Acute Myeloid Leukemia with t(8;21)(q22;q22), RUNX1-RUNX1T1



Acute Myeloid Leukemia with t(8;21)(q22;q22), RUNX1-RUNX1T1


Kaaren K. Reichard, MD





Key Facts


Terminology



  • AML with maturation


  • Diagnostic genetic abnormality: RUNX1-RUNX1T1 fusion


Microscopic Pathology



  • Increased myeloblasts


  • Evidence of neutrophilic maturation


  • Characteristic Auer rods



    • Single, thin, tapered ends


  • Abnormal neutrophilic precursors



    • Salmon-colored granules and dysplastic nuclear features


Ancillary Tests



  • Immunophenotyping



    • Increased myeloblasts; CD34(+), CD13(+), CD33(+)


    • May show expression of B-associated antigens; CD19, CD79a, Pax-5


    • May show expression of TdT or CD56


  • Cytogenetics/FISH/molecular



    • Demonstrate t(8;21) or RUNX1-RUNX1T1 fusion


Top Differential Diagnoses



  • AMLs ± recurrent genetic abnormalities (if blasts ≥ 20%)


  • Reactive neutrophilia (if low blast count)


  • Chronic myelogenous leukemia, neutrophilic variant


Reporting Considerations



  • Diagnose as AML with t(8;21)(q22;q22), RUNX1-RUNXIT1


  • “Low blast count” AML: Requisite ≥ 20% blasts not needed if genetic abnormality present






Peripheral blood smear shows 3 circulating blasts, 1 with a classic, thin Auer rod with tapered ends image in acute myeloid leukemia with translocation t(8;21)(q22;q22).






Karyogram reveals the recurring abnormality translocation (8;21)(q22;q22) in a case of de novo AML. Note the abnormal chromosomes image.


TERMINOLOGY


Abbreviations



  • Acute myeloid leukemia (AML)


  • AML with t(8;21)(q22;q22), RUNX1-RUNX1T1


Synonyms



  • AML with maturation


  • AML M2 in French-American-British classification


  • Core binding factor AML


  • AML with AML1-ETO fusion


Definitions



  • AML with specific genetic finding



    • t(8;21)(q22;q22) or variant or RUNX1-RUNX1T1 (a.k.a. AML1-ETO) gene fusion


  • Blast count may not meet typical requirement of ≥ 20%



    • So-called low blast count AML or oligoblastic AML


    • AML is defined by presence of genetic abnormality, regardless of blast count


ETIOLOGY/PATHOGENESIS


Environmental Exposure



  • None identified for de novo AML with t(8;21)


  • Therapy-related AML with t(8;21)



    • Prior exposure to cytotoxic agents &/or radiotherapy


Molecular Pathogenesis



  • Normal



    • Core binding factor (CBF) alpha subunit (a.k.a. RUNX1) interacts with CBF beta subunit


    • CBF alpha and beta form transcription factor complex


    • CBF alpha subunit binds to DNA promoter sequences involved in hematopoiesis


  • Abnormal



    • t(8;21) results in chimeric fusion protein RUNX1-RUNX1T1


    • Downregulates normal transcriptional activity


  • “Multi-hit” model of AML



    • Class 1 and class 2 mutations


    • RUNX1-RUNX1T1 fusion is considered a class 2 mutation



      • Insufficient alone for leukemia formation


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


Discovery of t(8;21)



  • 1st AML reciprocal translocation identified with common banding techniques (1975)


Association with Systemic Mastocytosis



  • AML with t(8;21) is most common AML associated with mastocytosis


  • WHO 2008 terminology



    • Systemic mastocytosis with associated hematological non-mast cell lineage disease (SM-AHNMD)


  • KIT D816V mutation in blasts and mast cells may indicate common progenitor


CLINICAL ISSUES


Epidemiology



  • Incidence



    • 10-15% of pediatric AML cases


    • 7% of adult AML cases


  • Age



    • Predominates in younger patients (20-40 years)


  • Gender



    • Equal male:female ratio


  • Ethnicity



    • More frequent in African-Americans than Caucasians compared to AML with inv(16)



