The Hematologist

November-December 2017, Volume 14, Issue 6

Lymphocytic-Variant Hypereosinophilic Syndromes

Paneez Khoury, MD, MHSc Allergist-Immunologist
National Institutes of Health, Bethesda, MD

Published on: October 27, 2017

Hyperesinophilic syndromes (HES) are rare disorders defined by elevation of absolute eosinophil count (>1.5 × 109/L) in the peripheral blood, accompanied by end-organ or tissue involvement.1 Clinical presentations are varied and range from benign cutaneous involvement to severe manifestations such as endomyocardial fibrosis and thromboembolism. HES are classified into various subtypes encompassing those with known etiology such as myeloid neoplasms with well-described molecular abnormalities, to idiopathic forms with no known etiology. Lymphocytic variant HES (LHES) are a subtype of HES defined by the presence of a monoclonal T cell population detected in conjunction with immunophenotypically aberrant T cell populations. Although these clones are described to overproduce eosinophil-promoting cytokines ex-vivo2 that cause a reactive eosinophilia, many questions remain as to the underlying mechanisms by which these cells develop, optimal treatment and monitoring, and factors that might contribute to development of lymphoma in a subset of patients with LHES.

Characteristics of the Aberrant T Cell Population in LHES
The most common immunophenotype of the aberrant population in LHES is CD3CD4+, but other populations such as CD3+CD4CD8 and CD4+CD7, among others (including phenotypically normal–appearing T cells), have been reported in detail in various publications.2-6 A common question is whether cells lacking CD3 are in fact T cells. T cell lineage markers on the surface of these cell populations (CD2, CD5),7 demonstration of intracellular CD3 by flow cytometry after permeabilization also seen in angioimmunoblastic T cell lymphoma (AITL),8 and evidence of T cell receptor genes by Southern blotting9 demonstrate that these cells derive from T cells. One possible explanation for the lack of surface CD3 is defective NFATc2 overexpression in LHES resulting in defective CD3[Symbol] gene transcription.10 These populations are neither inert nor anergic. They have been shown to be stable in long-term cultures; produce varying degrees of IL-4 and IL-5 in vitro at baseline,2 or more commonly, upon stimulation with mitogens11; and can be activated by engagement of costimulatory receptors CD2 and CD28.12 The elaboration of IL-4 is believed to be the cause of the increase in CCL17/TARC,13 B-cell expansion, and production of polyclonal Ig including IgE,14 and their production of IL-5 is believed to cause reactive eosinophilia in patients with LHES.

Clinical Diagnosis
Patients with LHES may present with a range of cutaneous findings, including eczematous dermatitis, nodules, papules, poikiloderma, plaques, pruritis, urticaria and/or angioedema and erythroderma.2,15 Gastrointestinal or rheumatological symptoms, thromboembolism,16 and lymphadenopathy16,17 are also common, though patients can have involvement of any organ system with varying degrees of severity. Histopathology of lymph nodes can show eosinophilia, rare plasma cells, mild-moderate effacement of lymph node architecture, and atypical lymphoid cells,16 and T cells may be clonally rearranged in the lymph node. Skin biopsies of involved areas may show the clonal T cell population18 on immunohistochemical staining. Bone marrow biopsies have varying degrees of eosinophilia, scattered lymphocytes, and plasma cells, and karyotype is frequently normal with rare exceptions reported.19-21

Laboratory and Diagnostic Workup
During the diagnostic evaluation of hypereosinophilic syndrome,22 certain laboratory and research tests may indicate a diagnosis of LHES. Most patients have an elevated IgE.23 Polyclonal hypergammaglobulinemia may also be seen, but the presence of characteristic aberrant T cell immunophenotypes, such as CD3CD4+ and molecular evidence of T cell clonality in the appropriate clinical context, help make the diagnosis. Unfortunately, rearrangement of the T cell receptor by itself is not sufficient for diagnosis of LHES since clonal T cells have been detected in the blood of healthy volunteers, aging populations, and in the setting of antigen-specific expansion.24 The absence of a characteristic population does not rule out LHES since demonstration of phenotypically normal–appearing T cells4,6 producing high levels of eosinophil promoting cytokines has been shown. Although demonstration of elevated CCL17 (TARC)25 and production of type II cytokines by cultured cells after stimulation in vitro, or intracellularly after permeabilization by flow cytometry, have been suggested for confirmation of LHES diagnosis, these tests are not routinely available or practical for clinical diagnosis. Clearly, future studies investigating additional biomarkers or means of diagnosis would be beneficial for this patient cohort.

