Pathology Review-Term2

1. As is our Pathology, so is our Practice. -- Sir William Osler, M.D. (Father of Modern Medicine & Founding professor of John Hopkins, developed first residency program for physicians.) Pathology: The science of medicine !

2. CPC21: Week Overview 2013 Term 2 CPC 1 Title: Haematopoetic 1/2 Anaemia System: Haematopoietic system Aim: To train students in: Clinical, pathological & population studies of patients with anemia (RBC disorders) Objectives: 1. History taking & clinical examination of patients with anaemia 2. Physical examination for anaemia and related illnesses. 3. Pathophysiology of common and important rare causes of anaemia, particularly in the tropics and Indigenous populations. 4. Review of Basic sciences relating to bone marrow, red blood cell production and turnover of iron, routine blood test parameters, measurement of iron stores, and precursors important for red cell production. 5. Pathophysiology of acute anaemic processes. 6. Complications of anaemia. 7. Anaemia as a presentation for other pathologies and as an illness in itself.

3. Core Learning Issues: • Basic Science Review: –RBC life cycle, structure, functions. –Iron, B12 & Folate, Hemoglobin/bilirubin metabolism. • Major Learning: –CBC – Principles & Interpretation (reticulocytes). –Microcytic, Macrocytic & Normocytic anemia. –Overview & Classification of Anemias –Common An: IDA, MA, Hemolytic & ACD •Minor Learning: –Congenital anemia– sickle, thalassaemia, G6PD, HS. –Aplastic and hypoplastic anemia. –Disorders of excess RBC – Polycythemia. –Myelodysplastic syndromes (refractory anemia). 3

4. Haemopoiesis: Leukemia 4

5. 5

6. Blood Smear - Normal RBC crenated RBC Lymphocyte 6

7. Blood count - C.B.C / F.B.C • Haemoglobin - 15±2.5, 14 ±2.5 - gms/dl. • PCV/HCT - 0.47 ±0.07, 0.42 ±0.05 - lit/lit (%) – RBC vol – better than Hb for anemia diagnosis. • RBC count - 5.5 ±1, 4.8 ± 1 x1012/lit • MCHC - Hb/PCV - 30-36 – grams/deci lit. – Hb synthesis within RBC • MCH - Hb/RBC - 29.5 ± 2.5 pg picogram (wt) – Average Hb in RBC • MCV - PCV/RBC 85 ± 8 – fl femto litres (vol) 85 33 30 7

8. Reticulocyte: Immature RBC Reticular RNA - Methylene blue stain. Reticulocyte RBC (Bluish, Large (high MCV) Reticulocytes (Immature RBC)  Increased RBC production Reticulocytosis  Hemolytic anemia/bleeding 5-7 days

9. Anemia clinical Types & Diagnosis MCV Microcytic Normocytic Macrocytic Measure Ferritin Measure B12 + folate Normal/high Low Low Normal Anemia of chronic disease/ Congenital Hb dis. Iron def Anemia Megaloblastic anemia Reticulocyte count Anemia of chronic disease Renal failure Marrow failure high low Hemolytic anemia or blood loss

10. Haemopoiesis in Def. anemias Low DNA, Normal Hb Less Cell division Megaloblasts Normal DNA & Hb Normal cell division Normoblasts Normal DNA, Low Hb More cell division Micro-Normoblasts Macropoly, pancytopenia Iron Def. Anem Normal Megaloblastic 10

11. IDA – Clinical Features Angular chelitis Pale creases …Why? Bald Fissured - Glossitis 11

12. Stages of Iron Deficiency: 12

13. Hypochromic Microcytic RBC 13

14. Megaloblastic Anaemia: Marrow Hyperplasia Erythroblasts - Megaloblasts Giant metamyelocyte - Macropolycyte Megaloblastic marrow 14

15. ANEMIA OF CHRONIC DISEASE: • Defective iron transfer. • By Inflammatory mediators. •  erythropoietin production. •  Iron transfer. • IDA with normal or increased iron stores. • Does not respond to hematenic therapy. • Responds to erythropoietin or resolution of inflammation. 15

16. “The future belongs to those who believe in the beauty of their dreams.” –Eleanor Roosevelt

17. Self-pity is an opiate! --Napoleon Hill

18. Hemolytic anemia: Morphology • Abnormal shapes (here a spherocyte) • Polychromatophil (large, bluish, no central palor) • Nucleated RBC (small, pyknotic) Thalassemia 18

19. Hemolytic Anemia - Types: • Acquired/External causes: – Immune Hemolytic Anemia • Warm Antibody HA (WAHA) & Cold Ab (CAHA) • Allo immune hemolytic anemia. – Mechanical Damage • Valve, Microangiopathy (DIC), prosthesis, march – Infection induced • Clostridia, malaria, septicemia • Congenital/Internal Defects • Membrane (Hereditary Spherocytosis) • Enzyme defect (G6PD deficiency) • Hb defects (Qual: Sickle cell dis, Quant: Thalassemias) 3 Commonest 1 2 19

20. Autoimmune Hemolytic An: AIHA • Auto antibody binding to red cell surface antigens / Drug complex. • RBC phagocytosis in spleen or complement fixation and intravascular hemolysis. • Warm (IgG) & Cold (IgM) types. • Warm: Drugs, Ideopathic. • Cold: Infections, Lymphoma • Lab diagnosis: Coombs Test, Direct / Indirect. Warm / IgG Cold / IgM 20

21. AIHA: Lab diagnosis – Coombs test. Direct Coombs Test: (for antigen on patient RBC) Pos Indirect Coombs Test: (for antibodies in the serum.) Neg 21

22. Sickle Cell Anemia - Pathology

23. Sickle Cell Anemia Commonest congenital hemolytic anemia. Hemoglobinopathy – β chain 6(ValGlu)  HbS Deoxigenation  cryst. Hb  rigid sickle  obstruction, hemolysis. BS - Sickle cells, anisocytosis, poikilocytosis, and target cells. Hemolytic anemia, Multiple Infarcts, autosplenectomy(adult), pigment gall stones, hemosiderosis. • • • • •

24. Thalassemia: • Quantitative Hb defect. • Defective protein chain synthesis. • α, β, , , … types. • α thal  α  Hb   β (β β or β tetramers) • Decreased normal Hb. • Abnormal Hb (α/β tetramers). • Like IDA (minor) Destruction  hemolytic anemia (major) • Minor: micro hypo, target cells • Major: severe with hemolysis. Minor / Trait Major / Disease 24

25. “The only person who never makes a mistake is a person who never does anything” - Theodore Roosevelt 25

26. CPC22: Week Overview 2013 Term 2 CPC 2 Title: Haematology 2/2 System: Aim: Haematopoetic System To train students in: Clinical and pathological presentation of haematological malignancy 1. History taking & clinical examination of patients with haematological malignancy 2. Physical examination of haematopoeitic system and related systems in malignancy. 3. Pathophysiology of haematological malignancies. 4. Review of basic sciences relating to bone marrow, red blood cell production and turnover of iron, routine blood test parameters, measurement of iron stores, and precursors important for red cell production. 5. Pathophysiology 6. Complications of haematological malignancies. Objectives:

27. Normal Blood Cells: Non-Specific Immunity Eosinophil Specific Immunity Neutrophil Lymphocyte Basophil Non granular, Mononuclears Granulocytes, Polymorphs 27

28. WBC Absolute counts in disease: Penia Neutro Philia Penia Eosino Philia Penia Mono cytosis Penia Lympho cytosis

29. Granulopoiesis – Leukocytosis – Shift to left

30. Leukemia Classification • Acute Leukemias: – Acute Myeloid Leukemia - AML • AML M0, M1, M2, M3, M4, M5, M6 & M7 – Acute Lymphoid Leukemia - ALL • ALL - L1, L2 & L3 - maturity • Chronic Leukemias: – Chronic Myeloid Leukemia- CML • Eosinophilic, neutrophilic, myelomonocytic etc. – Chronic Lymphoid Leukemia - CLL • Myeloma, Hairy cell, prolymph, Sezary sy. etc.

31. ALL - AML

32. Leukemia - Clinical Features Decreased Hemopoiesis: • Anemia (low RBC) • Fever - Infections (low WBC) • Bleeding tendency (low PLT) Organ Infiltration: • Bone pain / back pain. • Lymphadenopathy. • Hepato-spleenomegaly.

33. ALL - AML • Fine lacy chromatin • Many nucleoli • More cytoplasm • Cytoplasmic granules • Dense chromatin • Few nucleoli • Scanty cytoplasm. • No cytoplasmic granules.

34. CML CLL • Middle age 40-60y • Philadelphia chrom. t(9:22) • Anemia, Fever & Bleeding • Marked leucocytosis – >50,000 (abnormal) • Marked splenomegaly, Hepatomegaly. • Elderly age • Anemia, fever & bleeding – slow over years. • Lymphocytosis & Lymphadenopathy • Marked Spleenomegaly • Common B cell (CD5 +ve) Chronic phase Accelerated crisis Clinical course 

35. Lymphoma • Definition: Neoplasms of lymphoid tissue • Etiology: Idiopathic, Genetic, Infective. • Pathogenesis: – overexpression of antiapoptotic gene – t(14-18)  bcl-2+IgM.  B Lymph. neoplasia * • Clinical: Lymphadenopathy, weight loss, Fever, Anemia. • Hodgkins lymphoma (HL) – RS cells. • Non-Hodgkins lymphoma (NHL) – no RS. – B, T & Histiocytic “B commonest”

