Eosinophil and Mast Cell Disorders

Question 1

Discuss the diagnosis of myeloid/ lymphoid neoplasms with PDGFRA rearrangement

Answer 1

• Most common rearrangement= FIP1L1- PDGFRA rearrangement: cytogenetically cryptic deletion at 4q that can be detected on FISH or RT PCR (nested)
• Chronic phase typically manifested by a chronic eosinophilic leukaemia
• Can also present or transform into AML, ALL
• Usually present with eosinophilia, may have abnormal eosinophils
• Granulocytic dysplasia may be present and blasts may be increased
• Mast cells are often increased and may have similar features to SM

Question 2

Discuss the diagnosis of myeloid/ lymphoid neoplasms with PDGFRB rearrangement

Answer 2

• Most common rearrangement= ETV6-PDGFRB rearrangement: translocation with a 5q breakpoint usually evident on cytogenetics, confirmed with FISH
• Specific PDGFRB translocations involving partner genes associated with Ph like ALL are excluded from this category
• Chronic phase typically manifested by CMML with eosinophilia
• Generally transforms into AML
• Mast cells may be increased and spindle shaped. Usually express CD2 and CD25 as in mast cell disease

Question 3

Discuss the diagnosis of myeloid/ lymphoid neoplasms with FGFR1 rearrangement

Answer 3

• Clinically heterogenous. In different stages of the disease the neoplastic cells may be precursor or mature.
• A variety of translocations with an 8p11 breakpoint can underlie this syndrome.
• Cases can present as a myeloproliferative/ dysplastic neoplasm in the chronic phase or as AML, acute lymphoblastic leukaemia/ lymphoma or mixed phenotypic leukaemia in the acute phase.
• Poor prognosis

Question 4

What are the bone marrow features of neoplasms with PCM1-JAK2

Answer 4

• Eosinophilia
  Increased erythropoiesis with prominent dyserythropoiesis. Sheets of proerythroblasts, as seen in acute leukaemia, may be present.
• Dysgranulopoiesis and myelofibrosis may be present.

Question 5

What is the major criteria for a diagnosis of systemic mastocytosis?

Answer 5

• Multifocal dense infiltrates of mast cells (≥15 mast cells in aggregates) detected in sections of bone marrow and/or other extracutaneous organs.

Question 6

What are the minor criteria for a diagnosis of systemic mastocytosis?

Answer 6

• > 25% of mast cells in the aspirate smears have immature, spindle shaped or atypical morphology
• Activating mutation in KIT at codon 816
• Aberrant expression of CD2 and/or 25
• Serum tryptase >20 (unless there is an associated myeloid neoplasm)

Question 7

What are the B findings in systemic mastocytosis?

Answer 7

Burden of disease

• High mast cell burden: >30% infiltration of cellularity by mast cells and serum tryptase >200ng/ml
• Signs of dysplasia or myeloproliferation in non-mast cell lineages that does not meet criteria for an associated haematological neoplasm
• Hepatomegaly without impairment of liver function, splenomegaly without hypersplenism or lymphadenopathy

Question 8

What are the C findings in systemic mastocytosis?

Answer 8

Cytoreduction requiring

• Cytopenia due to mast cell infiltration (Hb <100, ANC <1, Plts <100)
• Hepatomegaly with impaired liver function, portal HTN or ascites
• Skeletal involvement: osteolytic lesions +/- pathological fractures
• Splenomegaly with hypersplenism
• Malabsorption with weight loss due to GI involvement

Question 9

What are the different subgroups of systemic mastocytosis?

Answer 9

1) Indolent mastocytosis:
- ≤1 B finding no C findings
- Skin lesions almost invariably present.

2) Bone marrow mastocytosis: as above but with bone marrow involvement only, no skin lesions.

3) Smouldering mastocytosis:
- ≥2B findings, no C findings

4) Systemic mastocytosis with an associated haematological malignancy: meets WHO criteria for a myeloid (usually) or lymphoid neoplasm.

5) Aggressive systemic mastocytosis:
- ≥1 C finding

6) Mast cell leukaemia: diffuse bone marrow infiltration by atypical, immature cells, ≥20% mast cells on aspirate smears
- In classic cases mast cells account for ≥10% of peripheral white blood cells (the aleukaemic variant, with mast cells <10% is actually more common)

Question 10

What cytological and immunohistochemical stains can be used to identify mast cells in systemic mastocytosis

Answer 10

Mast cell tryptase, toluidine blue

CD2, CD25, CD68, CD117;

Question 11

What mutations is found in systemic mastocytosis?

Answer 11

KIT D816V mutations in 90%