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New Frontiers in Pathology Hematopathology Break-out Session

New Frontiers in Pathology Hematopathology Break-out Session. Bryan Coffing, M.D. Hematopathology Fellow. Disclaimer. The cases reviewed here have been slightly modified for illustrative purposes Terms borrowed from the 2008 WHO blue book have been formatted to fit our lexicon

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New Frontiers in Pathology Hematopathology Break-out Session

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  1. New Frontiers in PathologyHematopathology Break-out Session Bryan Coffing, M.D. Hematopathology Fellow

  2. Disclaimer • The cases reviewed here have been slightly modified for illustrative purposes • Terms borrowed from the 2008 WHO blue book have been formatted to fit our lexicon • (Leukaemia  Leukemia, etc)

  3. Goals • Examine two cases of acute leukemia with ambiguous lineage • Discuss the specificity of “lineage specific” markers in acute leukemia • Compare the European Group for the Immunological Characterization of Leukemia (EGIL) schema to the new WHO guidelines for lineage designation • Summarize a few of the characteristics of the acute leukemias of ambiguous lineage

  4. Case Presentation #1 • 64 year old male with hypertension, diabetes, coronary artery disease • Seen for routine follow-up in cardiology • CBC: WBC 4.4; Hgb 8.1; Plt 76

  5. 18%

  6. Additional history • Patient reports: • Fatigue for 2-3 months • Persistent sinus infection for 4-6 weeks • Easy bruising • Referred to hematology for further workup • Bone marrow biopsy, aspirate • Flow cytometry • Cytogenetic and molecular analysis

  7. 74.2% blasts 3.6% granulocytic precursors beyond promyelocytes 19.2% erythroid precursors 3% lymphocytes

  8. Ancillary Testing • Molecular testing negative • Cytogenetic analysis • Complex abnormalities, multiple clones • Hypotetraploid with del(5), del(21), add(13) • Abnormality seen in AML as well as ALL

  9. Flow Cytometry

  10. Flow Cytometry

  11. Positive CD34 (mod) CD33 (dim, sub) CD117 (dim-mod) CD38 (dim) CD45 (dim) cCD22 (dim, sub) cCD79a (dim, sub) Tdt (dim, sub) 5-7% MPO (+) by IHC Negative CD19 CD20 CD10 CD3 (surf & cyto) Other T cell markers Monocytic markers Flow Summary

  12. Differential Diagnosis • AML, without maturation (M1) • B Lymphoblastic Leukemia/Lymphoma • (with aberrant expression of MPO?) • Acute leukemia of ambiguous lineage • Biphenotypic/Bilineage (B-cell and myeloid)

  13. Acute Leukemias of Ambiguous Lineage • WHO 2001 • 3 categories (Undiff, Biphenotypic, Bilineage) • Pages 106-107 • WHO 2008 • Combined two categories (Biphenotypic and Bilineage) • Pages 149-155 • Created 6 new categories

  14. Acute leukemias of ambiguous lineage No lineage-specific antigens Antigens of > 1 lineage Acute undifferentiated leukemia Mixed phenotype acute leukemia (MPAL) Separate blast populations of different lineages OR One blast population expressing antigens >1 lineage With additional genetic abnormalities MPAL B/myeloid NOS MPAL T/myeloid NOS MPAL with t(9;22) BCR-ABL1 MPAL with t(v;11q23) MLL rearr Other

  15. Lineage Assignment • European Group for the Immunological Characterization of Leukemias (EGIL)

  16. B Lymphoid Markers in AML • CD7 and TdT expression in AML is well known • CD79a expression in AML • Cruse 2005: 4/46 (8.7%) • Tiacci 2004: 10/160 (1.6%) • El-Sissy 2006: 1/34 (2.9%) • CD19 expression • Tiacci 2004: 10/160 (1.6%) • El-Sissy 2006 4/34 (11%) • CD22 (EGIL score 2) • El-Sissy 2006 1/34 (2.9%)

  17. Lymphoid markers in AML • t(8;21)(AML1;ETO) • CD19 • cCD79a • Weak TdT • More than 30% show PAX5 expression Pax5 in t(8;21) Gibson, 2006

  18. AML with cytogenetic abnormalities • AML with inv(16) or t(16;16) • CD2 expression • AML with t(15;17) • CD2 expression in microgranular variant • AML with t(6;9) • 50% TdT expression • M1 and M2 (AML, NOS) • 10-20% positive for CD2, CD4, CD19, or CD56 American Society of Hematopathology Image Bank

  19. Aberrant Markers in ALL • Park et al, 1992 • 137 ALL cases in adults • Phenotyped by immunofluoresence • B-ALL more often • CD13 (1%) and CD33 (2%) • CD2 (1%) and CD5 (1%) • T-ALL • CD13 (8.3%) • CD10 (16.7%)

  20. Kalina et al, 2005 381 B-ALL pediatric patients Flow cytometric immunophenotyping CD33 (23%) CD15 (20%) CD13 (16%) Vitale et al, 2007 374 adult ALL patients Flow cytometric immunophenotyping of CD13 and/or CD33 T-ALL (24%) B-ALL (38%) Myeloid markers in ALL

