Evaluation of peripheral blood and bone marrow for an indication of persistent eosinophilia can be a challenging task because there are many causes of eosinophilia and the morphologic differences between reactive and neoplastic causes are often subtle or lack specificity. The purpose of this review is to provide an overview of the differential diagnosis for eosinophilia, to recommend specific steps for the pathologist evaluating blood and bone marrow, and to emphasize 2 important causes of eosinophilia that require specific ancillary tests for diagnosis: myeloproliferative neoplasm with PDGFRA rearrangement and lymphocyte-variant hypereosinophilic syndrome.

Eosinophilia is graded based on absolute eosinophil count: mild (500–1500/μL), moderate (1500–5000/μL), or severe (>5000/μL). A patient can be described as having idiopathic hypereosinophilia if there is persistent moderate or severe eosinophilia for at least 6 months without an identified cause, and the diagnosis of hypereosinophilic syndrome (HES) is applicable when end-organ damage occurs because of persistent moderate or severe eosinophilia.1 

The most common causes of eosinophilia are often taught with the pneumonic device of 3 W's: wind, worms, and wonder drugs. Wind refers to asthma and other allergic causes, worms refer to tissue-invasive parasites, and wonder drugs refer to a nonspecific reaction to various medications or drug-induced hypersensitivity. Another common cause in the inpatient setting is critical illness, which leads to suppressed adrenal function, resulting in decreased steroid production and disinhibition of eosinophil production.2  There are several multiorgan autoimmune or idiopathic diseases that can cause significant eosinophilia. The autoimmune/idiopathic disorders most commonly associated with eosinophilia are eosinophilic granulomatosis with polyangiitis (EGPA, also known as Churg-Strauss syndrome), Kimura disease, immunoglobulin (Ig)G4–related disease, diffuse fasciitis with eosinophilia, and eosinophilic myositis.3  Diagnosis of these rare autoimmune disorders is challenging and requires assessment of a variety of clinical and laboratory findings, in addition to histopathologic evaluation of affected tissues. However, EGPA is the autoimmune condition that most frequently causes sustained hypereosinophilia. The main features that distinguish EGPA from other causes of HES are prominent asthmatic symptoms, perinuclear antineutrophil cytoplasmic antibodies with antimyeloperoxidase specificity (present in 30%–40% of patients with EGPA), and biopsy-proven eosinophilic vasculitis.4  Single-organ eosinophilic diseases can also cause significant peripheral blood eosinophilia. The organs most frequently involved are the lungs, gastrointestinal tract, and skin.57 

In addition to the nonneoplastic etiologies described above, eosinophilia can be caused by a variety of myeloid, lymphoid, and epithelial neoplasms. Myeloid neoplasms can result in primary eosinophilia because of overproduction of eosinophils from abnormal stem cells. Carcinomas and lymphoproliferative disorders can trigger cytokine production causing secondary eosinophilia. Rare congenital syndromes can also enter into the differential diagnosis of eosinophilia, especially in children, and include hyper-IgE syndrome, Omenn syndrome, and familial eosinophilia.8,9  The differential diagnosis for persistent peripheral blood eosinophilia is summarized in Table 1.

Table 1. 

Differential Diagnosis of Eosinophilia

Differential Diagnosis of Eosinophilia
Differential Diagnosis of Eosinophilia

MYELOID NEOPLASMS WITH EOSINOPHILIA

When a pathologist receives a peripheral blood or bone marrow specimen to evaluate for eosinophilia, the main focus of investigation should be myeloid and lymphoid neoplasia because there is little that can be done to identify specific nonneoplastic causes of eosinophilia in these specimens. The myeloid neoplasms associated with eosinophilia (Table 2) include chronic myelogenous leukemia (CML); genetically defined neoplasms with rearrangements of PDGFRA, PDGFRB, FGFR1, JAK2, and FLT3; chronic eosinophilic leukemia, not otherwise specified (CEL, NOS); and acute myeloid leukemia (AML) with core-binding factor translocations, such as inversion 16 or t(8;21). Although mild eosinophilia is common with core-binding factor AML, hypereosinophilia caused by AML is rare. There are rare cases of eosinophilic myeloproliferative neoplasms associated with JAK2 V617F.1013  The morphologic findings in these cases tend to be nonspecific, such as, hypercellular bone marrow with eosinophilia and mild fibrosis, and testing for JAK2 V617F is necessary to make the diagnosis. The myeloid neoplasms listed so far are associated with primary eosinophilia, meaning that the eosinophils are produced from abnormal myeloid progenitor cells. In contrast, Langerhans cell histiocytosis and systemic mastocytosis (SM) are myeloid neoplasms associated with secondary eosinophilia because the eosinophils appear to be reactive, rather than arising from a neoplastic clone.

Table 2. 

