Chronic myeloid neoplasms
Myeloproliferative neoplasms (MPN)
Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS)

Author: Lynh Nguyen, M.D. (see Authors page)
Editor: Ling Zhang, M.D.

Revised: 2 February 2018, last major update January 2018

Copyright: (c) 2002-2018, PathologyOutlines.com, Inc.

PubMed Search: Chronic eosinophilic leukemia[TI] full text[sb]

Cite this page: Nguyen, L. Chronic eosinophilic leukemia, not otherwise specified (CEL, NOS). PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/myeloproliferativeCEL.html. Accessed February 19th, 2018.
Definition / general
  • Persistent increase in eosinophils in the peripheral blood (≥ 1.5 x 109/L), bone marrow and tissue accompanied by increased blasts (2 - 19% in the peripheral blood or 5 - 19% in the bone marrow) 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
Essential features
  • Rare myeloproliferative neoplasm (MPN) characterized by a gradual increase in circulating eosinophils with cytologic atypia, left shifted granulocytic maturation and often hepatomegaly or splenomegaly
  • Organ / tissue infiltration by eosinophils and eosinophilic microabcesses are frequently present, leading to tissue damage and organ dysfunction
  • Clinical course is usually indolent although transformation to acute myeloid leukemia is common
    • Fatal cardiac damage has been documented secondary to the release of cytokines produced by eosinophils
    • This diagnosis should be made after exclusion of reactive causes of eosinophilia, myeloid and lymphoid neoplasms associated with PDGFRA, PDGFRB, FGFR1 rearrangements and JAK2 fusion, and confirmation of clonality (Am J Hematol 2017;92:1243)
Cell of origin
  • Pluripotent lymphoid myeloid stem cell
Epidemiology
  • Due to difficulty in distinguishing chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) from idiopathic hypereosinophilic syndrome (HES) the true incidence of CEL, NOS is unknown
  • Some reports show that men in the seventh decade are more commonly affected (Mod Pathol 2016;29:854, Am J Hematol 2012;87:643)
Sites
  • Peripheral blood and bone marrow are always involved
  • Splenic and hepatic involvement are also common
  • Other frequent sites of involvement include the heart, lungs, central nervous system (CNS), skin and gastrointestinal (GI) tract
Clinical and laboratory features
  • Usually asymptomatic, longstanding eosinophilia without specific etiology (i.e. allergy, asthma, drug reaction, parasitic infection or connective disease)
    • Eosinophil count can vary from 1.5 - 400 x 109/L
  • Other laboratory findings include leukocytosis (20 - 30 x 109/L), anemia and thrombocytopenia
    • Some patients may have thrombocytosis
  • Symptoms: weight loss, night sweats, fever (12%), fatigue (26%), myalgias or angioedema (14%), cough (12%), dyspnea (16%), pruritus and diarrhea
  • Skin manifestations are the most common, followed by lung (44%) and GI tract (38%)
  • Endomyocardial fibrosis followed by restrictive cardiomegaly
    • Hypertension, atherosclerosis and heart failure can be consequential findings
  • Scarring of mitral and tricuspid valves leading to regurgitation, thrombi formation and embolization in end organs
  • Peripheral neuropathy, CNS dysfunction, pulmonary symptoms and rheumatologic findings (Am J Hematol 2012;87:643)
Diagnostic criteria (WHO 2017 classification)
  • Persistent eosinophilia (≥ 1.5 x 109/L) in which reactive causes have been excluded
  • Does not meet diagnostic criteria for chronic myeloid leukemia (CML) with t(9;22)(q34.1;q11.2) / BCR-ABL1 gene fusion, polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic neutrophilic leukemia (CNL), chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML) (BCR-ABL1 gene fusion negative) or systemic mastocytosis (SM)
  • Blasts account for < 20% of cells in the peripheral blood and bone marrow and do NOT have the following cytogenetic aberrations:
    • PDGFRA, PDGFRB or FGFR1 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
    • 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
    • t(9;22)(q24;q31) / BCR-ABL1 fusions
  • Presence of clonal cytogenetic or molecular genetic abnormality(ies)* or a blast count ≥ 2% in the peripheral blood or ≥ 5% in the bone marrow
    • *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 clonal hematopoiesis of indeterminate potential (CHIP)
Prognosis and predictive factors (2017 WHO classification)
Case reports
  • 52 year old man with chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) with t(5;12)(q31;p13) / ETV6-ACSL6 gene fusion, a novel variant of myeloid proliferative neoplasm with eosinophilia (Hum Pathol (N Y) 2016;5:6)
  • 68 year old woman with CEL, NOS with liver infiltration resembling Budd-Chiari syndrome (Rinsho Ketsueki 2007;48:505)
  • 72 year old man with chronic eosinophilic leukemia presenting with autoimmune hemolytic anemia and erythrophagocytosis by eosinophils (Am J Hematol 2006;81:458)
Microscopic (histologic) description
  • Peripheral blood:
    • Striking eosinophilia (≥ 1.5 x 109/L) mainly composed of mature eosinophils and occasional immature eosinophilic precursors
      • Circulating blasts can be seen but comprise < 20%
    • Spectrum of nonspecific eosinophil abnormalities: sparse granulation, cytoplasmic vacuolation, nuclear hyper / hyposegmentation or increased size
    • Occasional cases of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) show normal eosinophilic morphology and lack dysplasia; however, lack of eosinophilic dysplasia generally favors reactive eosinophilia (Mod Pathol 2016;29:854)
    • Often accompanied by neutrophilia, some with mild monocytosis (usually < 1000/uL) and few with mild basophilia
  • Bone marrow:
    • Hypercellular marrow due to eosinophilic proliferation; however, maturation is orderly without disproportionate increase in myeloblasts
    • Charcot-Leyden crystals often present
    • Usually normal erythropoeisis and megakaryocytopoiesis, however, abnormal megakaryocytes are occasionally seen
      • Subpopulation of patients (27%) show morphologic features resembling BCR-ABL1 negative myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS) or myelodysplastic / myeloproliferative neoplasms (MDS / MPN) (Mod Pathol 2016;29:854, Haematologica 2017;102:1352)
    • Increased myeloblasts (commonly 5 - 19% in bone marrow)
    • 1/3 of cases show myelofibrosis; severe fibrosis is rare
  • Tissue:
    • Eosinophilic infiltration or microabcesses, Charcot-Leyden crystals and fibrosis are common
    • Fibrosis is caused by the degranulation and release of eosinophilic basic and cationic proteins
Microscopic (histologic) images

