Precursor Lymphoid Neoplasms

1. 27 Precursor Lymphoid Neoplasms

2. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Define acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LBL) and differentiate them from acute myeloid leukemia (AML). • List and define the variants of ALL/LBL according to the WHO classification. continued on next slide

3. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Describe and recognize the typical peripheral blood picture (erythrocytes, leukocytes, blasts, thrombocytes) seen in ALL. • Give the typical results of flow cytometric analysis and genetic findings in ALL. continued on next slide

4. Learning Objectives—Level I At the end of this unit of study, the student should be able to: • Summarize the clinical signs and symptoms and the most frequent age groups associated with ALL. • Define the rare acute leukemias that are not included in AML and ALL groups.

5. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Compare and contrast the various presentations of ALL/LBL. • Predict the most likely WHO or immunophenotypic subgroup based on patient history, physical assessment, and laboratory findings. continued on next slide

6. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Correlate cellular presentation with prognosis and common complications in ALL/LBL. • Correlate Wright stain blast morphology in the ALL subgroups with flow cytometry and genetic testing results. continued on next slide

7. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Evaluate peripheral blood results in relation to oncological therapy (e.g., complete or partial remission, relapse). • Identify acute leukemia (AL) from a peripheral blood smear and recommend laboratory tests that may be useful in differentiation of acute leukemia of ambiguous lineage, AML, ALL, and the subgroups of ALL. continued on next slide

8. Learning Objectives—Level II At the end of this unit of study, the student should be able to: • Define the phases and purposes of chemotherapy for ALL. • Correlate clinical and laboratory findings with prognosis in ALL/LBL. • Contrast the clinical and laboratory findings of ALL to LBL.

9. Introduction • Lymphoid malignancies • Leukemias • Disorders that primarily involve the BM and PB • Lymphomas • Disorders that primarily involve the lymphoid organs • Lymph nodes, tonsils, spleen, thymus, lymphoid tissues of the GI tract continued on next slide

10. Introduction • Lymphoid malignancies • Cell of origin • CLP, or more differentiated progenitors of the T- or B-cell lineages

11. Etiology and Pathogenesis • Characterized by: • Malignant neoplastic proliferation and accumulation of immature and nonfunctional hematopoietic cells in BM • T- or B-cell phenotypes continued on next slide

12. Etiology and Pathogenesis • Characterized by: • Genetic alterations include: • Chromosomal rearrangements • Abnormalities of cell ploidy • Point mutations in oncogenes or tumor suppressor genes that alter cell function continued on next slide

13. Clinical Findings • ALL diagnosed in all age groups • Primarily disease of young children • Peak incidence 2–5 yrs and adults 60 yrs • Onset of disease • Insidious or abrupt with nonspecific signs and symptoms

14. Clinical Findings • Clinical presentation reflects degree of: • Marrow failure and extent of extramedullary disease • Symptoms related to: • Anemia, thrombocytopenia, neutropenia • 80% of patients complain of bone pain • May be CNS involvement

15. Clinical Findings • B-cell ALL • Inappropriate secretion of monoclonal Igs that ↑ blood viscosity, impair granulocyte and platelet function, interfere with coagulation • LBL occurs when there is primary involvement of nodal and extranodal sites with minimal or no involvement of BM or PB (skin, soft tissue, lymph nodes)

16. Clinical Findings • T-cell ALL/LBL • More aggressive clinical behavior • Involves extranodal and extramedullary sites • Lymphadenopathy and hepatosplenomegaly present

17. Laboratory Findings • Peripheral blood • WBC count may be ↑, ↓, N • Neutropenia • Lymphoblasts circulating in 90% cases, variable • T and B lymphoblasts not distinguishable by morphology continued on next slide

18. Laboratory Findings • Peripheral blood • WHO recommends blast count of 25%. • Normocytic, normochromic anemia • Thrombocytopenia • 48–52 × 109/L

19. Table 27-1 Initial Laboratory Findings Characteristic of ALL

20. Figure 27-1 (a) Lymphoblasts in peripheral blood from acute lymphoblastic leukemia. Notice the nuclear cleavage, condensed chromatin, and high N:C ratio. (b) Lymphoblasts in the bone marrow from the patient with ALL in (a). Note cells with a high N:C ratio, fine chromatin, and nucleoli (both Wright-Giemsa stain, 1000× magnification).