Myeloid Neoplasms With Eosinophilia

Myeloid Neoplasms With Eosinophilia
Myeloid Neoplasms With Eosinophilia

The 2008 World Health Organization classification of tumors of hematopoietic and lymphoid tissues includes the category of myeloid and lymphoid neoplasms with PDGFRA, PDGFRB, or FGFR1 rearrangements.14  The major disease entities within this category are myeloproliferative neoplasm (MPN) with PDGFRA rearrangement, MPN with PDGFRB rearrangement, and the so-called 8p11 myeloproliferative syndrome. The MPN with PDGFRA rearrangement is a much more common cause of eosinophilia than are neoplasms with PDGFRB or FGFR1 rearrangements, and specific testing for this entity is critically important because PDGFRA rearrangements are usually cryptic on routine karyotype. PDGFRA rearrangements are identified in 10% to 20% of patients with HES without an identifiable reactive etiology.15  Myeloproliferative neoplasm with PDGFRA rearrangement shows a marked male predominance of at least 30:1, based on reported case series.13,1623  It affects a broad range of ages with a median age of around 40 years. Initial presentation is usually with cutaneous or pulmonary symptoms. Splenomegaly, mucosal ulcers, and thromboembolic events are also common. The most serious complication is cardiac dysfunction, which occurs in 20% to 30% of patients if not successfully treated. Typical laboratory findings include markedly elevated serum vitamin B12 levels, often greater than 2000 pg/mL, and elevated serum tryptase, approximately 30 ng/mL on average. In contrast to reactive causes of eosinophilia, serum IgE is only elevated in a few patients. Eosinophils in the peripheral blood smear are often morphologically unremarkable, but, in some cases, the eosinophils show significant cytologic atypia, including hypogranulation, microgranulation, coarse basophilic granules, vacuolization, and nuclear hypersegmentation or hyposegmentation (Figure 1, A through D). Bone marrow findings include hypercellularity, increased eosinophils, increased and atypical mast cells, and reticulin fibrosis (Figure 1, E through I). The extent of reticulin fibrosis is highly variable from case to case. PDGFRA rearrangement usually causes a low-grade MPN, but rare cases of AML and T-lymphoblastic lymphoma associated with PDGFRA rearrangement have been reported.24,25  Key features of MPN with PDGFRA rearrangement are summarized in Table 3.

Figure 1.

Myeloproliferative neoplasm with FIP1L1-PDGFRA fusion. A through D, Atypical eosinophils in peripheral blood. Atypical features include hypogranulation, microgranulation, vacuolization (D), nuclear hyposegmentation (A and C), and hypersegmentation (B and D). E, Hypercellular bone marrow core biopsy with increased eosinophils. F, Anti-tryptase immunohistochemical stain highlights increased mast cells, including frequent spindled forms. G, Anti-CD25 immunohistochemical stain shows aberrant staining of mast cells. H, Bone marrow aspirate shows myeloid hyperplasia and a spindled mast cell (arrow). I, Bone marrow core biopsy of a fibrotic myeloproliferative neoplasm with FIP1L1-PDGFRA (Wright-Giemsa, original magnifications ×2000 [A through D] and ×1000 [H]; hematoxylin-eosin, original magnifications ×400 [E] and ×100 [I]; original magnification ×400 [F and G]).

Figure 1.

Myeloproliferative neoplasm with FIP1L1-PDGFRA fusion. A through D, Atypical eosinophils in peripheral blood. Atypical features include hypogranulation, microgranulation, vacuolization (D), nuclear hyposegmentation (A and C), and hypersegmentation (B and D). E, Hypercellular bone marrow core biopsy with increased eosinophils. F, Anti-tryptase immunohistochemical stain highlights increased mast cells, including frequent spindled forms. G, Anti-CD25 immunohistochemical stain shows aberrant staining of mast cells. H, Bone marrow aspirate shows myeloid hyperplasia and a spindled mast cell (arrow). I, Bone marrow core biopsy of a fibrotic myeloproliferative neoplasm with FIP1L1-PDGFRA (Wright-Giemsa, original magnifications ×2000 [A through D] and ×1000 [H]; hematoxylin-eosin, original magnifications ×400 [E] and ×100 [I]; original magnification ×400 [F and G]).

Table 3. 

Myeloproliferative Neoplasm With PDGFRA Rearrangement

Myeloproliferative Neoplasm With PDGFRA Rearrangement
Myeloproliferative Neoplasm With PDGFRA Rearrangement

The bone marrow and peripheral blood findings of MPN with PDGFRA rearrangement share similarities with systemic mastocytosis, and accurate differentiation between these diseases is important because of differences in therapy and the significant risk of cardiac disease associated with MPN with PDGFRA rearrangement.26  A comparison of the features of MPN with PDGFRA rearrangement and systemic mastocytosis with eosinophilia (SM-EO) is presented in Table 4. Usually, MPN with PDGFRA rearrangement can be differentiated from SM-EO based on the presence of PDGFRA rearrangement and the absence of urticaria, dense mast cell aggregates, and KIT D816V mutation. However, microdissection experiments have shown that the atypical mast cells in some cases of MPN with PDGFRA rearrangement harbor KIT D816V mutations, raising the possibility that the 2 diseases share more genetic similarities than previously understood.27  In addition, a case has been reported that met diagnostic criteria for both MPN with PDGFRA rearrangement and SM because of the presence of multiple dense mast cell aggregates in the bone marrow.28  Cases that fully meet the diagnostic criteria for both diseases are probably best classified as SM with an associated hematologic neoplasm, but it is still essential to document the presence of PDGFRA rearrangement because of the implications for therapy (ie, PDGFRA rearrangements are associated with excellent response to imatinib).

