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Idiopathic hypereosinophilic syndrome


Alexander Reese, D.O.
Lynh Nguyen, M.D.

Last author update: 4 August 2022
Last staff update: 26 September 2023

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PubMed Search: Idiopathic hypereosinophilic syndrome HES pathology

Alexander Reese, D.O.
Lynh Nguyen, M.D.
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Etiology | Clinical features | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Peripheral smear description | Peripheral smear images | Flow cytometry description | Molecular / cytogenetics description | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Reese A, Zhang L, Nguyen L. Idiopathic hypereosinophilic syndrome. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/myeloproliferativehypereosinophilicsyndrome.html. Accessed April 20th, 2024.
Definition / general
  • Idiopathic hypereosinophilic syndrome is a disorder defined by peripheral blood eosinophilia (absolute eosinophil count ≥ 1.5 x 109/L) for at least 6 months with organ damage / dysfunction attributable to tissue hypereosinophilic infiltrate per biopsy and no discernible underlying etiology
  • Diagnosis of exclusion
Essential features
  • Hypereosinophilia (HE) is defined by an increase in eosinophils in the peripheral blood (≥ 1.5 x 109/L); however, if eosinophilia is sustained for ≥ 6 months and there is associated tissue damage, this should be classified as hypereosinophilic syndrome (HES)
  • Clinically, if treatment is necessary to minimize tissue / organ damage, the criteria of 6 months might not be enforced and an eosinophil count ≥ 1.5 x 109/L on 2 occasions for ≥ 1 month apart may be sufficient (Pathobiology 2019;86:39)
  • Idiopathic hypereosinophilia diagnostic criteria
    • Eosinophil count ≥ 1.5 x 109/L for ≥ 6 months
    • Tissue or organ damage associated with eosinophilic infiltration
      • Cardiac and cutaneous manifestations are common but liver, CNS, muscle, pulmonary and nasal sinus involvement may occur as well
    • No discernible underlying cause
      • Exclude reactive causes of eosinophilia (allergy, infection including parasites, drug related, connective tissue disorder, etc.)
      • Exclude acute myeloid leukemia, myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms, systemic mastocytosis and myeloid / lymphoid neoplasms with eosinophilia and PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 rearrangement
      • Exclude cytokine producing, immunophenotypically aberrant T cell population
    • No cytogenetic or molecular abnormalities, however, must exclude clonal hematopoiesis (CHIP) mutations
Terminology
  • Idiopathic HES
ICD coding
  • ICD-10: D72.110 - idiopathic hypereosinophilic syndrome (IHES)
Epidemiology
Sites
  • Skin and cardiac involvement common
  • Minority of patients present with splenomegaly and lymphadenopathy
  • Liver, CNS, muscle, pulmonary and nasal sinus involvement occur more commonly than in eosinophilic leukemia (Haematologica 2014;99:e148)
Etiology
  • Cause is unknown
Clinical features
  • Onset of symptoms is often insidious with eosinophilia being detected incidentally; however, some patients initially present with severe and life threatening problems due to the rapid progression of cardiovascular and neurologic complications
  • Retrospective study of 188 patients with hypereosinophilia reported the frequency of symptoms at presentation (J Allergy Clin Immunol 2009;124:1319):
    • Dermatologic symptoms were most common, followed by pulmonary, gastrointestinal, cardiac and lastly neurologic
    • 6% of patients presented initially with incidentally detected asymptomatic hypereosinophilia
  • Dermatologic: angioedema, dermographism, eczema, erythroderma, pruritis, urticaria
  • Pulmonary: cough, dyspnea, wheezing
  • Gastrointestinal: weight loss, abdominal pain, vomiting, diarrhea, hepatitis, cholangitis, Budd-Chiari syndrome
  • Cardiac: cardiac damage, valvular fibrosis, thromboembolism
  • Neurologic: behavioral changes, confusion, ataxia, memory loss, peripheral neuropathy
Diagnosis
  • Unexplained eosinophilia of ≥ 1.5 x 109/L for at least 6 months that leads to tissue damage
    • Exclude reactive causes of eosinophilia (parasites, drug related, allergy, etc.)
    • Exclude acute myeloid leukemia, myeloproliferative neoplasms, myelodysplastic syndromes, myelodysplastic / myeloproliferative neoplasms and systemic mastocytosis
    • Exclude cytokine producing, immunophenotypically aberrant T cell population
    • Tissue damage present due to hypereosinophilia
  • Bone marrow with increased eosinophilic precursors; proposed criteria of ≥ 20% marrow cellularity with or without peripheral blood eosinophilia (Pathobiology 2019;86:39)
  • Affected organs may have increased eosinophils with eosinophil degranulation (Pathobiology 2019;86:39)
Laboratory
Prognostic factors
  • Slowly progressive clinical course with death occurring due to cardiac damage in some cases
Case reports
Treatment
  • Patients are typically observed during the initial stages of the disease
  • As HES progresses, initial treatment is often systemic glucocorticoid therapy with second line treatments including imatinib, interferon alfa and hydroxyurea
  • Recent study showed that mepolizumab could be effective at treating flares in HES (J Allergy Clin Immunol 2020;146:1397)
Microscopic (histologic) description
  • Bone marrow
    • Normocellular or hypercellular marrow with an increase in eosinophils and eosinophilic precursors with orderly maturation
    • Bone marrow eosinophilia proposed criteria: ≥ 20% marrow cellularity with or without peripheral blood eosinophilia (Pathobiology 2019;86:39)
    • Normal differential counts
    • No increase in blasts (< 5%)
    • No neoplastic process
  • Tissue / organ
    • Eosinophils are typically scattered or absent in normal tissue; affected organs may have increased eosinophils with eosinophil degranulation (Pathobiology 2019;86:39)
    • Possible eosinophilic microabscesses
    • Organs affected include gastrointestinal tract, lung, lymph nodes, spleen and thymus
Microscopic (histologic) images

