Leukaemia lecture 02 ALL transcript
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The document discusses acute lymphoblastic leukemia (ALL), the most common cancer in children, detailing its definition, classification, pathogenesis, clinical features, prognosis, lab diagnosis, and treatment. It outlines the differences between lymphoblasts and myeloblasts and describes various cytogenetic abnormalities associated with the disease. Treatment strategies are given for both children and adults, emphasizing the importance of chemotherapy and potential stem cell transplant options.
Leukaemia lecture 02 ALL transcript
- 1. Leukaemia Lecture 02 Acute Lymphoblastic Leukemia/Lymphomas (ALLs)
- 2. Leukaemia Lecture 02 (ALL) Dr. Rabiul Haque Lecturer, Department of Pathology, Holy Family Red Crescent Medical College, Dhaka
- 3. Visit pathologytutorials.weebly.com for transcript of uploaded lectures of immunology series. Follow facebook.com/Pathology.Tutorials for updates. Subscribe to youtube.com/c/RabiulHaque for more videos.
- 4. Learning Objectives Introduction Definition Difference between lymphoblast & myeloblast Incidence Classification Pathogenesis Clinical features Prognosis Lab Diagnosis Treatment
- 5. Introduction ALL is the most common cancer of children. Most occur in individuals younger than 15 years of age. Slightly more frequent in boys than in girls.
- 6. Definition Acute lymphoblastic leukemia/lymphomas (ALLs) are neoplasms composed of immature B (pre-B) or T (pre-T) cells, which are referred to as lymphoblasts. Ref. Robbins and Cortan Pathologic Basis of Disease 9th Edition
- 7. Difference Between Lymphoblast & Myeloblast Feature Myeloblast Lymphoblast Size Larger Smaller Nucleus Round or oval Round or oval Nucleoli 2-5 1-2 Nuclear Membrane Very fine Fairly dense Nuclear Chromatin Fine Coarse Cytoplasm Moderate Scanty
- 10. Lymphoblast Myeloblast Scanty cytoplasm Coarse nuclear chromatin Moderate cytoplasm Prominent nucleoli
- 11. Incidence 85% are B-ALLs that typically manifest as childhood acute leukaemias. T-ALLs are less common and typically manifest as thymic lymphomas in adolescent males. B-ALL peaks in incidence at about 3 years of age. Peak incidence of T-ALL is in adolescence. Considerable overlap in clinical behaviors of B-ALL and T-ALL are seen.
- 12. Classification
- 13. Classification There are two classification schemes. Morphological Classification of ALL (FAB classification, 1976). WHO Classification (2008) of ALL
- 14. FAB Classification of ALL Morphology L1 L2 L3 Size of blast cell Small Large heterogeneous Large homogeneous N/C Ratio High Lower Lower Cytoplasm Scanty Moderate Moderate, intensely basophilic Cytoplasmic vacuoles +/- +/- Prominent Nuclear membrane Regular Irregular with clefting Regular Nucleoli Invisible or indistinct 1-2, prominent 1-2, prominent
- 15. WHO Classification of ALL B lymphoblastic leukaemia/lymphoma, not otherwise specified B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities T lymphoblastic leukaemia/lymphoma
- 16. WHO Classification of ALL B lymphoblastic leukaemia/lymphoma, not otherwise specified B lymphoblastic leukaemia/lymphoma with recurrent genetic abnormalities B lymphoblastic leukaemia/lymphoma with t(9;22)(q34;q11.2); BCR ABL1 B lymphoblastic leukaemia/lymphoma with t(v;11q23); MLL (KMT2A) rearranged B lymphoblastic leukaemia/lymphoma with t(12;21)(p13;q22); ETV6 RUNX1 B lymphoblastic leukaemia/lymphoma with hyperdiploidy B lymphoblastic leukaemia/lymphoma with hypodiploidy B lymphoblastic leukaemia/lymphoma with t(5;14)(q31;q32); IL3 IGH B lymphoblastic leukaemia/lymphoma with t(1;19)(q23;p13.3); TCF3 PBX1 T lymphoblastic leukaemia/lymphoma
- 17. Cytogenetic Abnormalities in B-cell ALL Chromosomal abnormality Hyperdiploidy (>50) (Favourable) Hypodiploidy (<44) t(12;21)(p13;q22) (Favourable) t(1;19)(q23;p13.3) t(9;22)(q34;q11.2) t(v;11)(v;q23) t(8;14)(q24;q32)
- 18. Pathogenesis of ALL Chromosomal aberrations dysregulate expression and function of transcription factors needed for normal lymphocyte development. These lead to maturation arrest and induce increased self renewal.
- 19. Acute Leukaemia Self-renewal is maintained or increased Apoptosis Differentiation Proliferation is increased Proliferative and survival advantage with block in differentiation and in apoptosis leading to accumulation of undifferentiated cells.
- 20. Clinical Features Due to depression of marrow function: Pallor, fatigue due to anaemia. Bruising, petechiae due to thrombocytopenia. Persistent fever due to neutropenia. Due to organ infiltration: Bone pain due to marrow expansion and subperiosteal infiltrates Lymphadenopathy Splenomegaly Hepatomegaly Central nervous system, testis, eye, gastrointestinal tract, and kidneys may also be involved. In T-ALL, complications related to compression of large vessels and airways in the mediastinum
- 21. Prognosis Factors associated with favorable prognosis: Age between 2 and 10 years. Low white blood cell count. Trisomy of chromosome 4,7 and 10. Presence of t(12;21) Hyperdiploidy
- 22. Prognosis Factors associated with worse prognosis: Age younger than 2 years. Presentation occurring in adolescence or adulthood. Peripheral white blood blast counts greater than 100,000.
