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Eosinophilia and Chronic Eosinophilic Leukemia, Including Myeloid/Lymphoid Neoplasms with Eosinophilia and Rearrangement of PDGFRA, PDGFRB, FGFR1 , or JAK2


Eosinophilia is an increase in the number of circulating eosinophils accompanied by an increase of eosinophils and precursors in the bone marrow and often in other tissues as well. The upper limit of normal for the eosinophil count, if subjects with trivial allergic conditions are excluded, is about 0.46 × 10 9 /L; however, 0.5 × 10 9 /L is a practical working limit. The eosinophilia may vary from mild to marked, but patients with prolonged eosinophilia, particularly when the eosinophilia is marked (≥1.0 × 10 9 /L), are at risk of having serious organ damage because of release of the contents of eosinophilic granules. Cardiac damage is most common, with congestive cardiac failure and arrhythmias being common manifestations. Essentially any organ can be involved, however, and symptoms related to damage to the central nervous system, lungs, gastrointestinal tract, and skin are also observed. It is therefore essential to recognize and to treat the underlying cause of the eosinophilia as quickly as possible.

Recognizing the cause can be challenging at times. Eosinophilia may be reactive because of an underlying infection or an immune response that results in increased interleukin (IL)-5, IL-3, or other cytokines produced by activated T cells or by the cells of a neoplastic process such as Hodgkin's or non-Hodgkin's lymphoma. In other cases, the eosinophils themselves are part of a clonal neoplastic hematopoietic neoplasm, such as chronic myeloid leukemia, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). When the eosinophils are clonal and are the dominant component and they number 1.5 × 10 9 /L or more in the peripheral blood, the possibility of chronic eosinophilic leukemia (CEL) should also be considered. Sometimes the underlying pathologic process remains elusive and unknown. In these cases, the diagnosis of idiopathic eosinophilia is the last diagnostic option, as long as the reason for the eosinophilia has been fully investigated.

This chapter focuses on the evaluation of eosinophilia and on the various reactive and neoplastic conditions in which it can be found ( Box 50-1 ).

Box 50-1
Classification of Eosinophilia by Cause

Reactive

  • Allergy

    • Asthma

    • Atopic eczema

    • Urticaria

    • Allergic rhinitis

    • Allergic bronchopulmonary aspergillosis

    • Adverse drug reaction

  • Skin disease

    • Pemphigus vulgaris

    • Bullous pemphigoid

    • Dermatitis herpetiformis

  • Parasitic infection

    • Nematodes (e.g., ascariasis, hookworm infection, strongyloidiasis, filariasis)

    • Trematodes (e.g., fascioliasis, fasciolopsiasis, schistosomiasis)

    • Cestodes (e.g., cysticercosis, echinococcosis)

  • Fungal infection

    • Coccidioidomycosis

  • Neoplasia

    • Carcinoma

    • Sarcoma

    • Hodgkin's lymphoma

    • Non-Hodgkin's lymphoma

    • Acute lymphoblastic leukemia

    • Systemic mastocytosis *

      * Eosinophilia can be reactive or neoplastic.

  • Vasculitis

    • Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis)

    • Systemic necrotizing vasculitis

  • Endocrine disorder

    • Addison's disease

    • Hypopituitarism

  • Administration of cytokines

    • Interleukin-3

    • Interleukin-5

Neoplastic

  • Acute myeloid leukemia (occasionally)

  • Myeloid and lymphoid neoplasms with PDGFRA rearrangement

  • Myeloid and lymphoid neoplasms with PDGFRB rearrangement

  • Myeloid and lymphoid neoplasms with FGFR1 rearrangement

  • Myeloid and lymphoid neoplasms with JAK2 rearrangement

  • Chronic eosinophilic leukemia, not otherwise specified

  • Eosinophilic transformation of myeloproliferative neoplasms (e.g., chronic myeloid leukemia, primary myelofibrosis)

