REVIEWPathogenesis, classification, and therapy of eosinophilia and eosinophil disorders
Section snippets
Biology of eosinophils and reactive eosinophilia
Eosinophils are myelopoietic effector cells that produce and store a number of biologically active molecules, including eosinophil cationic protein (ECP), major basic protein (MBP), eosinophil neurotoxin, lipid mediators (prostaglandins, leukotriens, and thromboxan A2), and cytokines such as tumor necrosis factor (TNF) alpha.[1], [2], [3] Once activated, eosinophils release their mediators and cytokines, thereby influencing homeostasis and tissue integrity.3 In case of massive and permanent
Diagnostic algorithm and initial investigations
Several different pathologic conditions may lead to an increased production and/or accumulation of reactive/non-neoplastic eosinophils. In most instances, an underlying cause is known or is revealed after initial investigations. Such investigations include a detailed case history, thorough physical examination, X-ray of chest (and lung function test if necessary), electrocardiogram and echocardiogram, ultrasound of abdomen, a complete blood count with microscopic differential count, and a
The hypereosinophilic syndrome (HES)
Major diagnostic criteria for the so called hypereosinophilic syndrome are (i) a permanent eosinophil count of >1500/μL (for at least 6 months) and (ii) the typical end organ damage.[29], [30], [31], [32], [33], [34] In addition, unrelated disorders and transient eosinophilia have to be excluded. Patients with HES may suffer from multiorgan involvement or from isolated end organ damage. In many cases, lung- or endomyocardial fibrosis is seen. In other patients, thrombosis, neurologic symptoms,
Diagnostic approach in patients with suspected hematologic neoplasm
In patients in whom eosinophilia is unlikely to be reactive and/or is accompanied by other blood count abnormalities or by typical end organ damage (HES), specific blood tests are performed, and the bone marrow is examined. Fig. 2 provides a diagnostic algorithm for these patients. Most molecular studies can be performed using peripheral blood and thus yield rapid diagnostic results.[25], [34], [35] Depending on clinical and blood findings, initial tests include markers indicative of (a) a stem
Chronic eosinophilic leukemia (CEL)
Chronic eosinophilic leukemia (CEL) is a myeloproliferative neoplasm defined by the following criteria: persistent eosinophilia (>1500/μL for at least 6 months) and molecular or/and cytogenetic evidence of monoclonal eosinophils, and/or presence of blast cells in the peripheral blood (>2%) or bone marrow (5–19%), and exclusion of all other hematologic and non-hematologic causes of eosinophilia, with recognition of the principle possibility of coexistence of two separate disorders (e.g.
Myeloproliferative and stem cell neoplasms, myelodysplastic syndromes (MDS), and overlap syndromes
Eosinophilia is typically found in various myeloproliferative neoplasms (MPN). In Philadelphia chromosome positive (Ph+) CML, eosinophilia and basophilia are almost always present at diagnosis, and often also when the disease progresses. In patients with typical JAK2 V617F+ MPN, eosinophilia is less frequently detected, but may also occur.25 However, in distinct variants of (atypical) MPN, namely those that develop on the basis of (in association with) an oncogenic form of PDGFRA, PDGFRB, or
Mast cell disorders – systemic mastocytosis (SM) and mast cell leukemia
Although indolent and aggressive variants of SM may be accompanied by eosinophilia (SM-eo), an increase in eosinophils is more frequently observed in advanced forms of the disease, i.e. smouldering SM (SSM-eo), aggressive SM (ASM-eo), and mast cell leukemia (MCL-eo).[51], [52] Moreover, eosinophilia in SM is of prognostic significance.52 A subvariant of ASM-eo is lymphadenopathic SM with eosinophilia.[36], [53] In advanced SM and some patients with ISM, eosinophils are considered to belong to
Malignant lymphomas and other lymphoid neoplasms
A number of lymphoid neoplasms may be accompanied by eosinophilia. Such neoplasms include T cell lymphomas, Hodgkin’s disease, and less frequently B cell Non Hodgkin’s lymphomas (NHL), NK cell neoplasms, acute lymphoblastic leukemia (ALL), and other B cell malignancies.[25], [33], [38], [39] In an early phase of disease, eosinophilia may be the only sign for a (T cell) lymphoma. In other patients, a monoclonal T cell population (clone) is detected by PCR or immunophenotyping, but does not
The WHO classification of eosinophil disorders
The WHO classification 2008 defines two groups of patients with neoplastic eosinophils.[60], [61] One group of patients is suffering from a “myeloid or lymphoid (or stem cell) neoplasm with eosinophilia and abnormalities in PDGFRA, PDGFRB, or FGFR1 genes”.60 The second group, integrated in a subchapter as MPN category, is termed “chronic eosinophilic leukemia, not otherwise specified”.61 The advantage of the WHO classification is that it is based on potential targets, and therefore is in
Therapy of patients with hypereosinophilic disorders
A number of molecular targets related to CEL or to other hematopoietic malignancies presenting with eosinophilia have been defined recently.[25], [38], [39], [40], [41], [42], [43], [44], [62] A summary of potential targets is shown in Table 3. In the individual patient, it is of importance to define the nature of eosinophilia by application of such markers, but also to define the clinical impact of eosinophilia by appropriate staging and assessment of organ infiltration and organ damage, i.e.
Summary and future perspectives
Eosinophilia is an important diagnostic and/or prognostic feature in various myeloid neoplasms. We recommend the use of the appendix ‘eo’ (e.g. MPN-eo, SM-eo) for patients in whom this important diagnostic checkpoint has been reached. Cytogenetic and molecular markers are then applied, and are helpful for determining the final diagnosis. In addition, several of these markers also represent important therapeutic targets. Patients with oncogenic variants of the PDGFR are candidates for treatment
Conflict of interest statement
The author has no conflict of interest.
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