Table 4. 

Comparison of Myeloproliferative Neoplasm (MPN) With PDGFRA Rearrangement and Systemic Mastocytosis With Eosinophilia (SM-EO)a

Comparison of Myeloproliferative Neoplasm (MPN) With PDGFRA Rearrangement and Systemic Mastocytosis With Eosinophilia (SM-EO)a
Comparison of Myeloproliferative Neoplasm (MPN) With PDGFRA Rearrangement and Systemic Mastocytosis With Eosinophilia (SM-EO)a

PDGFRA rearrangements can be detected by fluorescence in situ hybridization (FISH) or reverse transcription-polymerase chain reaction. Only a few PDGFRA rearrangements can be detected by routine karyotype. The most common PDGFRA rearrangement is an 800-kb internal deletion in the q12 region of chromosome 4, which causes fusion of the FIP1L1 and PDGFRA genes. Because FIP1L1 and PDGFRA are relatively close together in the wild-type configuration, FISH probes to evaluate FIP1L1-PDGFRA fusions usually include a probe to detect loss of intervening genetic material, typically either the CHIC2 or LNX genes. All the PDGFRA rearrangements associated with MPNs have a breakpoint in exon 12 of PDGFRA, which disrupts an inhibitory domain.15  Regardless of the fusion partner, the PDGFRA rearrangements seem to manifest the same phenotype and show excellent response to imatinib. There are also rare cases of MPN with PDGFRA point mutations without gene rearrangement.29 

The most common PDGFRB rearrangement associated with myeloid neoplasia is t(5;12)(q33;p13); ETV6-PDGFRB, but more than 20 different PDGFRB translocations have been described.25,30,31  Myeloproliferative neoplasm with PDGFRB rearrangement most often presents with a combination of monocytosis and eosinophilia but can also present as AML or with features resembling atypical CML, SM, or primary myelofibrosis. Rare cases of composite MPN and T-lymphoblastic lymphoma with PDGFRB rearrangements have also been described.25  Myeloproliferative neoplasms with PDGFRB rearrangement show excellent response to imatinib.31  The 8p11 myeloproliferative syndrome is caused by FGFR1 translocations, usually t(8;13)(p11;q12); ZMYM2-FGFR1, and typically presents with a mixture of myeloid and lymphoid neoplasia.25,32  The classic presentation is the triad of nodal T-lymphoblastic lymphoma, peripheral blood eosinophilia, and myeloid hyperplasia in the bone marrow. These patients show frequent progression to AML, but acute lymphoblastic leukemia (ALL) or mixed-lineage leukemia can also occur. The neoplasms with FGFR1 rearrangement do not respond to imatinib.

In addition to PDGFRA, PDGFRB, and FGFR1 gene rearrangements, rearrangements of the JAK2 and FLT3 genes have been associated with eosinophilic myeloid neoplasms. The t(8;9)(p22;p24); PCM1-JAK2 fusion causes an MPN that can resemble atypical CML, chronic eosinophilic leukemia, or primary myelofibrosis.3335  It shows male predominance with a broad age range and has a high risk of transformation to AML or Philadelphia-like B-cell ALL (B ALL). Treatment and outcome data for MPN with PCM1-JAK2 fusion are limited, but some patients have responded to treatment with JAK2 inhibitors. The t(12;13)(p13;q12); ETV6-FLT3 fusion also causes an MPN with eosinophilia and high-risk of AML. Only 5 cases have been reported in the literature; of which, 3 presented with concurrent T-cell lymphoma.3639 

If the genetically defined eosinophilic neoplasms have been ruled out, the next consideration is CEL, NOS. The diagnostic criteria are persistent eosinophilia greater than 1500/μL, no definitive features of other myeloid neoplasms, and the presence of either increased blasts (>2% in blood or >5% in bone marrow) or a nonspecific clonal genetic abnormality, such as trisomy 8 or isochromosome band 17q.40  Chronic eosinophilic leukemia, NOS, shows frequent transformation to AML and carries a poor prognosis.41 

LYMPHOID NEOPLASMS WITH SECONDARY EOSINOPHILIA

In the myeloid neoplasms described above, eosinophilia results from overproduction of eosinophils from abnormal myeloid progenitor cells. In contrast, lymphoid neoplasms can cause significant eosinophilia because of cytokine production (Table 5). T-cell neoplasms are most commonly associated with eosinophilia, and significant eosinophilia is most frequently seen in the context of cutaneous T-cell lymphoma, adult T-cell leukemia/lymphoma, and angioimmunoblastic T-cell lymphoma.42  The B-cell neoplasms most significantly associated with eosinophilia are classical Hodgkin lymphoma and B-lymphoblastic leukemia/lymphoma, especially B ALL with t(5;14)(q31;q32); IGH-IL3. This uncommon translocation causes eosinophilia from overproduction of interleukin (IL) 3 by the neoplastic B cells.43  The t(5;14)(q31;q32) translocation associated with B ALL and eosinophilia should not be confused with t(5;14)(q35;q32); TLX3-BCL11, which is associated with T-cell ALL.