  • Systemic mastocytosis *

Unknown

  • Idiopathic hypereosinophilic syndrome

Evaluation of Eosinophilia

The differential diagnosis and definitive diagnosis of hyper­eosinophilic conditions cannot be based solely on laboratory data. An initial clinical history and physical examination are required to orient the diagnostic process. Questioning should specifically seek any history of atopy (eczema, asthma, hay fever), cyclic angioedema, drug intake (particularly any recent changes and including alternative medicines), and travel (particularly to the tropics, remote in time as well as recent, and any illness while there). The physical examination should be thorough and systematic; of particular note are abnormalities that might provide a clue to the cause of eosinophilia, such as lymphadenopathy, hepatomegaly, splenomegaly, and cutaneous lesions (erythema, eczematous rash, edema, and more specific lesions, such as urticaria pigmentosa or lymphomatous infiltration). The examination should also be directed at abnormalities that might indicate tissue damage by eosinophils or their secreted products, such as cardiac valvular lesion, cardiac failure, bronchospasm, peripheral neuropathy, and vasculitis.

How the investigation proceeds depends on the degree of eosinophilia, the differential diagnosis based on the history and examination, and whether the situation appears to be clinically urgent. Clinical urgency is indicated by any cardiac signs or symptoms, a seriously ill appearance, a very high eosinophil count (>100 × 10 9 /L), a high proportion of degranulated eosinophils, or the suspicion of a hematopoietic or non-hematopoietic malignant neoplasm. If there is clinical urgency, it is important to identify any readily treatable conditions rapidly, so it may be necessary to do multiple unrelated investigations within a short time. If the situation is not urgent, a logical sequence can be followed, as suggested by the clinical features. In fact, most causes of hypereosinophilia are amenable to treatment, but ideally, treatment should be targeted correctly by first establishing the diagnosis. Mild eosinophilia that can be explained by the history and physical examination (e.g., due to atopy or skin disease) does not necessarily require any further investigation. Eosinophilia that is more than trivial (1.5 × 10 9 /L or greater) and unexplained should generally be investigated. In the absence of clinical urgency, the initial investigation should focus on the diagnoses that seem most probable ( Table 50-1 ). Flow charts for diagnostic pathways are provided in Figures 50-1 to 50-3 .

Table 50-1
Investigations Indicated for Unexplained Persistent Hypereosinophilia
Modified from Fletcher S, Bain B. Eosinophilic leukaemia. Br Med Bull . 2007;81:115-127.
Investigation Possible Diagnostic Yield
Blood film Lymphoblasts, myeloblasts, or lymphoma cells indicating hematologic neoplasm
Investigation of stool, urine, or blood for parasites; serology for parasitic infection Parasitic infection
Immunoglobulin E and tests for allergy Allergic disease
Bone marrow aspiration and trephine biopsy Eosinophilic leukemia, Hodgkin's or non-Hodgkin's lymphoma, or systemic mastocytosis
Cytogenetic analysis of bone marrow aspirate Eosinophilic leukemia
Molecular analysis of peripheral blood cells for FIP1L1-PDGFRA fusion gene Eosinophilic leukemia
Molecular analysis of bone marrow cells for KIT mutation Systemic mastocytosis
Serum tryptase Eosinophilic leukemia or systemic mastocytosis
Immunophenotyping of peripheral blood T cells Cytokine-driven eosinophilia
Computed tomography scan of chest and abdomen Underlying lymphoma or other neoplasm

Figure 50-1, Flow chart of the suggested diagnostic process in a patient with hypereosinophilia when there is clinical urgency. CEL, chronic eosinophilic leukemia.

Figure 50-2, Flow chart of the suggested diagnostic process in a patient with hypereosinophilia when there is no clinical urgency. CEL, chronic eosinophilic leukemia.

Figure 50-3, Flow chart of various diagnostic pathways in patients with hypereosinophilia. CEL, chronic eosinophilic leukemia.

Causes of Eosinophilia

Parasitic Infection

This diagnosis requires a detailed history of previous residence and travel. It is important to be aware that strongyloidiasis can present clinically as long as 50 years after exposure, and schistosomiasis can also present a considerable time after leaving an endemic area. Parasitic infection is particularly prevalent among refugees from endemic areas who have lived in overcrowded, unsanitary conditions as well as among immigrants from rural areas of relevant countries. Examination of the stool for ova, cysts, and parasites and examination of blood films for microfilariae (when indicated) should be carried out whenever there is a possibility of exposure. Three separate stool specimens should be examined. Serology is more sensitive than stool examination in the diagnosis of strongyloidiasis and schistosomiasis, and it is also applicable to the diagnosis of fascioliasis and clonorchiasis. It is the primary diagnostic method for gnathostomiasis, opisthorchiasis, trichinosis, and toxocariasis. Urine should be examined for parasite ova when Schistosoma japonicum infection is suspected.

