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 38
  • 39.  < 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 39
  • 40.  Age 2-10 y/o  Low WBC count  Early pre-B phenotype  Hyperploidy or t(12;21) 40
  • 41. 41 1. Chronic Lymphocytic Leukemia & Small Lymphocytic Lymphoma 2. Follicular Lymphoma 3. Diffuse Large Cell Lymphoma 4. Extranodal marginal zone Lymphoma 5. Burkitts Lymphoma
  • 42. 42
  • 43. •Similar - Morphological, Phenotype, Genotype •Differ only in degree of peripheral blood Lymphocytosis 43
  • 44. • 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 44
  • 45. Chronic Lymphocytic Leukemia 45
  • 46. • 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 46
  • 47. 47
  • 48. 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 48
  • 49. 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 49
  • 50. Clinical Features • 50-60% show ▫ Generalized Lymphadenopathy ▫ Hepatosplenomegaly • VARIABLE INVOLVEMENT OF SPLEEN & HEPATIC PORTAL TRATS 50
  • 51. Clinical Features •Disrupts Immune function ▫ Hypogammaglobulinemia – Susceptible to INFXN ▫ Autoimmune  Auto-Antibodies produced by non- neoplastic B cells ▫ 10-15% develop Hemolytic anemia /Thrombocytopenia 51
  • 52. •Extremely Variable ▫ Depend mostly on Stage •Overall Median is 4-6 years •Minimal Tumor burden  10 years 52
  • 53. • 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 53