Table 5. 

Lymphoid Neoplasms With Secondary Eosinophilia

Lymphoid Neoplasms With Secondary Eosinophilia
Lymphoid Neoplasms With Secondary Eosinophilia

Another important lymphocytic cause of eosinophilia is proliferation of abnormal T helper 2–type T cells, which is known as lymphocyte-variant hypereosinophilic syndrome (Table 6). The name of this disease has caused some confusion because the term lymphocytic HES was used for many years to refer to any etiology of HES associated with increased cytokine production by lymphocytes.44  The current usage of the term lymphocyte-variant hypereosinophilic syndrome (L-HES) refers to an eosinophilic condition caused by a T-cell lymphoproliferative disease characterized by immunophenotypically aberrant and/or clonal T cells. Lymphocyte-variant HES accounts for 10% to 20% of HES without another definitive reactive or neoplastic cause.22,4547  The diagnosis is often challenging because symptoms usually develop gradually and resemble an allergic reaction, and most patients do not have significant lymphadenopathy or lymphocytosis. Patients usually present with an erythematous or papular/nodular pruritic rash. Urticaria, poikiloderma, and episodic angioedema can also occur. Episodic angioedema with eosinophilia is also known as Gleich syndrome, and identification of clonal CD3, CD4+ T cells in most patients with Gleich syndrome suggests that it is probably a subtype of L-HES.48  The abnormal T-cell populations in L-HES produce T helper 2 cytokines, including IL4, IL5, and IL13, and stimulate production of CCL17/TARC (thymus and activation-regulated cytokine); however, testing for production of these cytokines is currently performed using research assays and is not readily available as a clinically validated test.

Table 6. 

Lymphocyte-Variant Hypereosinophilic Syndrome (L-HES)

Lymphocyte-Variant Hypereosinophilic Syndrome (L-HES)
Lymphocyte-Variant Hypereosinophilic Syndrome (L-HES)

Peripheral blood lymphocytes are cytologically unremarkable in most cases of L-HES; however, atypical lymphocytes can be identified on the peripheral blood smear in some cases.49  These cells have moderately abundant cytoplasm, which is lightly basophilic and agranular (Figure 2, A through H). Mild nuclear-contour irregularities may occur, but the classic cerebriform nuclei of Sézary cells are not present. Flow cytometry is the most definitive method for diagnosing L-HES. The classic immunophenotype associated with L-HES is CD4+ T cells with dim-to-negative surface CD3 and CD7 and an abnormally bright CD5 signal (Figure 3, A and B). However, the classic pattern is present in less than half of cases. Other abnormal T-cell immunophenotypes commonly occurring in L-HES include CD3+and CD4+ T cells with loss of CD7 and/or CD2; and CD3+, CD4, CD8, and T-cell antigen receptor (TCR)-AB+ T cells.46  When flow cytometry results are equivocal, identification of a T-cell clone by polymerase chain reaction (PCR) can help support the diagnosis of L-HES. It is controversial whether L-HES can be diagnosed when PCR identifies a T-cell clone, but flow cytometry does not reveal an abnormal population. A recent study identified clonal T-cell populations by PCR in 23% of otherwise typical cases of MPN with PDGFRA rearrangement.23  This finding emphasizes the importance of carefully evaluating all potential causes of eosinophilia rather than assuming that detection of a clonal T-cell population is diagnostic of L-HES.

Figure 2.

Atypical lymphocytes in lymphocyte-variant hypereosinophilic syndrome (L-HES). A through H, Selected lymphocytes from the peripheral blood smear of a patient with L-HES show atypical features, including irregular nuclear contours, occasionally prominent nucleoli, and moderately abundant agranular cytoplasm (Wright-Giemsa, original magnification ×3000).

Figure 2.

Atypical lymphocytes in lymphocyte-variant hypereosinophilic syndrome (L-HES). A through H, Selected lymphocytes from the peripheral blood smear of a patient with L-HES show atypical features, including irregular nuclear contours, occasionally prominent nucleoli, and moderately abundant agranular cytoplasm (Wright-Giemsa, original magnification ×3000).

Figure 3.

Classic immunophenotype of lymphocyte-variant hypereosinophilic syndrome. A, Flow cytometry identifies a population of atypical CD4+ T cells (purple), which are negative for surface CD3. B, The atypical T cells also have abnormally bright anti-CD5 staining. Normal lymphocytes are colored red.

Figure 3.

