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Atypical Chronic Myeloid Leukemia, BCR-ABL1 Negative

Definition

  • Neutrophilic leukemic disorder with myeloproliferative and myelodysplastic features but lacking specific cytogenetic abnormalities

Diagnostic Criteria

  • Peripheral blood leukocytosis must be >13 x 109/μL
    • May be marked (>300 x 109/μL)
      • Primarily due to neutrophils and neutrophilic precursors
    • Promyelocytes, myelocytes and metamyelocytes usually make up 10-20% of WBC
    • Monocytes must be <10% of WBC (may rarely slightly exceed 1 x 109/μL)
    • Basophils usually <2% of WBC
  • Blasts <20% in blood and marrow
  • Hypercellular bone marrow, predominantly granulocytic
    • Erythrocytic and megakaryocytic hyperplasia may also be present
  • Prominent granulocytic dysplasia must be present in blood and marrow
    • Erythrocytic and megakaryocytic dysplasia may also be present
  • Ph chromosome, BCR-ABL1, PDGFRA, PDGFRB, FGFR1 abnormalities and acute myeloid leukemia-defining translocations (e.g. inv(16), t(8;21)) must be absent
    • Nonspecific karyotypic abnormalities and/or mutations are present in most cases

Myelodysplasia is defined by morphologic features of abnormal cellular maturation in at least one bone marrow lineage

  • Not all features are applicable to all disorders
  • Dyserythropoeisis
    • Peripheral blood erythrocyte abnormalities
      • Normocytic, normochromic anemia
      • Macrocytosis
      • Dimorphic red blood cells (RBC)
      • Basophilic stippling
      • Poikilocytosis
        • Varying shapes, frequently macro-ovalocytes
    • Bone marrow erythroid lineage abnormalties
      • Erythroid hyperplasia or hypoplasia
        • Megaloblastoid / megaloblastic changes
          • Dyssynchronous maturation of nucleus and cytoplasm of erythroid precursors
            • Nucleus lags behind cytoplasm
      • Ring sideroblasts
        • ≥5 iron granules encircling ≥1/3 of the nucleus
        • Usually either many or none
      • Cytoplasmic vacuoles
        • Also seen in copper deficiency
      • Nuclear changes
        • Multinuclearity
        • Nuclear budding, hyperlobulation and satellite nuclei
        • Internuclear bridging
  • Dysgranulopoiesis
    • Peripheral blood and/or bone marrow findings (easier seen in peripheral blood)
      • Hypogranularity
        • Pale cytoplasm almost indistinguishable from background on slide
      • Nuclear hypolobation or irregular hypersegmentation (>5 lobes)
        • Pseudo Pelger-Huet anomaly
          • Two equal size nuclear lobes connected by a thin strand of chromatin
      • Infrequent findings
        • Abnormal cytoplasmic granules (pseudo Chediak-Higashi granules)
          • Giant grey to red granules
        • Dohle bodies
          • Small blue cytoplasmic inclusions
          • Often found at periphery of cell
        • Auer rods
          • Rod-like structures formed by fusion of primary granules
          • May be found in blasts or maturing granulocytes
  • Dysmegakaryopoiesis
    • Peripheral blood platelet abnormalities
      • Giant
        • Larger than a red blood cell
      • Bizarre
        • Irregular shapes and protrusions
      • Hypogranularity
        • Compare to normal platelets with purple granules
    • Bone marrow megakaryocyte abnormalities
      • Micromegakaryocytes
        • Smaller than a promyelocyte
      • Nuclear hypolobation
        • Prominent in 5q- syndrome
        • A single lobe is typically seen in a small megakaryocyte
      • Multinucleation
        • Distinct nuclei without a connecting strand of chromatin
      • Cytoplasmic hypogranularity

Dita Gratzinger MD PhD
Department of Pathology
Stanford University School of Medicine
Stanford CA 94305-5342

Original posting: 11/6/11

Supplemental Studies

Special stains
  • Nonspecific esterase, and CD68PG may be useful for identifying monocytes in tissue sections (to exclude CMML)

Genetic studies

  • Ph chromosome, BCR-ABL1, PDGFRA, PDGFRB translocations must not be present
  • Nonspecific karyotypic abnormalities and/or mutations are present in most cases
  • Most frequent cytogenetic abnormalities include +8 and del(20q)
  • Mutations in NRAS and KRAS may be present; JAK2 V617F generally absent

 

Disorder Molecular or Cytogenetic Alteration Test Used
Chronic myelogenous leukemia BCR-ABL1 CG, FISH, PCR on PB or BM
Hematolymphoid neoplasms with eosinophilia and PDGFR/FGFR abnormalities

FIP1L1-PDGFRA (usually CEL)

ETV6-PDGFRB (usually CMML with eosinophilia)

FGFR1 (various)

PDGFRa/b (various)

CG, FISH
Chronic eosinophilic leukemia NOS none specific, may have clonal CG abnormalities CG
Mastocytosis KIT D816V CG, PCR on BM, not PB
Acute myelogenous leukemia, even if <20% blasts inv or t(16)(p13.1q22); CBFB-MYH11 or t(8;21)(q22;q22) RUNX1-RUNX1T1 CG, FISH
PCR = polymerase chain reaction, PB = peripheral blood, CG = conventional cytogenetics, FISH = fluorescent in situ hybridization, BM = bone marrow, CEL = chronic eosinophilic leukemia, CMML = chronic myelomonocytic leukemia

Differential Diagnosis

Myeloproliferative and Mixed MDS/MPNs with Neutrophilia and/or Monocytosis
  CML-CP Atypical CML CMML-1 CNL
Ph Chromosome and/or BCR-ABL1 Translocation Almost 100% Absent Absent Absent

WBC

Left shifted neutrophilia* Left shifted neutrophilia Monocytosis, may have left shifted neutrophilia Neutrophilia
Blood basophils Increased Not increased Not increased Not increased
Blood monocytes Variable,** <1x103/μL Variable, <1x103/μL Always >1x103/μL <1x103/μL
Blood immature granulocytes >20% 10-20% Usually <10% <10%
Blood blasts Usually <2% >2% <5% <1%
Granulocytic dysplasia Absent ++ +/- Absent
*rare p230 BCR-ABL1 isoform may show mature neutrophilia, **rare p190 BCR-ABL1 isoform associated with monocytosis

Clinical

  • Median age 60-80 years
    • Has been reported between 10-20 years
  • Hepatosplenomegaly
  • Median survival 14-29 months
    • Death due to marrow failure or evolution to AML

Classification / Lists

WHO 2008 Classification of Myeloid Neoplasms

Myeloproliferative Neoplasms (MPN)

Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB or FGFR1

Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)

Myelodysplastic Syndromes (MDS)

Therapy Related Myeloid Neoplasms

 

Bibliography

  • Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2008
  • Xubo G et al, Eur J Haematol. 2009 Oct;83(4):292-301.. The role of peripheral blood, bone marrow aspirate and especially bone marrow trephine biopsy in distinguishing atypical chronic myeloid leukemia from chronic granulocytic leukemia and chronic myelomonocytic leukemia.
  • Hall J, Foucar K, Diagnosing myelodysplastic/myeloproliferative neoplasms: laboratory testing strategies to exclude other disorders, International Journal of Laboratory Hematology, 2010, 32
  • Orazi A, Germing U. (2008) The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia, 22, 1308–1319.
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