AFIP images

Bone marrow aspirate

Peripheral smear description
Peripheral smear images

AFIP images

40% eosinophils with normal morphology

Flow cytometry description
Molecular / cytogenetics description
  • No cytogenetic or molecular genetic abnormalities identified by definition (Jaffe: Hematopathology, 2nd Edition, 2016)
  • Must exclude neoplasms with rearrangements of BCR-ABL1, PDGFRA, PDGRB or FGFR1 or PCM1-JAK2, ETV6-JAK2, BCR-JAK2 or FLT3 fusions as well as activating PDGFRA gene mutation
Sample pathology report
  • Bone marrow, posterior iliac crest, core biopsy, clot section, aspirate smears and touch imprint:
    • Hypereosinophilic syndrome (see comment)
    • Hypercellular (80 - 90%) bone marrow with myeloid hyperplasia with markedly increased eosinophils and no overt increase in blasts (< 5%)
    • No evidence of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 gene rearrangements
    • No evidence of BCR-ABL1, CBFB-MYH11 / inv(16) gene rearrangements
    • No gene mutations identified per next generation sequencing (NGS) panel
    • Comment: There is no morphologic evidence of a myeloid neoplasm associated with eosinophilia. Clinically there are no identifiable etiologies of reactive eosinophilia such as allergic reactions, parasitic infections, autoimmune diseases and medications. The patient presents with a persistent eosinophilia for over 6 months (ranging from 1600 - 5500/µL). Electrocardiogram and echocardiograms were reportedly abnormal. Imaging studies showed subendothelial fibrosis within the ventricles. The corresponding tissue biopsy showed eosinophilic infiltration (20 - 40 eosinophils/high power field) with degranulation within the myocardium.
    • Flow cytometric analysis demonstrates occasional CD34+ myeloblasts which comprise about 1.0% of total events. Hematogones are absent. No clonal B cell population or immunophenotypically abnormal T cells (e.g. CD3- / CD4+) were noted to suggest lymphoid variant of hypereosinophilic syndrome or T cell lymphoma. No clonal plasma cell population is identified.
    • Additional immunohistochemical stains performed on the core biopsy show no increase in CD34 or CD117 positive immature myeloid precursors. CD117 also highlights occasional normal appearing mast cells which do not form aggregates. CD3 and CD20 highlight scattered T and B cells respectively. CD138 stains plasma cells, which comprise < 1% of the marrow cellularity.
    • Peripheral smear: Manual review of the peripheral blood shows normochromic, normocytic anemia, mild leukocytosis, absolute eosinophilia and essentially normal platelets. There is no absolute monocytosis or circulating blasts. Morphologically, RBCs show normochromic, normocytic anemia with mild anisopoikilocytosis. WBCs: slightly increased in number (13000/µL) without neutrophilia, blastosis or immature monocytosis. Occasional circulating immature granulocytic precursors, e.g. metamyelocytes and myelocytes, are noted. A manual 500 cell differential count reveals 42.0% of eosinophils, resulting in an absolute eosinophilic count of 5500/µL and 3.0% monocytes, resulting in an absolute monocyte count of 390/µL. No dysplastic granulocytes such as hypogranular or hyposegmented forms are identified. Platelets: normal by count with occasional large platelets.
    • Bone marrow biopsy: Quality: adequate. Cellularity: 80 - 90%. Hematopoiesis: trilineage maturation with mild myeloid hyperplasia and relatively normal erythropoiesis. Megakaryocytes are identified and normally distributed. There is no apparent increase in blasts or abnormal localization of immature myeloid precursors. Mature eosinophils are increased, making up approximately 30 - 40% of marrow cellularity. Special stains: reticulin: loose network of reticulin without significant intersections (minimal reticulin fibrosis). Small loose lymphoid aggregates composed of small mature lymphocytes are focally noted, overall < 5% of marrow cellularity.
    • Bone marrow clot section: Quality: adequate. Cellularity: 80 - 90%, morphologic features are similar to those observed in the core biopsy.
    • Bone marrow aspirate: Quality: adequate. Granulocytes: mildly increased; mild left shifted maturation without morphologic dysplasia. Eosinophilic precursors, predominantly mature forms, are markedly increased comprising approximately 40 - 50% of cellularity. Erythrocytes exhibit normal normoblastic maturation. Megakaryocytes appear normal by morphology and adequate in number. Myeloblasts: overall ~3% of nucleated cells. There is no monocytosis or increase promonocytes. Iron: storage iron is adequate (2+ on a scale of 0 - 4). No ring sideroblasts are present. Scattered mature mast cells are present (2%).
Differential diagnosis
Board review style question #1
In addition to tissue damage, what minimum level and duration of eosinophilia is required to make a diagnosis of hypereosinophilic syndrome?

  1. 1.0 x 109/L for at least 3 months
  2. 1.0 x 109/L for at least 6 months
  3. 1.0 x 109/L for at least 12 months
  4. 1.5 x 109/L for at least 6 months
  5. 1.5 x 109/L for at least 12 months
Board review style answer #1
D. 1.5 x 109/L for at least 6 months

Comment Here

Reference: Hypereosinophilic syndrome
Board review style question #2
Which of the following is true of idiopathic hypereosinophilic syndrome?

  1. Aberrant T cell population must be present
  2. Can accompany systemic mastocytosis
  3. Carries an autosomal dominant inheritance
  4. End organ damage is absent
  5. No cytogenetic or molecular abnormalities are present
Board review style answer #2
E. No cytogenetic or molecular abnormalities are present

Comment Here

Reference: Hypereosinophilic syndrome
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