The only parasitic infection in which the hematologist often has a diagnostic role is filariasis. However, other patients with unexplained eosinophilia may be referred to a clinical hematologist for investigation. The hematologist must also be aware of the possibility of occult parasitic infection, particularly strongyloidiasis, in patients with actual or predicted immune deficiency, including those with adult T-cell leukemia/lymphoma and those who are about to undergo combination chemotherapy or stem cell transplantation; in such patients, investigation (including serology) should not be confined to those with eosinophilia.

Coccidioidomycosis

A history of residence and travel is critical to determine the need to suspect and to investigate for coccidioidomycosis. Endemic areas include the southwestern United States (California, Arizona, New Mexico, Texas), northern Mexico, and some parts of Central and South America. Blood and bone marrow examinations are not relevant.

Other Reactive Eosinophilias

A history of atopy and recently added or altered medications may be relevant ( Fig. 50-4 ). Physical examination may disclose evidence of the primary disease. Causes of reactive eosinophilia include drug reactions, lymphomas (Hodgkin's and non-Hodgkin's), acute lymphoblastic leukemia (ALL), solid tumors, and autoimmune diseases. A blood film, bone marrow aspiration, computed tomography and other imaging studies, and tissue biopsy may be needed to investigate these possibilities. Information is available online on drugs known to cause pulmonary hypereosinophilia. Causes of reactive eosinophilia that are sometimes diagnosed by examination of the peripheral blood and bone marrow include Hodgkin's and non-Hodgkin's lymphoma and ALL ( Fig. 50-5 ). Bone marrow aspiration and particularly trephine biopsy can lead to a diagnosis of Hodgkin's lymphoma or metastatic non-hematopoietic malignant neoplasm underlying eosinophilia. Increased serum immunoglobulin E is seen not only in atopy but also in T-cell–driven hypereosinophilia (lymphocytic variant of hypereosinophilic syndrome) and even occasionally in eosinophilic leukemia. Serum IL-5 may be elevated in reactive and T-cell–driven hypereosinophilia. The mechanism of eosinophilia in ALL with t(5;14)(q31.1;q32.1) is of interest, the IL3 gene encoding IL-3 being dysregulated by proximity to the IGH locus. This and other reactive eosinophilias associated with ALL must be distinguished from lymphoblastic leukemias in which the associated eosinophils are part of the neoplastic clone (see later). The diagnosis of cyclic angioedema with eosinophilia rests on the clinical history and observation of cycling of both the eosinophil count and the body weight; pathologic investigation is not particularly useful. Likewise, Churg-Strauss syndrome (eosinophilic granulomatosis with polyangiitis) generally cannot be diagnosed by examination of the peripheral blood and bone marrow; tissue biopsy and serology are needed. The American College of Rheumatology has provided diagnostic criteria.

Figure 50-4, Reactive eosinophilia.

Figure 50-5, Reactive eosinophilia and acute lymphoblastic leukemia.

Acute Myeloid Leukemia

Eosinophilia is uncommon as the predominant manifestation of AML. It has been reported in rare patients with AML associated with t(8;21)(q22;q22.1), in one patient leading to a hypereosinophilic syndrome. In AML associated with inv(16)(p13.1q22) or t(16;16)(p13.1;q22), peripheral blood eosinophilia is usually minor but occasionally marked. In the rare patients in whom eosinophilia is a feature of AML, other peripheral blood features suggestive of acute leukemia are usually present, and bone marrow examination and cytogenetic analysis give the diagnosis.