Classic immunophenotype of lymphocyte-variant hypereosinophilic syndrome. A, Flow cytometry identifies a population of atypical CD4+ T cells (purple), which are negative for surface CD3. B, The atypical T cells also have abnormally bright anti-CD5 staining. Normal lymphocytes are colored red.

Usually, L-HES is a chronic disease and is indolent. It is not considered to be a malignancy, even though immunophenotypic aberrancy and genetic clonality are present in most cases. The symptoms caused by L-HES can be managed with corticosteroids and immunomodulatory agents, and cytotoxic chemotherapy has not proven effective in eliminating the abnormal T-cell clone.46  In reported case series, 10% to 25% of patients eventually developed an overt T-cell lymphoma.45,47,4951  Secondary lymphomas reported in patients with L-HES include angioimmunoblastic T-cell lymphoma; peripheral T-cell lymphoma, not otherwise specified; cutaneous T-cell lymphoma, and ALK anaplastic large cell lymphoma; and these lymphomas mostly arose 3 to 10 years after initial diagnosis of L-HES.45,47,4953  The diagnosis of angioimmunoblastic T-cell lymphoma or anaplastic large cell lymphoma after L-HES is straightforward because these lymphomas have highly specific morphologic and immunohistochemical features. In some cases, the differential diagnosis between L-HES and cutaneous T-cell lymphoma may be difficult because both can present with erythematous skin, eosinophilia, and abnormal T cells in the peripheral blood. However, L-HES presents with a gradual onset of cutaneous symptoms and causes hypereosinophilia much earlier in the course of the disease compared with Sézary syndrome. Widespread erythroderma and classic Sézary cells are not typical of L-HES and should raise suspicion for Sézary syndrome even if the patient has a history of L-HES. Although abnormal T cells can be detected in skin biopsies of patients with L-HES, they usually show a perivascular and dermal pattern of infiltration and do not show significant epidermotropism or other features of mycosis fungoides, such as Pautrier microabscesses or formation of patches, plaques, and tumors.49  A recent series of L-HES cases from the French Eosinophil Network (Lille, France) found that some patients had numerous abnormal, circulating T cells and infiltration of lymph nodes by atypical T cells but remained stable for many years, with only 2 patients progressing to overt lymphoma.49  The published literature does not offer firm conclusions on what degree of lymphadenopathy, cytologic atypia, or peripheral blood involvement defines the border between L-HES and peripheral T-cell lymphoma, not otherwise specified; however, a rapid increase in peripheral blood involvement or lymphadenopathy is strongly suggestive of progression to malignancy. Cytogenetic abnormalities have been detected in a few cases of L-HES.51,52,54  One case with del(6q) and one with t(6;11) subsequently developed peripheral T-cell lymphoma, not otherwise specified51,52 ; however, the predictive value of genetic abnormalities in L-HES has not been established.

DIAGNOSTIC WORKUP OF PERIPHERAL BLOOD AND BONE MARROW

To test for the neoplastic causes of eosinophilia described above, a thorough and consistent approach to the evaluation of peripheral blood and bone marrow is recommended. Peripheral blood testing should include assessment of morphology, flow cytometry, molecular diagnostics, and serum chemistry (Table 7). The morphologic assessment should include looking for blasts, basophilia, and granulocytic left shift, which could indicate AML, ALL, or CML. The eosinophils should be evaluated for cytologic atypia, even though myeloid neoplasms with primary eosinophilia often lack significant atypia. The peripheral blood smear should also be scanned for Sézary cells or other atypical lymphocytes because of the frequent association of secondary eosinophilia with T-cell neoplasms. The main utility of flow cytometry for eosinophilia is detecting abnormal T-cell populations, which is critical for the diagnosis of L-HES. There are currently no clinically validated flow cytometric assays that differentiate reactive and neoplastic eosinophils.

Table 7. 

Peripheral Blood Evaluation for Eosinophilia

Peripheral Blood Evaluation for Eosinophilia
Peripheral Blood Evaluation for Eosinophilia

The most useful molecular diagnostic tests are FISH or PCR for PDGFRA gene rearrangement (including FIP1L1-PDGFRA fusion), PCR for assessment of T-cell clonality, FISH or PCR for BCR-ABL1 fusion, and PCR for JAK2 V617F. Testing for PDGFRA gene rearrangement is especially important because it has critical diagnostic and therapeutic implications and is usually not detected on routine karyotype. Polymerase chain reaction for KIT D816V can be helpful to identify SM with eosinophilia; however, consideration of patient history and clinical findings before testing for KIT D816V is suggested to promote efficient use of this test. Serum chemistry for levels of IgE, tryptase, and vitamin B12 can help narrow the differential diagnosis of eosinophilia.22  Immunoglobulin E is usually elevated in patients with secondary eosinophilia but only rarely in patients who have myeloid neoplasms with primary eosinophilia. Tryptase is significantly elevated in systemic mastocytosis and MPN with PDGFRA rearrangement. Vitamin B12 is usually markedly elevated in patients with MPN with PDGFRA rearrangement and is often elevated in association with other myeloid neoplasms.