Images hosted on PathOut server:

Images contributed by Dr. Lynh Nguyen (bone marrow biopsy):

Numerous eosinophilic precursors

Myeloid preponderance

Marked hypercellularity

Granulocytic hyperplasia

Reticulin fibrosis



AFIP images (from cases before molecular studies were indicated):

Markedly fibrotic marrow #1 (therapy was unsuccessful); #2 shows blasts and immature cells throughout fibrotic tissue

Markedly hypercellular due to
eosinophils and precursors,
megakaryocytes are markedly reduced,
reticulin fibers are increased

Peripheral smear images

Images hosted on PathOut server:

Images contributed by Dr. Lynh Nguyen:

Moderately degranulated eosinophils

Patient with longstanding hypereosinophilia

Circulating abnormal eosinophils

Marked increased eosinophils

Immunophenotype
  • No specific immunophenotype has been associated with chronic eosinophilic leukemia, not otherwise specified (CEL, NOS); however, immunophenotyping is important to exclude T lymphocyte driven eosinophilia or acute leukemia
Electron microscopy images

Images hosted on PathOut server:

Abnormal eosinophil with decreased
granules, most granules are homogeneous
(normal eosinophilic granules have dense
core surrounded by less dense capsule)

Molecular / cytogenetics description
  • No specific cytogenetic or molecular genetic abnormality identified
  • Must exclude neoplasms with rearrangements of BCR-ABL1, PDGFRA, PDGRB or FGFR1 or PCM1-JAK2, ETV6-JAK2 or BCR-JAK2 fusions
  • Presence of recurrent translocations and karyotypic abnormalities that are seen in myeloid disorders [-8, -7, i(17q)] support the diagnosis of chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) (Br J Haematol 1996;95:2, Br J Haematol 1986;62:659)
  • Common mutations seen in CEL, NOS include ASXL1, TET2 and EZH2; occasional cases may have JAK2 mutation (Blood 2005;106:2162, Mod Pathol 2016;29:854)
    • However, mutations in TET2, ASXL1 and DNMT3A can be detected in the elderly population without neoplasms, namely clonal hematopoiesis of indeterminate potential (CHIP) and should not be considered definitive evidence of a neoplastic cause of eosinophilia (N Engl J Med 2014;371:2477, Nat Med 2014;20:1472)
  • Four cases have demonstrated a somatic activating KIT M541L mutation that was responsive to low dose imatinib therapy; however, the frequency of this mutation is not known (Oncotarget 2014;5:4665)
  • X linked polymorphism analysis of AR (HUMARA) and PGK genes have been used in female patients to demonstrate clonality (Blood 1999;93:1651, Blood 1994;84:349)
Differential diagnosis
Board review question #1
Which of the following is useful in definitively diagnosing the lymphocytic variant of hypereosinophilic syndrome (L-HES)?

  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
Board review answer #1
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.
Board review question #2
Which of following morphologic or molecular genetic findings is frequently identified in chronic eosinophilic leukemia, not otherwise specified (CEL, NOS)?

  1. Dysplastic noneosinophilic granulocytes
  2. ETV6-JAK2 fusion
  3. Hypercellular marrow with increased eosinophils
  4. KIT D816V gene mutation
  5. Marked monocytosis
Board review answer #2
C. Hypercellular marrow along with eosinophilic proliferation, though nonspecific, is the most common feature for CEL-NOS. Morphologic features resembling myeloproliferative neoplasms (MPN) or myelodysplastic / myeloproliferative neoplasms (MDS / MPN) or clonal cytogenetic and molecular evidence, as well as exclusion of reactive or paraneoplastic eosinophilia are diagnostic clues. KIT(V816D) mutation is often found in systemic mastocytosis, while KIT(M541L) somatic mutation is recently reported in CEL, NOS and responds to low dose imatinib (Oncotarget 2014;5:4665). ETV6-JAK2 and BCR-JAK2 fusions are considered provisional variants of PCM1-JAK2 fusion in the recently updated 2017 WHO under myeloid neoplasms with PDGFRA, PDGFRB or FGFR1 rearrangement or PCM1-JAK2, ETV6-JAK2 or BCR-JAK2 fusion. A small number of ETV6-JAK2 and BCR-JAK2 cases have presented as myeloid neoplasms with variable presence of eosinophilia or features of BCR-ABL1-like acute lymphoblastic leukemia / lymphoma. Dysplastic eosinophils are typically seen in CEL, NOS with variable hypogranulation, cytoplasmic vacuolation and nuclear hyper / hyposegmentation. Mild monocytosis can be seen in a subset of CEL, NOS. If monocytosis is significant and persistent, with or without excess blasts, chronic myelomonocytic leukemia (CMML) or acute myelomonocytic leukemia (AMML) should be considered. Myeloid neoplasms with PDGFRB rearrangement may also present with monocytosis.