21. Figure 27-2 (a) Lymphoblasts in peripheral blood from acute lymphoblastic leukemia. Note the fine chromatin and nucleoli (Wright-Giemsa stain, 1000× magnification). (b) Lymphoblasts in the bone marrow from patient in (a). Note the blasts with vacuoles (Wright-Giemsa stain, 500× magnification)

22. Laboratory Findings • Bone marrow • Hypercellular • Infiltrated with malignant lymphoblasts • ≥ 20% lymphoblasts (WHO) • Prefer > 25% blasts • Most patients have > 65% blasts in BM • No Auer rods

23. Laboratory Findings • Tissue involvement • Lymphoma • Mass lesion of lymphoid or other tissue with little or no involvement of BM or PB • B-LBL • Diffuse patterns of infiltration with mitotic figures • T-LBL • Involves paracortical area with “starry sky” effect

24. Laboratory Findings • Other laboratory findings • Proportional to tumor burden • ↑ uric acid, LD, calcium • ↑ BUN, creatinine, phosphorus if kidney affected (common) • CSF analysis • CNS frequent site of leukemic infiltration

25. Identification of Cell Lineage • Differentiate ALL from AML • Through morphology and cytochemistry • Identify blast lineage continued on next slide

26. Identification of Cell Lineage • Differentiate ALL from AML • Further classify into subgroups • Immunophenotyping, cytogenetics, molecular genetic methods • Subtype T cell or B cell • Cell's maturation stage and evidence of clonality continued on next slide

27. Identification of Cell Lineage • Differentiate ALL from AML • Further classify into subgroups • Immunophenotyping, cytogenetics, molecular genetic methods • Provides prognostic information for optimizing treatment • Reveals distinct genetic abnormalities associated with subgroups of ALL/LBL

28. Identification of Cell Lineage • Morphology and cytochemistry • Morphology important for characteristic cell features, but might not differentiate ALL from AML alone • Cytochemistry • MPO, SBB negative lymphoblasts • PAS (periodic acid-Schiff) positive with coarse granular positivity in lymphoblasts

29. Identification of Cell Lineage • Terminal deoxynucleotidyl transferase (TdT) • Aids in differentiating early precursor lymphoblasts from more mature cells • Not present in normal mature lymphocytes • Found 65% of thymic population of lymphocytes continued on next slide

30. Identification of Cell Lineage • Terminal deoxynucleotidyl transferase (TdT) • Aids in differentiating early precursor lymphoblasts from more mature cells • Found in very early B cells and myeloblasts • 1–3% normal BM cells TdT positive

31. Identification of Cell Lineage • Immunophenotyping • Differentiates ALL from minimally differentiated AML • Identifies subtypes of lymphoblast (T or B) • Recognizes leukemias of mixed lineage • Helps determine minimal residual disease

32. Figure 27-3 B lymphocyte maturation pathway with leukemic and other lymphoproliferative counterparts.ALL = acute lymphoblastic leukemia; CLL = chronic lymphocytic leukemia; PLL = prolymphocytic leukemia; HCL = hairy cell leukemia; clg = cytoplasmic immunoglobulin; slg = surface immunoglobulin

33. Identification of Cell Lineage • Cytogenetic analysis • Chromosomal abnormalities present 75% ALL • Provides diagnostic and prognostic information

34. Identification of Cell Lineage • Molecular analysis • Determines presence of rearrangements of Ig heavy and/or light chain genes and T-cell receptor (TCR) genes • Helps establish clonality and lineage of T and B cells • Differentiate normal from neoplastic cells

