Acute Myeloid Leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22), CBFB-MYH11



Acute Myeloid Leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22), CBFB-MYH11


Kaaren K. Reichard, MD





Key Facts


Terminology



  • AML with abnormal eosinophils


  • AML with CBFB-MYH11 fusion


Microscopic Pathology



  • Increased blasts and blast equivalents: Myeloblasts, monoblasts, and promonocytes


  • Abnormal eosinophils with mixed eosinophil and basophil-type granules


  • May not see abnormal eosinophil component in peripheral blood


  • Hypercellular marrow


Ancillary Tests



  • Flow cytometric analysis



    • Myeloblasts: CD34, CD33, and CD45 (weak) positive


    • Monocytic cells: CD33 (bright), CD45, and CD36/CD64 positive


  • Cytogenetic &/or FISH analysis: Essential



    • Abnormality may be subtle &/or overlooked


  • Molecular testing for CBFB-MYH11



    • For diagnosis and residual disease monitoring


Top Differential Diagnoses



  • AMLs ± recurrent genetic abnormalities [e.g., t(8;21), t(9;11)] or other


  • Therapy-related inv(16) (need clinical history)


Reporting Considerations



  • Diagnose as AML with inv(16)(p13.1q22) or t(16;16) (p13.1q22); CBFB-MYH11


  • Low blast count AML; required threshold of ≥20% blasts for AML not required






Bone marrow aspirate smear demonstrates an increased population of blasts image, immature-appearing monocytes image, and abnormal eosinophils image in acute myeloid leukemia with inversion 16.






Conventional cytogenetic analysis reveals a classic inversion 16 in a case of acute myeloid leukemia. Abnormal chromosome image is on the right (G-banded partial karyogram).


TERMINOLOGY


Abbreviations



  • Acute myeloid leukemia (AML)


  • AML with inv(16)(p13.1q22) (WHO)


Synonyms



  • AML with abnormal eosinophils


  • AML M4eo in French-American-British classification


  • Often referred to as core binding factor acute myeloid leukemia (along with AML with t[8;21])


Definitions



  • Acute myeloid leukemia harboring distinctive cytogenetic/molecular finding



    • inv(16)(p.13.1q22)


    • Translocation (16;16)(p13.1;q22)


    • CBFB-MYH11 genetic fusion



      • Core binding factor beta (CBFB)


      • Myosin heavy chain gene (MYH11)


  • AML with recurring genetic abnormality (WHO)


  • Low blast count AML



    • Diagnosis is established despite occasional cases with blast count < usual requisite 20%


    • Presence of genetic abnormality warrants diagnosis of AML


ETIOLOGY/PATHOGENESIS


Environmental Exposure



  • None presently identified for de novo AML with inversion 16


  • Exposure to cytotoxic agents &/or radiotherapy may result in therapy-related AML with inversion 16


Molecular Pathogenesis



  • In normal cells: Core binding factor (CBF) beta protein interacts with CBF alpha subunit (a.k.a. RUNX1) to form CBF transcription factor complex


  • In cells with inv(16) or variant: Genetic rearrangement results in a CBFB-MYH11 molecular fusion



    • Persistent transcriptional activation and leukemogenesis


  • Abnormal CBFB-MYH11 chimeric protein acts by preventing normal proteolysis of CBF complex


  • “Multi-hit” model of AML



    • Both class 1 and class 2 mutations are needed for leukemogenesis


    • CBFB-MYH11 fusion is considered class 2 mutation


    • Development of overt leukemia requires class 1 mutation (e.g., KIT, FLT3, or RAS mutation)


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Approximately 6-12% of pediatric AML


    • Approximately 8% of adult AML


  • Age



    • Median: 40-45 years


  • Gender



    • Equal male:female ratio


Presentation



  • Abnormal CBC



    • Anemia


    • Neutropenia


    • Thrombocytopenia


    • Variable white blood cell count (WBC)


    • Variable percent blast count


    • Variable percent monocytic cells


    • Absolute monocytosis common


  • Extramedullary involvement common



    • More common than AML with t(8;21)


    • Skin, especially scalp; central nervous system


Treatment



  • Chemotherapy




    • High-dose cytarabine-based, generally


Prognosis



  • Favorable risk


  • Complete remission very common



    • Rates reach ˜ 90% after standard induction therapy


  • Prognostic genetic factors



    • 1 or more secondary chromosome abnormalities



      • Trisomy 22 may be associated with lower risk of relapse


    • KIT mutations



      • May be found in 22-27% of cases


      • Prognostic impact not well defined


      • Some studies show higher risk of relapse


  • Minimal residual disease (MRD) monitoring



    • Quantitative RT-PCR studies



      • Identify molecular remission while on therapy


      • Molecular remission predictive of durable complete remission


      • Complete absence of CBFB-MYH11 fusion may not be necessary for long-term remission


    • Anticipate impending disease relapse prior to morphologic or hematologic relapse



      • Intervene appropriately


MACROSCOPIC FEATURES


General Features



  • Extramedullary involvement



    • Gingival hyperplasia


    • Subcutaneous nodules


  • Splenomegaly in 30% of patients


  • Hepatomegaly



    • Reported but rare


MICROSCOPIC PATHOLOGY


Predominant Cell/Compartment Type



  • Blast


  • Eosinophil precursor


  • Monocyte


  • Myeloblast


Key Microscopic Features

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Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Acute Myeloid Leukemia with inv(16)(p13.1q22) or t(16;16)(p13.1;q22), CBFB-MYH11

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