Systemic Mastocytosis

Eosinophilia can be a feature of systemic mastocytosis. The eosinophils may be part of the neoplastic clone, but there may also be reactive eosinophilia as a result of the release of cytokines by the neoplastic mast cells. The bone marrow is usually infiltrated, so a bone marrow aspirate and particularly a trephine biopsy are indicated if systemic mastocytosis is suspected. Elevated serum mast cell tryptase may provide a clue, although this can also occur in CEL and other myeloproliferative neoplasms (MPN). Serum tryptase levels are higher in systemic mastocytosis, but there is some overlap. In the bone marrow, the infiltrating mast cells are cohesive, are often spindle shaped, and may be preferentially located in a periarteriolar or paratrabecular position. There may be an associated increase of eosinophils and lymphocytes ( Fig. 50-6 ). Immunohistochemistry for mast cell tryptase is very useful to confirm the nature of a suspected mast cell infiltrate. Eosinophilia as a result of mastocytosis must be distinguished from CEL (see later), which can also exhibit bone marrow infiltration by neoplastic mast cells. Mastocytosis is characterized by a KIT mutation, usually KIT D816V, whereas CEL often has rearrangement of PDGFRA or PDGFRB .

Figure 50-6, Eosinophilia and mast cell disease.

Lymphocytic Variant of Hypereosinophilic Syndrome

An aberrant cytokine-secreting lymphocyte population can lead to eosinophilia, sometimes designated the lymphocytic variant of hypereosinophilic syndrome . Clinical features are mainly cutaneous and include pruritus, eczema, erythroderma, urticaria, and angioedema. There may be lymphadenopathy or a history of atopy. In contrast to CEL (see later), cardiac involvement is uncommon, and the sex incidence is equal. The blood count shows eosinophilia and a normal or slightly elevated lymphocyte count but is otherwise normal. The bone marrow shows increased eosinophils and precursors. The lymphocytes are abnormal on flow cytometry. They usually lack CD3 but do express CD4, often with expression of CD2, overexpression of CD5, and loss of CD7 expression. Other cases have shown a range of different aberrant phenotypes, such as CD3 + /CD4 − /CD8 − or CD3 + /CD4 + /CD7 − (weak). In patients whose lymphocytes express CD3, there is restricted use of T-cell receptor β gene variable regions (but specialized immunophenotyping to detect this is not widely available). The lymphocytes can express markers of activation, such as CD25 and HLA-DR. It may be possible to demonstrate clonality by the analysis of T-cell receptor genes ( TCB and TRG loci). Serum IL-5 is often increased, and sometimes there is a polyclonal increase of serum immunoglobulins (G and M). Serum vitamin B 12 is not increased. It is important to distinguish the lymphocytic variant of hypereosinophilic syndrome from overt T-cell lymphoma with reactive eosinophilia; skin infiltration and marked lymphadenopathy suggest the latter diagnosis. Some patients who present with the lymphocytic variant of hypereosinophilic syndrome subsequently have T-cell lymphoma, with reported intervals ranging from 3 to 20 years. In addition to corticosteroids, the lymphocytic variant of hypereosinophilic syndrome responds to mepolizumab, an anti–IL-5 monoclonal antibody.

Chronic Eosinophilic Leukemia and Other Myeloid and Lymphoid Neoplasms Associated with PDGFRA Rearrangement

Definition

Many patients who would have been regarded as having idiopathic hypereosinophilic syndrome in the past are now known to have CEL as a result of a cryptic deletion of part of chromosome 4q that leads to the FIP1L1-PDGFRA fusion gene. At least five other genes have also contributed to a fusion gene with PDGFRA , and point mutations of PDGFRA have been described. These leukemias are defined by the presence of the fusion gene, and because they can be manifested initially as AML or T-lineage ALL or transform into either one, they have been designated myeloid and lymphoid neoplasms associated with PDGFRA rearrangement in the 2008 World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues. Rarely, in cases associated with BCR-PDGFRA , transformation has been to B-lineage ALL.

Epidemiology

There is a remarkable male predominance and a wide age range.

Etiology

No etiologic factors have been identified.

Clinical Features

Clinical features include fever, weight loss, malaise, cardiac signs and symptoms (dyspnea, chest pain, palpitations), cough, diarrhea, skin lesions (angioedema, urticaria), mucosal and genital ulceration, and peripheral neuropathy. There may be embolic phenomena, including splinter hemorrhages of the nail beds. Serum immunoglobulin E is usually normal, but an increase does not exclude the diagnosis. Increased serum IL-5 does not exclude the diagnosis either.

