Myeloid neoplasms with eosinophilia D72.1, C47.5

Myeloid neoplasms with eosinophilia are a clinically, morphologically, genetically, and prognostically heterogeneous group of clonal diseases characterized as follows:

• Initially, a persistent proliferation of clonal eosinophilic granulocytes in the peripheral blood.
• a hypercellular bone marrow
• if necessary, splenomegaly (Valent Pet al. 2012).

In morphology, the assessment of qualitative and quantitative changes in the non-eosinophil series (megakaryocytes, monocytes, mast cells, blasts) and bone marrow fibrosis is significant. By means of molecular genetic investigations, cytogenetic aberrations (e.g. reciprocal translocation, deletion, inversion, trisomy, complex karyotype), rearrangements of genes (FISH analysis), fusion genes (FISH analysis, RT-PCR) or mutations (allele-specific PCR, NGS) are included in the diagnosis. The causative genetic aberrations are characterized by a variable risk of progression to a myeloid or lymphoid blast phase (with a corresponding unfavorable prognosis).

Note: In the presence of significant and persistent eosinophilia in the peripheral blood, hypercellular bone marrow and splenomegaly, the umbrella term "myeloid neoplasia with eosinophilia" is initially used until a morphologically or molecularly clearly defined entity is demonstrated.

WHO defines two groups of entities (Swerdlow SH et al (2016):

The "myeloid/lymphoid neoplasia with eosinophilia (+ rearrangement of PDGFRA, PDGFRB , FGFR1 or PCM1-JAK2 fusion gene").

• Myeloid neoplasia with eosinophilia (MLN-Eo) with rearrangement of FIP1L1-PDGFRA
• Myeloid neoplasia with eosinophilia (MLN-Eo) with rearrangement of PDGFRB
• Myeloid neoplasia with eosinophilia (MLN-Eo) with rearrangement of FGFR1
• Myeloid neoplasia with eosinophilia (MLN-Eo) with rearrangement of JAK2
• Myeloid neoplasia with eosinophilia (MLN-Eo) with rearrangement of ETV6-ABL1
• Myeloid neoplasia with eosinophilia (MLN-Eo) with rearrangement of ETV6-FLT3 and other FLT3 fusion genes

Chronic eosinophilic leukemia (CEL)'not otherwise specified' (CEL, NOS). CEL, NOS' is diagnosed when cytogenetics (e.g. deletion, trisomy, monosomy, complex karyotype) or molecular genetics (e.g. mutation by allele-specific PCR or NGS) reveal a clonal marker or a proliferation of blasts.

Primary, neoplastic (clonal) eosinophilia can be detected in 5-20% of patients with persistent eosinophilia (Jovanovic JV et al. 2007; Pardanani A et al. 2004). However, the vast majority of patients with eosinophilia have reactive, nonclonal eosinophilia.

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The diagnosis of a primary, neoplastic eosinophilia is confirmed by the detection of causative genetic aberrations that fulfill the criteria of a myeloid neoplasia. For clonal eosinophilia, fusion genes involving tyrosine kinases and various mutations are pathogenetically significant. Mutations are pathogenetically significant. In case of persistent unclear eosinophil proliferation, especially in connection with splenomegaly, leukocytosis or a thromboembolic event, clonality should always be clarified.

Reactive, non-clonal eosinophilia occur, for example, in allergies, autoimmune diseases or reactive in neoplasms (e.g. lymphomas, carcinomas, sarcomas or rarely in melanomas).

Complicating both pathogenetic groups (reactive group, primary neoplastic group), hypereosinophilia syndromemay occur. The hypereosinophilia syndrome is a (non-specific) multi-etiological constellation, a multisystem involvement caused by eosinophils. Clinical features are persistent eosinophilia + organ damage caused by eosinophil infiltration.

Patients with clonal eosinophilia may remain symptom-free for a long time. However, non-specific general symptoms such as fatigue, night sweats, weight loss and splenomegaly may also be present. Eosinophilia-related organ manifestations occur in clonal eosinophilia with an incidence of about 10%. Further significant complications are thromboembolism (arterial, cardiac, venous). It is diagnostically important that the monotopic infestation of various organs (lungs, intestines, veins) is not a rare occurrence. The monotopic involvement of various organs (lung, intestine, skin) is almost never associated with clonal eosinophilia.

An important clinical and diagnostic criterion for a reactive esoinophilia is a good response to corticosteroids. Furthermore, the more organs involved, the more likely reactive eosinophilia.

The following organs are involved in eosinophilia - associated myeloproliferative disorders:

Lung: Pulmonary involvement should be considered differentially from a diagnostic (eosinophilic granulomatosis with polyangiitis) and therapeutic (use of corticosteroids) point of view (e.g. bronchial asthma, eosinophilic pulmonary infiltrates, pleural effusion, pulmonary fibrosis). Cave: Bronchial asthma and polyneuropathy are important diagnostic criteria for eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome).

Skin: Eosinophilic skin lesions(hypereosinophilic dermatitis) are characterized by seizure-like or persistent pruritus and urticarial manifestations. Furthermore, reactive histoeosinophils occur in a variety of dermatological skin conditions (see there).

Spleen: Splenomegaly: Isolated splenomegaly is typical of clonal eosinophilia. It is not observed in reactive eosinophilia.

Heart: Endocarditis/myocarditis/myocardial fibrosis are signs of cardiac involvement in prolonged hematoeosinophilia.

Gastrointestinal: Eosinophilic esophagitis, gastritis and colitis. Note: Eosinophilic colitis is the most common misdiagnosis of intestinal infiltration in systemic mastocytosis (mast cells are not seen on conventional staining).

Lymph nodes: Eosinophilic lymphadenopathy. This eosinophilic manifestation is in urgent need of clarification. A lymphoma (eosinophilia clonal or reactive!) or a systemic mastocytosis (especially retroperitoneal lymph nodes) must be clarified and excluded.

• Blood count with persistent eosinophilia
• Leukocytosis with/without left shift
• Clonal eosinophilia: tryptase elevated (typical for TK fusion genes, usually <100µg/l, >100µg/l pretty sure SM)
• LDH elevated (cell turnover, clonal and reactive)
• AP elevated (typical for systemic mastocytosis)
• IgE elevated (myeloid neoplasia rather unlikely)
• Autoantibodies (myeloid neoplasia rather unlikely)
• Vitamin B12 elevated (increased formation of haptocorrin, which binds Vit. B12 in serum and tissue, non-specific in all MPN)
• KM histology: assessment of non-eosinophil cell series! Cellularity, dysplasia, megakaryocytes, monocytes, mast cells, blasts, fibrosis decide the question of clonality of eosinophilia.
• Genetics: RT-PCR or FISH analysis.
• T cell clonality (aberrant T cells by FACS analysis, T cell receptor rearrangement by PCR).
• Technical examinations: sonography, echocardiography; CT, MRI; cardio-MRI.
• If lung involvement or multi-organ involvement is suspected: endoscopy/BAL/histology, gastro/colonoscopy); neurology (PNP, MRI); skin (skin biopsy).

Sonography, echocardiography; CT, MRI; cardio-MRI

Reactive (non-clonal) eosinophilia Comment: The most important differential diagnostic task is the separation between clonal and reactive eosinophilia. Within clonal eosinophilia, there are important distinctions between chronic phase or blast phase myeloid neoplasms and acute, usually myeloid leukemias.

The differential diagnostic differentiation within reactive eosinophilia with its multitude of causes is difficult. Most important seems to be the diagnosis of eosinophilia-associated autoimmune disease, with eosinophilic granulomatosis with polyangiitis (EGPA).

Furthermore, systemic mastocytosis (tryptase, CD117, CD25) has to be differentiated.

The prognosis of clonal eosinophilia depends on the subtype, genetic aberration and stage of disease. Patients with PDGFRA / -B fusion genes have the best prognosis, regardless of disease stage. Significantly worse, due to high rates of primary and secondary blast stages, is the prognosis when FGFR1 fusion genes are detected. Long-term survival of patients with CEL-NOS is short, 1-2 years, due to limited treatment options and mostly rapid progression to a blast phase. In all other myeloid neoplasms with eosinophilia, prognostically negative somatic mutations are frequently detected.

Molecular diagnostics have provided significant advantages in deciphering the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases arising from dysregulated fusion tyrosine kinase (TK) genes is categorized by the World Health Organization (WHO) as "Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2."

In addition to myeloproliferative neoplasms (MPN), these patients may also present with myelodysplastic syndrome/MPN and de novo or secondary leukemias or lymphomas with a mixed phenotype.

Eosinophilia is a common but not invariant feature of these diseases. The natural history of neoplasms with PDGFRA and PDGFRB arrangement has been dramatically altered by imatinib.

In contrast, patients with FGFR1 and JAK2 fusion TK genes have a more aggressive course and variable sensitivity to current tyrosine kinase inhibitors, and in most cases long-term disease-free survival can only be achieved by allogeneic hematopoietic stem cell transplantation.

Similarly poor prognoses can be observed in FLT3 or ABL1 rearrangements (both of which are frequently associated with ETV6), and further investigation is required to confirm their inclusion in the group of eosinophilia-associated TK fusion neoplasms currently defined by WHO.

The diagnosis of chronic eosinophilic leukemia not otherwise specified (CEL, NOS) is assigned to patients with myeloproliferative neoplasms (MPN) with eosinophilia and nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts.

Myeloid mutation panels have identified somatic variants in patients with a provisional diagnosis of hypereosinophilia of undetermined significance and reclassified some of these cases as eosinophilia-associated neoplasms.

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