36. Hodgkins Lymphoma: • Only Reed-Sternberg cells are malignant „B‟ cells. Others cells are reactive. • Types: • Nodular sclerosis HL • Lymphocyte-rich classical HL • Mixed cellularity HL • Lymphocyte depletion HL • More RS cells = poor prognosis. • Progresses by continuity – nearby LN first. • Staging is important for prognosis. (x NHL)

37. Hodgkins Lymphoma: • B cell lymphoma with special RS cells. • Only Reed-Sternberg cells are malignant „B‟ lymphocytes. Others cells are mixed inflammatory cells with eosinophils. • Many sub types: based on % of RS cells. • More RS cells = poor prognosis. 1. Lymphocyte-rich classical HL 2. Nodular sclerosis HL – commonest. 3. Mixed cellularity HL 4. Lymphocyte depletion HL • Spread to nearby LN not distant. • Good prognosis, cure likely* RS RS RS

38. Non-Hodgkins Lymphoma: • Large group of lymphatic malignancies. • types B, T & Histiocytic. “B common” • Clinical Features: – Fever, anemia, infections, – Lymphadenopathy. Spleen+/-. – low, intermediate & high grade. • Pathology – Lymphnode tumour – no RS cells, all one type. – Follicular / Diffuse, Small / Large / mix Cells. • Special types: – Burkitts lymphoma – lymphoblastic. – Multiple Myeloma – plasma cell.

39. NHL types- Diffuse & Nodular types

40. Lymphoma: Hodgkins Non Hodgkins Average age is about 67. Average age is 27.7 with two peaks, 15-24y , >55. ~ 15% of all lymphomas above the collar bone 85% (the mediastinum), Extranodal in 4% Age ~ 85% of all lymphomas Chest in 40%, more abdomen (exception lymphoblastic lymphoma) Extranodal in ~23% & BM B, T, Histiocytes, NK Cells depending on the subtype Occurrence Location B-Lymphocytes characterized by the Reed-Sternberg Cell More likely to have systemic ("B") Symptoms Affected Lymph Cells Symptoms Less likely to have "B“ symptoms.(27%) Early diagnosis, Predictable, continuous involvement. Better prog. Late stages, less predictable more spread. Good to Worse prognosis. Progression

41. Burkitt‟s lymphoma: B cell. • Young children, EBV virus. • Endemic in Africa • High grade, fast growing, • Tumour in jaw bones. • Lymphoblastic lymphoma • Many macrophages – “starry sky” appearance.

42. Multiple Myeloma: • Malignancy of Plasma cells (Mature B lymphocytes with Ab production) • Hyper gammaglobulinemia • Monoclonal antibody – neoplastic. • Thick viscous blood – infarctions, visual difficulties & even blindness. • Old age, males common. • Multiple, punched out Lytic bone lesions (Osteolysis) & fractures. • Immunodeficiency – infections.

43. "Creativity is inventing, experimenting, growing, taking risks, breaking rules, making mistakes, and having fun." -- Mary Lou Cook

44. MyeloProliferative Syndromes: • Neoplastic, Proliferation, Slow, chronic, & Mature cells. • JAK2 gene mutation on 9p*  Erythropoietin hypersensitivity. • Increased number (Functionally abnormal) • Extramedullary spread – Hepatosplenomegaly. • May transform to Acute Leukemia (AML). • Classification: – RBC - Polycythemia vera (PV) – WBC • Chronic Myeloid Leukemia (CML) • Chronic neutrophilic leukemia • Chronic eosinophilic leukemia/HE syndrome. – PLT - Essential Thrombocythemia (ET) – Fibroblasts - Myelofibrosis (MF)

45. ET - Blood Film & clinical. Plenty of Platelets Megakaryocyte

46. Polycythemia Rubra Vera (PV) Hypercellular Marrow, Red skin & Hepatosplenomegaly

47. MPS : MF. Hepatosplenomegaly Massive hepato-splenomegaly secondary to Extramedullary hematopoiesis due to Myelofibrosis.

48. Myelodysplastic Syndromes: • Excess proliferation & destruction of dysplastic cells in BM  Peripheral pancytopenia. • Also known as Refractory Anemia‟s FAB classification RA : Refractory Anemia (BM Blasts <1%) RARS : RA with Ring Sideroblasts (<1%) RAEB : RA with excess blasts (<5%) RAEB in T : RAEB in transformation (5-30%) (>30% blasts in BM  Leukemia) Abnormal cells & Recurrent infections in MDS

49. Worrying is like a rocking chair, it gives you something to do, but doesn't get you anywhere. -- Anonymous. ….Instead.. join winners club….!

50. The goal of mankind is knowledge, which is is inherent in man. No knowledge comes from outside: it is all inside. What man 'learns' is really what he “discovers” by taking the cover off his own soul. Swami Vivekananda Education… from Eduse (latin) to bring out..