Bone marrow neoplastic

• Chronic eosinophilic leukemia (CEL) is an autonomous, clonal proliferation of eosinophils that leads to a persistent increase in eosinophils in peripheral blood, bone marrow and sometimes tissue
  • Absolute eosinophil count is ≥ 1.5 x 10⁹/L on at least 2 occasions for 4 weeks (notable change from 6 months in the 4th edition of WHO)
  • Bone marrow shows abnormal morphology (e.g., dysmegakaryopoiesis, eosinophilic infiltrate associated overt fibrosis)
  • Clonal
• Clonal myeloid or lymphoid neoplasms and reactive causes of eosinophilia should be excluded

• World Health Organization (WHO) classification (5th edition)
  • Essential
    • Persistent eosinophilia (≥ 1.5 x 10⁹/L) on at least 2 occasions over a minimum of 4 weeks in which reactive and genetically defined causes have been excluded
    • Evidence of clonality (see note 2)
    • Abnormal bone marrow morphology
    • Does not meet WHO diagnostic criteria for other myeloid or lymphoid neoplasms (see note 3)
      • Blasts of < 20% in peripheral blood and bone marrow cells and does not have the following cytogenetic aberrations
        • Tyrosine kinase gene fusions including PDGFRA, PDGFRB or FGFR1 rearrangements
        • FLT3 rearrangements (Leukemia 2022;36:1703)
        • ETV6::ABL1 fusion (Leukemia 2022;36:1703)
        • JAK2 rearrangements: t(8;9)(p22;p24.1) / PCM1::JAK2, t(9;12)(p24.1;p13.2) / ETV6::JAK2 or t(9;22)(p24.1;q11.2) / BCR::JAK2 fusions
        • AML with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22) / CBFB::MYH11; t(15;17)(q22;q11-12) / PML::RARA or t(8;21)(q22;q22.1) / RUNX1::RUNX1T1
        • CML with t(9;22)(q24;q31) / BCR::ABL1
  • Notes
    • Note 1
      • Interval of eosinophilia has been reduced from 6 months (4th edition of WHO) to 4 weeks
      • Both clonality and abnormal bone marrow morphology are required for diagnosis
      • A blast count ≥ 2% in the peripheral blood or ≥ 5% in the bone marrow are no longer considered alternatives to clonality requirement
    • Note 2: possibility of clonal hematopoiesis of indeterminate potential (CHIP) should be considered
      • Certain gene mutations (e.g., DNMT3A, TET2, ASXL1 with variant allele frequency ≥ 2%) can be seen in a subpopulation of elderly patients who do not have hematologic disorders, otherwise known as CHIP
      • Diagnostic interpretation should be done with caution (N Engl J Med 2014;371:2477, Nat Med 2014;20:1472)
      • Mutations in other genes with variant allele frequency (VAF) > 10% in combination with other mutations is a better indicator of clonality
    • Note 3: including myeloproliferative neoplasms (MPN), myelodysplastic syndrome (MDS), MDS / MPN, myeloid / lymphoid neoplasms with eosinophilia (MLN-eo), mastocytosis and acute myeloid leukemia (AML)

• International Consensus Classification (ICC) criteria; requires all 6 criteria
  • Hypereosinophilia (≥ 1.5 x 10⁹/L) with eosinophils comprising ≥ 10% of white blood cells
  • Does not meet criteria for AML; blasts < 20% in the peripheral blood and bone marrow, excluding AML with recurrent genetic abnormalities
    • AML with recurrent genetic aberrations with < 20% is also excluded
  • No tyrosine kinase fusion genes including BCR::ABL1, other ABL, PDGFRA, PDGFRB, FGFR1, JAK2 or FLT3 fusions
  • Does not meet criteria for MPN, chronic myelomonocytic leukemia (CMML) or systemic mastocytosis (SM)
    • Of note, although eosinophilia can be seen with SM, true CEL, NOS may also occur as SM with an associated myeloid neoplasm (Blood 2022;140:1200)
  • Marrow shows increased cellularity with dysplastic megakaryocytes with or without dysplasia in other cell lineages; often with significant myelofibrosis, associated eosinophilic infiltrate or increased blasts ≥ 5% in bone marrow or ≥ 2% in peripheral blood
  • Clonal cytogenetic abnormality or somatic mutation identified
  • If no clonality / somatic mutation demonstrated or no increased blasts, persistent eosinophilia may suffice provided the bone marrow findings are supportive and other causes of eosinophilia have been ruled out

Contributed by Lynh Nguyen, M.D. and AFIP

Contributed by Lynh Nguyen, M.D.

AFIP images

Which of the following is useful in definitively diagnosing the lymphocytic variant of hypereosinophilic syndrome?

1. Abnormal T cell population (e.g., CD3- / CD4+)
2. Elevated IL5 level
3. Eosinophilia ≥ 1.5 k/L
4. Eosinophilic tissue infiltrate
5. Skin rush and pruritus

A. Abnormal T cell population (e.g., CD3- / CD4+). Lymphocytic variant of hypereosinophilic syndrome (L-HES) is characterized by abnormal cytokine release by clonal T cells. CD3- / CD4+ T cells are often found in circulating blood but CD3+ / CD4+ / CD7- and CD3+ / CD4- / CD8- T cells have also been described. TCRγδ rearrangements are frequently identified in these patients; however, TCRαβ+ L-HES has also been reported. Answers B - D are incorrect because elevated IL5 levels, eosinophilia and eosinophilic infiltration can be seen in a number of reactive, neoplastic and iatrogenic conditions and are not diagnostic or specific for L-HES. Answer E is incorrect because pruritus and skin rash can occur as a result of eosinophilia but this finding is not specific.

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Reference: Chronic eosinophilic leukemia

Which of following morphologic or molecular genetic findings is frequently identified in chronic eosinophilic leukemia, not otherwise specified?

1. Dysplastic noneosinophilic granulocytes
2. ETV6::JAK2 fusion
3. Hypercellular marrow with markedly increased eosinophils and left shifted myelopoiesis
4. KIT D816V gene mutation
5. Marked monocytosis

C. Hypercellular marrow with markedly increased eosinophils and left shifted myelopoiesis. Abnormal bone marrow findings are 1 of 3 key diagnostic features of CEL (see above). Hypercellular marrow along with eosinophilic proliferation and left shifted myelopoiesis, though nonspecific, are the most common features of CEL. Answers A and E are incorrect. Dysplastic megakaryocytes with or without dysplasia in other cell lineages can be seen in CEL. Spectrum of nonspecific eosinophil abnormalities can be seen (sparse granulation, cytoplasmic vacuolation, nuclear hyper / hyposegmentation or increased size). CEL often shows neutrophilia, some with mild monocytosis (> 1 x 10⁹/L) and a few with mild basophilia. Answers B and D are incorrect. ETV6::JAK2 fusion can seen in myeloid / lymphoid neoplasms with eosinophilia (MLN-eo) and tyrosine kinase (TK) gene fusions while KIT D816V gene mutation is frequently seen in systemic mastocytosis.

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Reference: Chronic eosinophilic leukemia