Bone marrow neoplastic

• Chronic eosinophilic leukemia, not otherwise specified (NOS)
• Persistent increase in eosinophils in peripheral blood (≥ 1.5 x 10⁹/L), bone marrow and tissue
• May be accompanied by increased blasts (< 20%) or clonal cytogenetic or molecular genetic abnormalities (Am J Hematol 2017;92:1243)
• Organ damage may occur as a result of infiltration and release of eosinophilic granules that contain cytokines and humoral factors
• Other clonal myeloid neoplasms and reactive eosinophilia should be excluded
• In the absence of blasts or evidence to prove clonality, a diagnosis of idiopathic hypereosinophilic syndrome should be made

Contributed by Lynh Nguyen, M.D. and AFIP images

Contributed by Lynh Nguyen, M.D.

AFIP images

• Acute myeloid leukemia with inv(16)(p13.1;q22) or t(16;16)(p13.1;q22) / CBFB / MYH11 (2017 WHO classification)
• Atypical chronic myeloid leukemia (aCML), BCR-ABL1 negative: besides features of myeloproliferative neoplasms and eosinophilia, dysplasia is present in > 10% of neutrophilic precursors but there is no monocytosis
• Chronic myelomonocytic leukemia (CMML) with eosinophilia: sustained monocytosis ≥ 1 x 10⁹/L for > 6 months with bone marrow morphologic findings compatible with CMML
• Idiopathic hypereosinophilic syndrome (HES) (2017 WHO classification):
  • Diagnosis of exclusion given when:
    1. Eosinophil count ≥ 1.5 x 10⁹/L for ≥ 6 months
    2. Exclude reactive causes of eosinophilia
    3. Exclude acute myeloid leukemia, myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms and systemic mastocytosis
    4. Exclude cytokine producing, immunophenotypically aberrant T cell population
    5. Tissue damage present due to hypereosinophilia
• Idiopathic hypereosinophilia: when criteria 1 - 4 listed above for idiopathic hypereosinophilic syndrome are met but there is no end organ damage
  • Subset of patients harbor certain gene mutations, such as ASXL1 (43%), TET2 (36%), EZH2 (29%), SETBP1 (22%), CBL (14%) and NOTCH1 (14%) (Mod Pathol 2016;29:854)
  • Presence of clonal genetic aberration favors chronic eosinophilic leukemia, not otherwise specified
• Lymphocytic variant of hypereosinophilic syndrome: abnormal cytokine release by immunophenotypically abnormal or clonal T cells
  • Aberrant CD3- / CD4+ T cell population which can be detected by flow cytometry can be used to differentiate; absolute CD3- / CD4+ T cell count 0.01 - 28.3 k/L with median 0.35 k/L
    • TCRγδ rearrangements were frequently identified (76%) (Medicine (Baltimore) 2014;93:255)
  • Other phenotypic changes, e.g. CD3+ / CD4+ / CD7- and CD3+ / CD4- / CD8- TCRαβ+ have been reported (Immunol Allergy Clin North Am 2007;27:389, N Engl J Med 1999;341:1112)
• Medication related: administration of cytokines IL3, IL5 or GMCSF
• Myeloid neoplasms with rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2, ETV6-JAK2 or BCR-JAK2 fusion (Blood 2017;129:704)
• Paraneoplastic eosinophilia: T cell lymphoma, Hodgkin lymphoma, systemic mastocytosis, acute lymphoblastic leukemia, myeloproliferative neoplasms or certain solid tumors (e.g. lung cancer, metastatic renal cell carcinoma, etc.) associated with abnormal release of IL2, IL3, IL5 or GMCSF (Arch Pathol Lab Med 2013;137:259, Rinsho Ketsueki 1991;32:874, Acta Clin Belg 2011;66:293, Am J Hematol 2007;82:234, N Z Med J 1990;103:537)
• Reactive eosinophilia: parasitic or fungal infections, allergies, pulmonary disease (Löffler syndrome), cyclical eosinophilia, skin diseases (angiolymphoid hyperplasia), collagen vascular diseases such as Churg-Strauss syndrome and Kimura disease
• Systemic mastocytosis: clonal proliferation of atypical mast cells that meet 2017 WHO diagnostic criteria
  • Eosinophils are present or increased, which could be a secondary reaction or derived from a neoplastic clone

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 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. 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. 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, not otherwise specified (CEL, NOS)

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 increased eosinophils
4. KIT D816V gene mutation
5. Marked monocytosis

C. Hypercellular marrow along with eosinophilic proliferation, though nonspecific, is the most common feature for CEL-NOS.

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Reference: Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS)