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 by the following features:

• initially a permanent proliferation of clonal eosinophil granulocytes in the peripheral blood
• a hypercellular bone marrow
• possibly splenomegaly (Valent Pet al. 2012)

Morphologically, the assessment of qualitative and quantitative changes in the non-eosinophilic series (megakaryocytes, monocytes, mast cells, blasts) and bone marrow fibrosis is important. 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 by means of molecular genetic examinations. The causative genetic aberrations are characterized by a varying risk of progression into a myeloid or lymphatic blast phase (with a correspondingly unfavourable 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 detected.

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 a reactive, non-clonal 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 can remain symptom-free for a long time. However, non-specific general symptoms such as fatigue, night sweats, weight loss and splenomegaly can also contribute to the picture. Eosinophilia-related organ manifestations occur in clonal eosinophilia with an incidence of approx. 10%. Other significant complications are thromboembolisms (arterial, cardiac, venous). It is diagnostically important that the monotopic infestation of various organs (lungs, intestines, skin) can be diagnosed. Monotopic involvement of various organs (lungs, intestines, skin) is almost never associated with clonal eosinophilia.

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

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

Lungs: Pulmonary involvement must be considered 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 paroxysmal or persistent itching and urticarial manifestations. Furthermore, reactive histoeosinophilia occurs 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 long-term hematoeosinophilia.

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

Lymph nodes: Eosinophilic lymphadenopathy - This eosinophilic manifestation requires urgent clarification. A lymphoma (eosinophilia clonal or reactive!) or a systemic mastocytosis (especially retroperitoneal lymph nodes) should be clarified and ruled out.

• Blood count with persistent eosinophilia
• Leukocytosis with/without left shift
• Clonal eosinophilia: tryptase elevated (typical for TC fusion genes, usually < 100µg/l, > 100µg/l quite certain 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 vitamin B12 in serum and tissue, non-specific in all MPN)
• BM histology: assessment of the non-eosinophilic cell series! Cellularity, dysplasia, megakaryocytes, monocytes, mast cells, blasts and fibrosis determine the 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
• In case of suspected lung involvement or multi-organ involvement: endoscopy/BAL/histology, gastro/colonoscopy); neurology (PNP, MRI); skin (skin biopsy)

Sonography, echocardiography; CT, MRI; cardio-MRI

Reactive (non-clonal) eosinophilia

Remark: The most important differential diagnostic task is the separation between clonal and reactive eosinophilia. Within clonal eosinophilia there are important distinctions between chronic myeloid neoplasms in chronic or blast phase and acute, mostly myeloid leukemias.

The differential diagnosis of reactive eosinophilia with its many causes is difficult. The most important diagnosis appears to be eosinophilia-associated autoimmune disease, with eosinophilic granulomatosis with polyangiitis (EGPA).

Systemic mastocytosis (tryptase, CD117, CD25) must also be differentiated.

The prognosis of clonal eosinophilia depends on the subtype, the genetic aberration and the stage of the disease. Patients with PDGFRA / -B fusion genes have the best prognosis, regardless of the stage of the disease. Due to the high rates of primary and secondary blast phases, the prognosis is significantly worse when FGFR1 fusion genes are detected. The long-term survival of patients with CEL-NOS is short at 1-2 years due to the limited treatment options and the usually rapid progression into a blast phase. In all other myeloid neoplasms with eosinophilia, prognostically unfavorable somatic mutations can often be 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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