Differential Diagnosis
Lymphoproliferative disorders that may present with peripheral eosinophilia, aberrant T cell immunophenotype, and overlapping clinical features with LHES include IgG4-related disease,17 cutaneous T cell lymphomas26 such as mycosis fungoides or Sézary syndrome, peripheral T cell lymphomas such as AITL,27 and adult T cell leukemia/lymphoma.28 Workup to exclude these conditions at presentation may include computed tomography or positron emission tomography scans, biopsies of enlarged lymph nodes, bone marrow, or skin,29 and flow cytometry of the peripheral blood. In a referral population of patients with hypereosinophilia, median time to detection of a hematologic malignancy was 30 months,29 suggesting that the workup of these conditions is an iterative process. Making the distinction between erythrodermic forms of cutaneous T cell lymphoma (CTCL) and LHES can be tricky and requires assessment of a combination of clinical and histopathologic factors.30 Patients should be observed for development of features that may indicate progressive disease. Although not well studied, factors that might prompt additional workup include increasing eosinophilia,29 expansion of a known clone, progression to involve additional organs, and new or worsening adenopathy or skin lesions.

Natural History and Prognosis
LHES comprises 17 to 26 percent2,31 of patients with HES and is a rare entity. As such, understanding the natural history and clinical course relies on small published series, case reports, and expert opinion. Although patients with LHES typically present with milder manifestations overall compared with patients with myeloid HES, their disease course is complicated by repeated assessments for interval development of malignant neoplasms. Case series of LHES patients frequently include several patients for whom a diagnosis of lymphoma was eventually made during the course of follow-up. Depending on the series, the rate of progression ranges from 4 to 25 percent.2,32,33 Progression to lymphoma could take several months (suggesting this was the diagnosis at the outset),34 to a median of 2.75 to seven years,3,29 and up to 20 years after the detection of eosinophilia.

Treatment
In contrast to HES with rearranged PDGFRA or PDGFRB that are responsive to targeted therapy with tyrosine kinase inhibitors,35 LHES has no known targeted treatment. Further complicating matters is the lack of consensus as to whether clinical improvement or eosinophilic improvement is sufficient, or whether targeting of the clonal process is necessary. LHES has been classically described as responsive to glucocorticoids.16 Reports of response to corticosteroids are conflicting, with some reporting decrease in the aberrant population in a proportion of subjects,11,16 while others show no significant decline.36 Patients with LHES typically require higher doses of corticosteroids,37 and second-line agents are often used in addition to corticosteroids. Medications that have been used with efficacy include interferon (IFN)-[Symbol] and mepolizumab. IFN-[Symbol] has been demonstrated to have effects on both the eosinophilia and the aberrant T cell population.2,38 Subjects with LHES treated with intravenous mepolizumab 750 mg in a randomized placebo-controlled trial39 showed responsiveness with ability to taper corticosteroids overall. A subset of subjects40 had incomplete improvement of eosinophilia at study end despite ability to taper corticosteroids significantly. T cell clones remained stable in most, but increased in two of nine subjects during the study.40 Mepolizumab is U.S. Food and Drug Administration–approved for severe eosinophilic asthma (100 mg subcutaneously), but higher-dose administration is only available in the context of clinical trials for HES (300 mg; NCT02836496), or for compassionate use in severe, refractory HES (300-700 mg; NCT00244686). Other agents that have been used with clinical efficacy include cyclosporine,32,41,42 methotrexate,32 alemtuzumab,16,43 mycophenolate mofetil,44 and JAK inhibitors ruxolitinib and tofacitinib45 in small numbers of patients.

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Conflict of Interests

Dr. Paneez Khoury indicated no relevant conflicts of interest. This work was funded by the Division of Intramural Research, NIAID, NIH. back to top