Acute Myeloid Leukemia with t(9;11)(p22;q23), MLLT3-MLL



Acute Myeloid Leukemia with t(9;11)(p22;q23), MLLT3-MLL


Kaaren K. Reichard, MD





Key Facts


Terminology



  • Only AML with MLL translocation diagnosed as distinct biologic subtype


Clinical Issues



  • Extramedullary disease



    • Skin, CNS


  • Disseminated intravascular coagulation


Microscopic Pathology



  • ≥ 20% blasts/blast equivalents in PB &/or BM


  • Typically monoblasts and promonocytes


  • Hypercellular bone marrow


  • Minimal residual hematopoiesis


Ancillary Tests



  • Cytochemistry



    • MPO(-), NSE(+)


  • Immunophenotyping



    • Monocytic differentiation: CD4 (weak +), CD33 (bright +), CD36/CD64 coexpression, CD14 and CD163 (variable)


    • Blast markers often negative: CD34, CD117


  • Genetics



    • Cytogenetics reveal classic translocation


    • FISH useful to document MLL rearrangement


    • Molecular detection of MLL-MLLT3 fusion for MRD


Top Differential Diagnoses



  • G-CSF/GM-CSF therapy



    • Nonclonal


  • CMML



    • < 20% blasts/blast equivalents


  • Therapy-related myeloid neoplasm with t(9;11)



    • History of chemotherapy or radiation






This bone marrow aspirate smear demonstrates the classic cytology of AML with t(9;11). The cells are monoblasts with an abundant rim of cytoplasm containing MPO-negative azurophilic granules.






This karyogram shows t(9;11)(p22;q23) image in a case of AML with monocytic differentiation. At the molecular level, MLL (11q23) and MLLT3 are aberrantly juxtaposed, resulting in a chimeric fusion protein.


TERMINOLOGY


Abbreviations



  • AML with t(9;11)


Synonyms



  • Acute myeloid leukemia with MLL/11q23 abnormality


Definitions



  • Acute myeloid leukemia with t(9;11)(p22;q23) or variant &/or molecular evidence of MLL-MLLT3 fusion


  • Strong association with AML M5 and M4 subtypes (FAB classification)


  • Usually AML with monoblastic/monocytic differentiation


  • Blasts/blast equivalents ≥ 20%



    • Monoblasts and promonocytes


ETIOLOGY/PATHOGENESIS


Epidemiology



  • May occur at any age



    • ˜ 5-20% of pediatric AML


    • ˜ 4-5% of adult AML


  • Rare cases may originate from pre-B-cell harboring MLL-MLLT3 fusion


MLL



  • Mixed lineage leukemia gene


  • Human homologue of the trithorax gene in Drosophila


  • Encodes DNA-binding protein



    • Transcription regulatory factor (e.g., HOX genes)


    • Methylates histone H3


    • Chromatin remodeling


    • Plays major role in hematopoiesis


MLLT3



  • a.k.a. AF9


  • Involved in erythroid and megakaryocytic production


  • Involved in regulation of transcription


CLINICAL ISSUES


Presentation



  • Leukocytosis


  • Blood abnormality, NOS


  • Monocytosis


  • Extramedullary disease



    • Skin involvement, CNS symptoms, gingival hyperplasia


  • Disseminated intravascular coagulation (DIC)


Treatment



  • Drugs



    • Chemotherapy


Prognosis



  • Intermediate compared with other AMLs


  • Better than AMLs with other MLL (non MLLT3) rearrangements


  • Minimal residual disease monitoring



    • Early achievement of molecular negativity for MLL-MLLT3



      • May portend longer remission status


    • Increasing MLL-MLLT3 transcripts



      • May herald early disease relapse


MICROSCOPIC PATHOLOGY


Predominant Pattern/Injury Type



  • Diffuse


Predominant Cell/Compartment Type



  • Blast


  • Hematopoietic stem cell


Morphology



  • Peripheral blood




    • Variable WBC count


    • Often leukocytosis


    • Anemia


    • Thrombocytopenia


    • Circulating monoblasts and promonocytes



      • Usually > 20% of WBCs


    • Circulating myeloid blasts



      • Some cases show variable, usually small (< 5-10%) population of otherwise typical myeloblasts


    • Monoblasts



      • Large


      • Round nuclear contours


      • Fine chromatin


      • Prominent nucleolus


      • Abundant variably basophilic cytoplasm


      • Cytoplasmic azurophilic granules (MPO negative)


      • No Auer rods


    • Promonocytes



      • Intermediate to large


      • Smaller, variably prominent nucleoli


      • Abundant lightly basophilic/bluer cytoplasm


      • Gently lobulated nuclei with delicate nuclear folding


      • More even/dispersed chromatin pattern than typical monocyte


    • No significant granulocytic or platelet dysplasia


  • Bone marrow aspirate smears



    • Hypercellular


    • Usually sheets of monoblasts and promonocytes



      • Comprise > 80% of marrow nucleated cells


    • No significant background dysplasia


    • No significant basophilia or eosinophilia


  • Bone marrow core biopsy



    • Hypercellular


    • Predominant population of blasts/promonocytes


    • May see scattered residual hematopoietic elements


    • No significant, disease-related bony changes


Extramedullary Disease



  • Myeloid sarcoma


  • Sites most affected: Skin, gingiva, CNS


ANCILLARY TESTS


Cytochemistry



  • Myeloperoxidase (MPO)



    • Typically negative in monoblasts and promonocytes


  • Nonspecific esterase (NSE) (α naphthyl butyrate esterase)



    • Typically diffusely positive in monoblasts and promonocytes


Flow Cytometry

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Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Acute Myeloid Leukemia with t(9;11)(p22;q23), MLLT3-MLL

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