Even if the peripheral blood findings are diagnostic of a neoplastic process, bone marrow biopsy is still recommended to assess for findings that could change the diagnosis or prognosis. The key elements are blast count, aberrant mast cells, reticulin fibrosis, and karyotype (Table 8). In rare cases, bone marrow biopsy may reveal an occult metastatic malignancy causing secondary eosinophilia. Cultured bone marrow is usually superior to peripheral blood for cytogenetic analysis, and the bone marrow karyotype is helpful to identify translocations of PDGFRB, JAK2, FGFR1, and FLT3, as well as clonal abnormalities that could establish a diagnosis of CEL, NOS, in the appropriate context.

Table 8. 

Bone Marrow Evaluation For Eosinophilia

Bone Marrow Evaluation For Eosinophilia
Bone Marrow Evaluation For Eosinophilia

References

1
Gotlib
J.
World Health Organization–defined eosinophilic disorders: 2015 update on diagnosis, risk stratification, and management
.
Am J Hematol
.
2015
;
90
(
11
):
1077
1089
.
2
Angelis
M,
Yu
M,
Takanishi
D,
Hasaniya
NW,
Brown
MR.
Eosinophilia as a marker of adrenal insufficiency in the surgical intensive care unit
.
J Am Coll Surg
.
1996
;
183
(
6
):
589
596
.
3
Tamaki
H,
Chatterjee
S,
Langford
CA.
Eosinophilia in rheumatologic/vascular disorders
.
Immunol Allergy Clin North Am
.
2015
;
35
(
3
):
453
476
.
4
Greco
A,
Rizzo
MI,
De Virgilio
A,
et al.
Churg-Strauss syndrome
.
Autoimmun Rev
.
2015
;
14
(
4
):
341
348
.
5
Woolnough
K,
Wardlaw
AJ.
Eosinophilia in pulmonary disorders
.
Immunol Allergy Clin North Am
.
2015
;
35
(
3
):
477
492
.
6
Mehta
P,
Furuta
GT.
Eosinophils in gastrointestinal disorders: eosinophilic gastrointestinal diseases, celiac disease, inflammatory bowel diseases, and parasitic infections
.
Immunol Allergy Clin North Am
.
2015
;
35
(
3
):
413
437
.
7
de Graauw
E,
Beltraminelli
H,
Simon
HU,
Simon
D.
Eosinophilia in dermatologic disorders
.
Immunol Allergy Clin North Am
.
2015
;
35
(
3
):
545
560
.
8
Valent
P,
Klion
AD,
Horny
HP,
et al.
Contemporary consensus proposal on criteria and classification of eosinophilic disorders and related syndromes
.
J Allergy Clin Immunol
.
2012
;
130
(
3
):
607
612
.
9
Curtis
C,
Ogbogu
PU.
Evaluation and differential diagnosis of persistent marked eosinophilia
.
Immunol Allergy Clin North Am
.
2015
;
35
(
3
):
387
402
.
10
Jones
AV,
Kreil
S,
Zoi
K,
et al.
Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders
.
Blood
.
2005
;
106
(
6
):
2162
2168
.
11
Dahabreh
IJ,
Giannouli
S,
Zoi
C,
Zoi
K,
Loukopoulos
D,
Voulgarelis
M.
Hypereosinophilic syndrome: another face of Janus?
Leuk Res
.
2008
;
32
(
9
):
1483
1485
.
12
Helbig
G,
Majewski
M,
Wieczorkiewicz
A,
et al.
Screening for JAK2 V617F point mutation in patients with hypereosinophilic syndrome-in response to “Hypereosinophilic syndrome: another face of Janus?”
by Dahabreh et al published in
Leukemia Research Leuk Res
.
2009
;
33
(
3
):
e1
e2
.
13
Schwaab
J,
Umbach
R,
Metzgeroth
G,
et al.
KIT D816V and JAK2 V617F mutations are seen recurrently in hypereosinophilia of unknown significance
.
Am J Hematol
.
2015
;
90
(
9
):
774
777
.
14
Bain
BJ,
Gilliland
DG,
Horny
H-P,
Vardiman
JW.
Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
.
In
:
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. 4th ed
.
Lyon, France
:
IARC Press;
2008
:
68
73
.
World Health Organization Classification of Tumours; vol 2
.
15
Gotlib
J,
Cools
J.
Five years since the discovery of FIP1L1-PDGFRA: what we have learned about the fusion and other molecularly defined eosinophilias
.
Leukemia
.
2008
;
22
(
11
):
1999
2010
.
16
Cools
J,
DeAngelo
DJ,
Gotlib
J,
et al.
A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome
.
N Engl J Med
.
2003
;
348
(
13
):
1201
1214
.
17
Pardanani
A,
Brockman
SR,
Paternoster
SF,
et al.