35. WHO Classification • Two subgroups of ALL/LBL • Precursor B- and T-cell neoplasms (leukemia/lymphoma) • BM and PB involvement—acute lymphoblastic leukemia • Solid tumor presentation—acute lymphoblastic lymphoma continued on next slide

36. WHO Classification • Two subgroups of ALL/LBL • Precursor B- and T-cell neoplasms (leukemia/lymphoma) • Subgroup of B-cell ALL/LBL • ALL with recurrent cytogenetic abnormalities • Remainder are ALL not otherwise specified (NOS)

37. Table 27-2 Classification of Lymphoid Leukemia and Lymphoma by the World Health Organization

38. B Lymphoblastic Leukemia/Lymphoma • 80–85% of cases of childhood ALL is B cell • Long-term, event-free survival > 80% • 70% of cases of adult ALL is B-cell • Long-term, event-free survival 30-50% continued on next slide

39. B Lymphoblastic Leukemia/Lymphoma • Depends on age at diagnosis and disease subtype • If patient has mass lesion and ≤ 25% lymphoblasts in BM = lymphoma continued on next slide

40. B Lymphoblastic Leukemia/Lymphoma • Immunophenotyping • Establish B cell lineage • Necessary to distinguish between precursor B cell, mature B cell and T cell immunophenotypes • Majority of ALL/LBL arise from precursor B cells with same immunophenotype as normal immature B cells • CD10, CD19, CD34, CD22, and TdT continued on next slide

41. B Lymphoblastic Leukemia/Lymphoma • Immunophenotyping • Up to 50% of B cell ALL co-express a myeloid associated Ag • CD13, CD15, CD33 • Helps identify neoplastic clone

42. Table 27-3 Summary of Laboratory Features Helpful in Classification of ALL

43. B Lymphoblastic Leukemia/Lymphoma • Cytogenetics and pathogenesis • Translocations, hypodiploidy, hyperdiploidy • Most significant translocations have distinctive properties and important prognostic information. • t(12;21)(p13;q22.3)/ETV6-RUNX1 • t(4;11)(q21;q23)/MLL-AFF1—poor prognosis continued on next slide

44. B Lymphoblastic Leukemia/Lymphoma • Cytogenetics and pathogenesis • Most significant translocations have distinctive properties and important prognostic information • t(9;22)(q34;q11)/BCR-ABL1—poor prognosis • t(5;14)(q31;q32.3)/IL3-IGH2 • t(1;19)(q23.3;p13.3)/E2A-PBX1 (TCF3-PBX1)—poor prognosis continued on next slide

45. B Lymphoblastic Leukemia/Lymphoma • Cytogenetics and pathogenesis • Most common translocation (~25% cases) • t(12;21)(p13;q22.3) • 25% of all ALL cases • Childhood B cell ALL • Produces ETV6(TEL)-RUNX1(AML1) fusion gene continued on next slide

46. B Lymphoblastic Leukemia/Lymphoma • Cytogenetics and pathogenesis • Most common translocation (~25% cases) • Disrupts normal processes of cells • Associated with excellent prognosis and survival • Adults t(9;22)(q34;q11)/BCR-ABL1 translocation • 10–15% of cases

47. B Lymphoblastic Leukemia/Lymphoma • Prognosis • Pediatric remission rate ~95% • Adult remission rate 60–85% • Long-term, event-free survival • Pediatrics ~ 80% • Adults 30-50% • Depends on age, low or normal WBC, presence of hyperdiploid chromosomes at diagnosis

48. Table 27-4 Poor Prognostic Indicators in ALL

49. T Lymphoblastic Leukemia/Lymphoma • T-cell ALL, T-cell LBL • ~15% of childhood ALL; ~25% of adult ALL • Usually presents with • High WBC count • Often a mediastinal mass • Leukemic infiltration of thymus continued on next slide

50. T Lymphoblastic Leukemia/Lymphoma • T-cell ALL, T-cell LBL • Lymphoblasts variable in size • Cytoplasmic vacuoles can be present. • Acid phosphatase has focal intense positivity.