  21. Myeloid Markers in ALL • MPO in pediatric ALL • Austin 1998: (COG) 32/57 (56%) pediatric ALL expressed MPO at protein or mRNA level • All cases negative for t(9;22) • MPO in adult ALL • Arber 2001: 19/67 (23%) positive • 8/19 (42%) with bcr/abl • Polyclonal MPO antibody • Immunocytochemistry with monoclonal MPO negative pMPO in ALL, Arber 2001

  22. Most specific lineage markers • Distinctly difficult to find lymphoblastic leukemias with aberrant MPO • Burkitt like ALL • Myeloid leukemia with aberrant CD3 also distinctly uncommon • B cell markers seem to be most promiscuous

  23. Flow cytometry Immunohistochemistry Cytochemistry Monocytic differentiation Myeloid lineage MPO OR At least 2: NSE CD11c CD14 CD64 lysozyme

  24. Flow cytometry Immunohistochemistry Surface CD3 T lineage Cytoplasmic CD3 OR Rare in MPAL

  25. + At least ONE (strong): CD79a Cytoplasmic CD22 CD10 Weak CD19 B lineage Strong CD19 OR + At least TWO (strong): CD79a Cytoplasmic CD22 CD10

  26. MPAL - Exclusions recurrent AML-associated translocations - t(8;21) – freq expresses B cell markers - t(15;17) - inv (16) FGFR1 mutation associated leukemias CML blast crisis MDS-related AML therapy-related AML

  27. Case Presentation #2 • 47 year old male with cellulitis • Transferred to University of Michigan for pancytopenia and blasts on blood smear • CBC: WBC 2.9; Hb 8.6; Plt 71

  28. 38.6% blasts 5.2% progranulocytes 16.4% other granulocytic precursors 5% erythroid precursors 6.4% lymphocytes 0.8% eosinophils 23.8% basophils 3.4% monocytes 0.4% plasma cells

  29. 62%

  30. Ancillary Studies • Molecular • Negative for bcr/abl • Cytogenetics • 11q deletion, del(18) • FISH for MLL (11q23) rearrangements negative

  31. Flow Cytometry

  32. Flow Cytometry

  33. Positive Cytoplasmic CD3 CD5 CD7 Tdt CD11c CD13 CD33 CD34 CD38 CD45 CD117 Cytoplasmic MPO Negative CD2 CD3 surface CD4 CD8 CD10 CD14 CD19 CD20 CD33 CD56 Flow Summary

  34. Differential Diagnosis • AML with maturation (M2) • T Lymphoblastic Leukemia/Lymphoma • (with aberrant expression of myeloid markers) • Acute leukemia of ambiguous lineage • Biphenotypic/Bilineage (T-cell and myeloid)

  35. References • Arber, Daniel et al. Myeloperoxidase Immunoreactivity in Adult Acute Lymphoblastic Leukemia. Am J Clin Pathol 2001;116:25-33. • Austin G et al. Prevalence of myeloperoxidase gene expression in infant acute lymphocytic leukemia. Am J Clin Pathol. 1998;110:575-581. • Cruse, Julius et al. Aberrant expression of CD7, CD56, and CD79a antigens in acute myeloid leukemias. Experimental and Molecular Pathology 79 (2005) 39– 41. • El-Sissy et al. Aberrant Lymphoid Antigen Expression in Acute Myeloid Leukemia in Saudi Arabia. Journal of the Egyptian Nat. Cancer Inst., Vol. 18, No. 3, September: 244-249, 2006. • Gibson, et al. Expression of the B Cell–Associated Transcription Factors PAX5, OCT-2, and BOB.1 in Acute Myeloid Leukemia. Associations With B-Cell Antigen Expression and Myelomonocytic Maturation. Am J Clin Pathol 2006;126:916-924. • Huh YO, McCulloch EA, Buhring H-J, et al: c-kit in leukemia and myelodysplasia as detected by monoclonal antibodies. Blood 80 (suppl):25a, 1992 • Kalina, Thomas et al. Myeloid antigens in childhood lymphoblastic leukemia:clinical data point to regulation of CD66c distinct from other myeloid antigens. BMC Cancer. 5(38), 2005. • Park et al. Acute Leukemias with Unusual Phenotypes. Journal of Korean Medical Science. 7(4), 377-384, 1992. • Preti A, Huh YO, O'Brien SM, et al: Myeloid markers in adult acute lymphocytic leukemia. Cancer 76:1564, 1995. • Tiacci et al. PAX5 Expression in Acute Leukemias: Higher B-Lineage Specificity Than CD79a and Selective Association with t(8;21)-Acute Myelogenous Leukemia. Cancer Research. 64, 7399–7404, October 15, 2004 • Valbuena, Jose et al. Expression of B Cell–Specific Activator Protein/PAX5 in Acute Myeloid Leukemia With t(8;21)(q22;q22).Am J Clin Pathol 2006;126:235-240. • Vitale, Antonella et al. Absence of prognostic impact of CD13 and/or CD33 antigen expression in adult acute lymphoblastic leukemia. Results of the GIMEMA ALL 0496 trial. Haematologica, Vol 92, Issue 3, 342-348.

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