FIP1L1-PDGFRA fusion: prevalence and clinicopathologic correlates in 89 consecutive patients with moderate to severe eosinophilia
.
Blood
.
2004
;
104
(
10
):
3038
3045
.
18
Vandenberghe
P,
Wlodarska
I,
Michaux
L,
et al.
Clinical and molecular features of FIP1L1-PDFGRA (+) chronic eosinophilic leukemias
.
Leukemia
.
2004
;
18
(
4
):
734
742
.
19
Roche-Lestienne
C,
Lepers
S,
Soenen-Cornu
V,
et al.
Molecular characterization of the idiopathic hypereosinophilic syndrome (HES) in 35 French patients with normal conventional cytogenetics
.
Leukemia
.
2005
;
19
(
5
):
792
798
.
20
La Starza
R,
Specchia
G,
Cuneo
A,
et al.
The hypereosinophilic syndrome: fluorescence in situ hybridization detects the del(4)(q12)-FIP1L1/PDGFRA but not genomic rearrangements of other tyrosine kinases
.
Haematologica
.
2005
;
90
(
5
):
596
601
.
21
Baccarani
M,
Cilloni
D,
Rondoni
M,
et al.
The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRα-positive hypereosinophilic syndrome: results of a multicenter prospective study
.
Haematologica
.
2007
;
92
(
9
):
1173
1179
.
22
Ogbogu
PU,
Bochner
BS,
Butterfield
JH,
et al.
Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy
.
J Allergy Clin Immunol
.
2009
;
124
(
6
):
1319
1325.e3
.
23
Legrand
F,
Renneville
A,
Macintyre
E,
et al
for the French Eosinophil Network. The spectrum of FIP1L1-PDGFRA-associated chronic eosinophilic leukemia: new insights based on a survey of 44 cases [published online ahead of print August 26, 2013]
.
Medicine (Baltimore)
.
2013
;
92
(
5
):
e1
e9
. doi:
24
Metzgeroth
G,
Walz
C,
Score
J,
et al.
Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma
.
Leukemia
.
2007
;
21
(
6
):
1183
1188
.
25
Vega
F,
Medeiros
LJ,
Bueso-Ramos
CE,
Arboleda
P,
Miranda
RN.
Hematolymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB, and FGFR1
.
Am J Clin Pathol
.
2015
;
144
(
3
):
377
392
.
26
Maric
I,
Robyn
J,
Metcalfe
DD,
et al.
KIT D816V-associated systemic mastocytosis with eosinophilia and FIP1L1/PDGFRA-associated chronic eosinophilic leukemia are distinct entities
.
J Allergy Clin Immunol
.
2007
;
120
(
3
):
680
687
.
27
Schmitt-Graeff
AH,
Erben
P,
Schwaab
J,
et al.
The FIP1L1-PDGFRA fusion gene and the KIT D816V mutation are coexisting in a small subset of myeloid/lymphoid neoplasms with eosinophilia
.
Blood
.
2014
;
123
(
4
):
595
597
.
28
Florian
S,
Esterbauer
H,
Binder
T,
et al.
Systemic mastocytosis (SM) associated with chronic eosinophilic leukemia (SM-CEL): detection of FIP1L1/PDGFRalpha, classification by WHO criteria, and response to therapy with imatinib
.
Leuk Res
.
2006
;
30
(
9
):
1201
1205
.
29
Elling
C,
Erben
P,
Walz
C,
et al.
Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease
.
Blood
.
2011
;
117
(
10
):
2935
2943
.
30
Arefi
M,
Garcia
JL,
Peñarrubia
MJ,
et al.
Incidence and clinical characteristics of myeloproliferative neoplasms displaying a PDGFRB rearrangement
.
Eur J Haematol
.
2012
;
89
(
1
):
37
41
.
31
Cheah
CY,
Burbury
K,
Apperley
JF,
et al.
Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib
.
Blood
.
2014
;
123
(
23
):
3574
3577
.
32
Jackson
CC,
Medeiros
LJ,
Miranda
RN.
8p11 myeloproliferative syndrome: a review
.
Hum Pathol
.
2010
;
41
(
4
):
461
476
.
33
Reiter
A,
Walz
C,
Watmore
A,
et al.
The t(8;9)(p22;p24) is a recurrent abnormality in chronic and acute leukemia that fuses PCM1 to JAK2
.
Cancer Res
.
2005
;
65
(
7
):
2662
2667
.
34
Patterer
V,
Schnittger
S,
Kern
W,
Haferlach
T,
Haferlach
C.
Hematologic malignancies with PCM1-JAK2 gene fusion share characteristics with myeloid and lymphoid neoplasms with eosinophilia and abnormalities of PDGFRA, PDGFRB, and FGFR1
.
Ann Hematol
.
2013
;
92
(
6
):
759
769
.
35
Bain
BJ,
Ahmad
S.
Should myeloid and lymphoid neoplasms with PCM1-JAK2 and other rearrangements of JAK2 be recognized as specific entities?
Br J Haematol
.
2014
;
166
(
6
):
809
817
.
36
Vu
HA,
Xinh
PT,
Masuda