Presentation



  • Abnormal CBC



    • Anemia


    • Thrombocytopenia


    • Single, bi-, or pancytopenia


    • Variable white blood cell count


    • Variable percent blast count


    • Neutropenia common


  • Myeloid neoplasm



    • Myeloid sarcomas common



      • Skin and gingival involvement


Treatment



  • Chemotherapy



    • Cytarabine-based regimen


Prognosis



  • Favorable risk


  • Complete remission common



    • Especially with intensive postremission treatment



      • Multiple cycles of high-dose cytarabine


    • 50-60% cured with contemporary treatment


  • Prognostic genetic factors



    • ˜ 70% of patients harbor an additional chromosomal abnormality



      • -Y; worse overall survival


      • -X; no obvious impact


      • del(9q); better overall survival in non-white individuals


      • +8; no impact


    • KIT mutations



      • Found in 12-47% of patients


      • Occur mostly in exon 17


      • May confer adverse prognosis


    • FLT3 mutations



      • Infrequent; 4-12%


      • Internal tandem duplication and point mutations in the tyrosine kinase domain


      • Prognostic significance unknown


      • Some reports suggest worse prognosis


  • Minimal residual disease monitoring



    • Quantitative RT-PCR studies



      • Goal: Identify molecular remission while on therapy


      • Molecular remission predictive of durable complete remission


      • Absence of RUNX1-RUNX1T1 fusion may not be necessary for long-term remission


      • > 1 log increase in transcript levels associated with increased relapse risk


MACROSCOPIC FEATURES


Extramedullary Involvement



  • Less common than in AML with inv16


  • Gingival hyperplasia


  • Splenomegaly rare


  • Cutaneous involvement


MICROSCOPIC PATHOLOGY


Key Microscopic Features



  • Peripheral blood



    • Anemia


    • Thrombocytopenia


    • Circulating blasts; possibly with Auer rods


    • Generally leukocytosis dominated by blasts


    • Evidence of neutrophilic maturation


    • Occasionally monocytic component


    • WBC count rarely exceeds 100 × 109/L


  • Bone marrow aspirate



    • Increased myeloid blasts


    • Variable blast count



      • Some cases less than the required 20% (low blast count AML)


    • Characteristic Auer rods



      • Thin with tapered, “cigar-shaped” ends


      • Usually single within a cell


      • Seen in cytoplasm of blasts and maturing/mature granulocytes


    • Abnormal neutrophilic precursors



      • Numerous pink/salmon-colored granules



      • Granules may abnormally aggregate in discrete region of cytoplasm


      • Dysplastic nuclei with megaloblastoid change and abnormal nuclear segmentation


    • In < 20% of cases, monocytic component


    • Erythroid and megakaryocytic lineages often decreased due to marrow replacement by AML


    • Increased and atypical, spindled mast cells if concurrent systemic mastocytosis


  • Bone marrow core biopsy



    • 100% cellular


    • With an increasing proportion of neutrophilic maturation, sheets of blasts may not be conspicuous


    • Megakaryocytic lineage is decreased but morphologically unremarkable


    • May see associated mast cell disease



      • Focal, compact, dense aggregates of mast cells


      • Mast cell aggregates may be overshadowed by the AML (so-called occult mastocytosis)


      • Mastocytosis is often revealed after treatment of AML


      • Osteosclerotic bone


ANCILLARY TESTS


Cytology



  • Myeloperoxidase: Myeloblasts positive


Immunohistochemistry



  • Increased blasts: CD34, CD117 positive



    • May show Pax-5 positivity


  • Associated mast cell disease: Mast cells positive for tryptase &/or CD117, CD25 &/or CD2


Flow Cytometry



  • Myeloblasts: CD34, CD33, CD13, weak CD45


  • Aberrant antigen expression common



    • B-associated antigens: CD79a, CD19


    • TdT


    • CD56

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Jun 13, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Acute Myeloid Leukemia with t(8;21)(q22;q22), RUNX1-RUNX1T1

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