- 23. Lab Diagnosis Blood Picture Bone Marrow Examination Cytochemistry Immunophenotyping Cytogenetic Analysis
- 24. Blood Picture Peripheral blood generally shows normochromic normocytic anaemia and thrombocytopenia. TLC may show leukopenia to-normal TLC to leukocytosis. DLC shows large number of circulating lymphoblasts (generally in excess of 20%). Lymphoblasts have round to convoluted nuclei, high nucleo-cytoplasmic ratio and absence of cytoplasmic granularity. Some ‘smear cells’ may be seen in the peripheral blood representing degenerated leukocytes.
- 25. Bone Marrow Examination Bone marrow is hypercellular. Bone marrow examination shows 20-95% cells are malignant undifferentiated cells of precursor B or T cell origin (lymphoblasts). Demonstrated by immunophenotyping. Megakaryocytes are usually reduced or absent.
- 28. Cytochemistry May be used as an adjunct to Romanowsky staining for determining the type of leukaemia. Periodic acid-Schiff (PAS): Positive in immature lymphoid cells in ALL. Acid phosphatase: Focal positivity in leukaemic blasts in ALL. Myeloperoxidase: Negative in immature cells in ALL. Sudan Black: Negative in immature cells in ALL. Non-specific esterase (NSE): Negative in ALL.
- 29. Cytochemistry In L1 and L2 subtypes of ALL (B cell-ALL), PAS- positive ‘blocks’ are seen in lymphoblasts on a clear cytoplasmic background. In T cell-ALL and in L3 subtype of ALL, PAS reaction is negative.
- 32. Marker B- ALL T-ALL CD19 + _ cCD22 + _ cCD79a + _ CD10 + or _ _ cIg + (Pre-B) _ sIg _ _ TdT + +
- 33. Marker B-Cell T-Cell CD7 _ + cCD3 _ + CD2 _ + TdT + +
- 34. Cytogenetic And Molecular Genetic Analysis Cases are classified according to number of chromosomes in the tumor cells (ploidy) or by molecular genetic analysis. Hyperdiploidy (cells having more than 50 chromosomes) is the most frequent abnormality in childhood precursor B ALL and generally have a good prognosis. It is associated with high sensitivity to chemotherapy, complete remission rate of 100% and long-term disease- free survival of 90% cases. Hypodiploid cases have less than 44 chromosomes have a poor prognosis.
- 35. Specific Molecular Genetic Abnormalities t(12;21)(p13;q22) ETV6 RUNX1 translocation is the most common specific abnormality in childhood B-ALL. Philadelphia (Ph’) chromosome results from reciprocal translocation between chromosomes 9 and 22, i.e. t(9;22) (q34; q11) Frequency of the Ph' translocation t(9;22) increases with age and carries a poor prognosis. Translocations of chromosome 11q23 involve the MLL gene and are seen particularly in cases of infant leukaemia.
- 36. Treatment General Supportive Therapy Specific Therapy
- 37. General Supportive Therapy Insertion of central venous cannula. Blood product support. Prevention of tumor lysis syndrome.
- 38. Specific Therapy of ALL Specific Therapy in Children Specific Therapy in Adults
- 39. Specific Therapy in Children Specific therapy includes chemotherapy and radiotherapy. Treatment takes place in several phases. Induction (Remission induction) Consolidation (Intensification) Maintenance
- 40. Remission Induction Aim is to kill most of the tumor cells rapidly and achieve remission. In ALL remission is defined as Less than 5 % blasts in the bone marrow Normal peripheral blood count Absence of signs or symptoms of the disease Drugs commonly used: vincristine, asparginase, dexamethasone ± daunorubicin
- 41. Consolidation (Intensification) High doses of multidrug chemotherapy are used to eliminate the disease or reduce tumor burden to very low level. Drugs commonly used: vincristine, cyclophosphamide, cytosine arabinoside, daunorubicin, etoposide or mercaptopurine Given as blocks in different combinations
- 42. CNS Directed Therapy Intrathecal Methotrexate is used to prevent or treat central nervous system involvement. CNS relapse is treated with intrathecal methotrexate, cytosine arabinoside and hydrocortisone, with or without cranial irradiation and systemic chemotherapy.
- 43. Maintenance Therapy Given with daily oral mercaptopurine and once weekly oral methotrexate. At monthly or 3 monthly (in adults) intervals, Intravenous vincristine with a short course (5 days) of oral dexamethasone is added. Prophylactic immunoglobulin should be given to children who are lacking immunity to varicella or measles.
- 44. Maintenance Therapy In some protocols maintenance therapy may begin soon after remission induction and is interrupted by the periods of intensification chemotherapy. In typical regimens, intensive chemotherapy finishes around 38 weeks and after that maintenance therapy begins again and lasts until week 112 in girls or 164 in boys.
- 45. Treatment of Relapse If relapse is detected during or soon after maintenance therapy the outlook is poor. Treatment options include re-induction by combination chemotherapy, use of novel drugs followed by stem cell transplant (if possible) .
- 46. Specific Therapy in Adults Rate of relapse is much higher in adults. Genetic subtypes of ALLs differ with age. Lower doses of chemotherapy have been used in adult patients traditionally. For cranial prophylaxis intrathecal methotrexate, with or without cytosine arabinoside and steroid is used and high dose methotrexate and cytosine arabinoside is also given systemically. For BCR-ABL +ve ALL, specific tyrosine kinase inhibitor imatinib is used with chemotherapy.
- 47. Specific Therapy in Adults If suitable sibling or matched unrelated donor is available stem cell transplant is a treatment option for many patients.
- 48. Thank You !