M,
et al.
FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation
.
Leukemia
.
2006
;
20
(
8
):
1414
1421
.
37
Walz
C,
Erben
P,
Ritter
M,
et al.
Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3
.
Blood
.
2011
;
118
(
8
):
2239
2242
.
38
Chonabayashi
K,
Hishizawa
M,
Matsui
M,
et al.
Successful allogeneic stem cell transplantation with long-term remission of ETV6/FLT3-positive myeloid/lymphoid neoplasm with eosinophilia
.
Ann Hematol
.
2014
;
93
(
3
):
535
537
.
39
Falchi
L,
Mehrotra
M,
Newberry
KJ,
et al.
ETV6-FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant
.
Leukemia
.
2014
;
28
(
10
):
2090
2092
.
40
Bain
BJ,
Gilliland
DG,
Horny
H-P,
Vardiman
JW.
Chronic eosinophilic leukaemia, not otherwise specified
.
In
:
Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of the Haematopoietic and Lymphoid Tissues. 4th ed
.
Lyon, France
:
IARC Press;
2008
:
51
53
.
World Health Organization Classification of Tumours; vol 2
.
41
Helbig
G,
Soja
A,
Bartkowska-Chrobok
A,
Kyrcz-Krzemien
S.
Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation
.
Am J Hematol
.
2012
;
87
(
6
):
643
645
.
42
Roufosse
F,
Garaud
S,
de Leval
L.
Lymphoproliferative disorders associated with hypereosinophilia
.
Semin Hematol
.
2012
;
49
(
2
):
138
148
.
43
Meeker
TC,
Hardy
D,
Willman
C,
Hogan
T,
Abrams
J.
Activation of the interleukin-3 gene by chromosome translocation in acute lymphocytic leukemia with eosinophilia
.
Blood
.
1990
;
76
(
2
):
285
289
.
44
Simon
HU,
Rothenberg
ME,
Bochner
BS,
et al.
Refining the definition of hypereosinophilic syndrome
.
J Allergy Clin Immunol
.
2010
;
126
(
1
):
45
49
.
45
Simon
HU,
Plotz
SG,
Dummer
R,
Blaser
K.
Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia
.
N Engl J Med
.
1999
;
341
(
15
):
1112
1120
.
46
Roufosse
F,
Cogan
E,
Goldman
M.
Lymphocytic variant hypereosinophilic syndromes
.
Immunol Allergy Clin North Am
.
2007
;
27
(
3
):
389
413
.
47
Vaklavas
C,
Tefferi
A,
Butterfield
J,
et al.
‘Idiopathic' eosinophilia with an occult T-cell clone: prevalence and clinical course
.
Leuk Res
.
2007
;
31
(
5
):
691
694
.
48
Khoury
P,
Herold
J,
Alpaugh
A,
et al.
Episodic angioedema with eosinophilia (Gleich syndrome) is a multilineage cell cycling disorder
.
Haematologica
.
2015
;
100
(
3
):
300
307
.
49
Lefevre
G,
Copin
MC,
Roumier
C,
et al
for the French Eosinophil Network. CD3−CD4+ lymphoid variant of hypereosinophilic syndrome: nodal and extranodal histopathological and immunophenotypic features of a peripheral indolent clonal T-cell lymphoproliferative disorder
.
Haematologica
.
2015
;
100
(
8
):
1086
1095
.
50
Roufosse
F,
Schandené
L,
Sibille
C,
et al.
Clonal Th2 lymphocytes in patients with the idiopathic hypereosinophilic syndrome
.
Br J Haematol
.
2000
;
109
(
3
):
540
548
.
51
Helbig
G,
Wieczorkiewicz
A,
Dziaczkowska-Suszek
J,
Majewski
M,
Kyrcz-Krzemien
S.
T-cell abnormalities are present at high frequencies in patients with hypereosinophilic syndrome
.
Haematologica
.
2009
;
94
(
9
):
1236
1241
.
52
Ravoet
M,
Sibille
C,
Roufosse
F,
et al.
6q− is an early and persistent chromosomal aberration in CD3−CD4+ T-cell clones associated with the lymphocytic variant of hypereosinophilic syndrome
.
Haematologica
.
2005
;
90
(
6
):
753
765
.
53
Roufosse
F,
de Leval
L,
van Krieken
H,
van Deuren
M.
Lymphocytic variant hypereosinophilic syndrome progressing to angioimmunoblastic T-cell lymphoma
.
Leuk Lymphoma
.
2015
;
56
(
6
):
1891
1894
.
54
Roumier
AS,
Grardel
N,
Laï
JL,
et al.
Hypereosinophilia with abnormal T cells, trisomy 7 and elevated TARC serum level
.
Haematologica
.
2003
;
88
(
7
):
e104
e107
.

Competing Interests

Presented in part at the New Frontiers in Pathology; October 22–24, 2015; Ann Arbor, Michigan.

Author notes

The author has no relevant financial interest in the products or companies described in this article.