Morphology

The blood film generally shows eosinophilia ( Fig. 50-7 ), but this is not invariable. Eosinophils may be cytologically abnormal (degranulation, vacuolation, hyperlobation), but such features can also be seen in reactive eosinophilia. Sometimes there is neutrophilia. The bone marrow shows increased eosinophils and precursors ( Fig. 50-8 ). On trephine biopsy sections, there is an increase of eosinophils and precursors and often of mast cells as well, which may be spindle shaped ( Fig. 50-9 ). The mast cells do not usually form the cohesive infiltrates seen in systemic mastocytosis, but a histologic distinction from systemic mastocytosis is sometimes difficult. Reticulin may be increased.

Figure 50-7, Peripheral blood film from a patient with chronic eosinophilic leukemia associated with the FIP1L1-PDGFRA fusion gene. There is eosinophilia, and the eosinophils show extensive degranulation and some vacuolation.

Figure 50-8, Bone marrow aspirate film from another patient with chronic eosinophilic leukemia associated with the FIP1L1-PDGFRA fusion gene shows eosinophils and precursors. An eosinophil promyelocyte has a mixture of eosinophilic and proeosinophilic (purple-staining) granules; this feature can also be seen in reactive eosinophilia.

Figure 50-9, Bone marrow trephine biopsy sections from a patient with chronic eosinophilic leukemia associated with the FIP1L1-PDGFRA fusion (same patient as in Fig. 50-8 ). A, Hypercellular, disorganized marrow with increased eosinophils and precursors. B, Giemsa stain shows hypercellular marrow with increased eosinophil precursors. C, Scattered spindle-shaped mast cells and several cells with a high nuclear-to-cytoplasmic ratio that are likely to be hematopoietic precursors (immunoperoxidase for CD117).

Immunophenotype

Eosinophils may show immunophenotypic features of activation, but this is not diagnostically helpful.

Genetics and Molecular Findings

Cytogenetic analysis is usually normal, but occasionally there is a related chromosomal rearrangement with a 4q12 breakpoint or, more often, an unrelated chromosomal abnormality, such as trisomy 8, del(20q), or del(17p). The FIP1L1-PDGFRA fusion gene encodes a constitutively activated tyrosine kinase that is pathogenetic. A minority of patients have a different chromosomal rearrangement that also leads to rearrangement of PDGFRA but involves a different partner gene. Diagnosis is by polymerase chain reaction (nested polymerase chain reaction is often needed) or fluorescence in situ hybridization, or both. A combination of the two is recommended. Fluorescence in situ hybridization techniques often rely on detecting deletion of the CHIC2 gene, which is located between FIP1L1 and PDGFRA and is lost when this fusion occurs.

Postulated Cell of Origin

The cell of origin is a pluripotent lymphoid/myeloid stem cell.

Clinical Course

The clinical course may be chronic, but some patients die of cardiac or other complications; in some, there is transformation to AML. The prognosis is much improved since identification of the fusion gene and discovery of the marked sensitivity of this condition to imatinib therapy. Even patients who present in the acute phase may respond. Sensitivity to imatinib is greater than in chronic myeloid leukemia, and if molecular monitoring is available, treatment can start at the low dose of 100 mg daily.

Differential Diagnosis

The differential diagnosis includes other causes of hypereosinophilia, but as long as a sensitive technique for detecting the cryptic deletion or fusion gene is used, there is no diagnostic difficulty. The presence of abnormal bone marrow mast cells should not be misinterpreted as indicating systemic mastocytosis.

Chronic Eosinophilic Leukemia and Other Myeloid and Lymphoid Neoplasms Associated with PDGFRB Rearrangement

Definition

Myeloid or rarely lymphoid neoplasms in this group result from a translocation that leads to rearrangement of PDGFRB and formation of a fusion gene to which PDGFRB contributes. The most frequently observed translocation is t(5;12)(q32;p13.2), with formation of an ETV6-PDGFRB fusion, but at least 25 different translocations and fusion genes have been recognized, many of which have been reported in only single patients. The hematologic features are heterogeneous, even in patients with ETV6-PDGFRB .

It is recommended that cases of Ph-like B-ALL with specific fusion genes to which PDGRFB contributes, such as EBF1-PDGFRB , are not assigned to this category but rather are classified as B-lymphoblastic leukemia/lymphoma.

Epidemiology

There is a wide age range, from childhood to old age. The incidence in males is twice that in females.

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