Myeloid/Lymphoid Neoplasms with Eosinophilia and Gene Rearrangement Flashcards
What is a common feature
of these neoplasms ?
- they all result from a fusion gene or rarely from a mutation
- leads to the formation of an aberrant tyrosine kinase
- eosinophlia is characteristic but only to variable degrees
How do PDGFRA disorders
often present ?
- usually chronic eosinophilic leukemia with variable involvement of the mast cells
- sometimes the neutrophil lineage is affected
- less often
- AML
- T-ALL
- uncommon
- B-ALL
How do PDGFRB disorders
often present ?
- features of the MPN are more variable but are often those of CMML with eosinophilia
- generally have a proliferation of mast cells
- transformation
- usually myeloid
- rare reports of T-ALL
FGFR1 related diseases
often present how ?
- lymphomatous presentations are common, especially T-ALL with accompanying eosinophilia
- other presentations
- CEL
- B-ALL
- AML
Why is it important to recognize
these disorders?
- because they may be responsive to tyrosine kinase inhibitors
- PDGFRA and PDGFRB (imatinib)
- JAK2-PCM1 (ruxolitinib)
Note: no specific therapy has yet to be defined for FGFR1- related diseases
What type of analysis needs to be
performed on most PDGFRA related diseases
and why?
- must be analyzed by molecular
- Most cases result from a cryptic deletion
cytogenetics can be done for cases with PDGFRB, FGFR1 or JAK2
What is the definition of myeloid/lymphoid
neoplasms with PDGFRA rearrangement ?
- the most common MPN has the FIP1L1-PDGFRA gene fusion
- often cause by a cryptic deletion at 4q12
- present as CEL most often
- other presentations:
- AML
- T-ALL
- or both simultaneously
- acute transformation can occur with CEL
IMP: there are many variants of gene partners with PDGFRA
What is the clinical presentation ?
- organ damage occurs as a result of leukemic infiltration with damage caused by cytokines
- mast cells may also be infiltrative
- peripheral blood eosinophilia is marked
- < 20% blasts
- no BCR-ABL1 fusion
What is the epidemiology of
the FIP1L1-PDGFRA ?
- rare syndrome
- more common in men (17:1)
- median age of involvement is late 40s
What is the etiology of
FIPIL1-PDGFRA disorders ?
- cause is unknown but some have recurred following cytotoxic chemotherapy
What is the localization of
CEL (FIPIL1-PDGFRA) ?
- multisystem disorder (PB, BM, and other tissues)
- release of cytokines and other humoral factors
What are the clinical features
of FIPIL1-PDGFRA disorders ?
- usually present with fatigue, pruritus, respiratory or cardiac failure
- due to fibrosis
- rarely patients are asymptomatic
- serum tryptase can be elevated (>12 ng/mL)
- usually lower than mast cell disease but there is some overlap
- markedly elevated serum vitamin B12
**very sensitive to Imatinib (100x more than CML)
What are the microscopic findings
for FIPIL1-PDGFRA ?
- most striking feature is peripheral blood eosinophilia
- most are mature with some left shift
- other morphologic features including bizarre forms are similar to CEL
- but alone don’t mean anything because can see these features in reactive conditions as well
- Neutrophils can be increased but basophils and monocytes are not
- can have anemia and thrombocytopenia
- can see necrosis is the bone marrow when the disease is becoming more acute
What is a recognized feature of
FIPIL1-PDGFRA disorders?
- mast cell proliferation
- can be scattered or form clusters
- can have increased/spindle shaped mast cells
- may mimic mastocytosis
- reticulin is increased
What is the immunophenotype
of FIPIL1-PDGFRA ?
- eosinophils can show evidence of activation, including expression of CD23, CD25, and CD69
- the mast cells may show atypical expression as well including
- positive for CD25 and CD2
- also can have no abnormal IHC expression
What is the genetic profile
of FIPIL1-PDGFRA ?
- cytogenetics are usually normal unless there is evolution to a leukemia
- cryptic del4(q12)
- can be detected with RT-PCR
- or the CHIC2 probe (the gene that is deleted)
- OR you could do a break apart probe
- some have chromosomal gene rearrangements
- unrelated chromsome abnormalities (trisomy 8) likely mean clonal evolution
What are the prognostic and
predictive factors ?
- long-term prognosis still unknown but response to imatinib seems good
- particularly favorable if there is no cardiac damage
- Imatinib resistance
- T674I can occur
- can achieve molecular remission with imatinib even when presenting with leukemia
What is the definition of myeloid/
lymphoid neoplasms with PDGFRB rearrangement ?
- it is a rearrangement at 5q32 PDGFRB
- usually t(5;12) ETV6-PDGFRB
- other, less common variants do exist
- but fusions often seen in BCR-ABL1 like B-ALL are excluded from this category (p. 75 list)
- please note:
- there are a number of variants of molecular translocations
- t(5;12) causes synthesis of an aberrant, constituitively activated tyrosine kinase
What is the presentation of cases of
ETV6-PDGFRB MPNs?
- usually: CMML with eosinophilia
- other presentations
- atypical CML BCR-ABL1 negative with eos
- CEL
- MPN with eosinophilia
- acute transformation can occur in a relatively short amount of time
- cases are sensitive to Imatinib
What is necessary for diagnosis
of PDGFRB MPNs ?
- there are many variants with complex rearrangements
- PDGFRB can have many partner genes
- need a break apart probe to identify
- if not identified by breakapart probe analysis then no need to do molecular for this
What is the epidemiology
of PDGFRB MPNs ?
- more common in men than women
- 2:1
- peak incidence in middle age but there is a wide age range
What is the localization of the
MPNs associated with t(5;12) ?
- multisystem disorder
- peripheral blood and bone marrow are always involved
- spleen is enlarged in most cases
- tissue infiltration with eosinophils
What are the clinical findings of
PDGFRB MPNs ?
- most patients have splenomegaly
- some with hepatomegaly
- some have skin infiltration and cardiac damage
- Imatinib can successfully treat
What are the microscopic features of
PDGFRB MPNs ?
- WBC is increased
- variable increase in neutrophils, eosinophils, monocytes and neutrophil precursors
- basophils markedly increased in rare cases
- anemia and thrombocytopenia may be present
- bone marrow is hypercellular
- mostly due to granulopoiesis
- may have an increase in mast cells
- may have expression of CD2 and CD25
- reticulin may also be increased
- blasts <20%
What is the postulated cell
of origin in PDGFRB cases ?
- pleuripotent stem cell that can give rise to many different cell types including B cell lineage lymphoblasts in some cases
What is the genetic profile of
PDGFRB myeloid and lymphoid neoplasms ?
- usually see by cytogenetic analysis
- t(5;12) ETV6-PDGFRB gene fusion
- previously called TEL-PDGFRB
IMP: not all translocations characterized by t(5;12) lead to ETV6-PDGFRB
- cases without this fusion are NOT assigned to this category and likely will NOT respond to Imatinib
- may be due to increased IL-3
- can do RT-PCR for confirmation of ETV6-PDGFRB ONLY if breakapart shows the presence of translocation (many gene partners)
What are the prognostic and predictive
factors for PDGFRB myeloid/lymphoid neoplasms ?
- Imatinib as greatly improved survival
- median 65 months
- important to start therapy prior to cardiac damage
What is the definition of
myeloid/lymphoid neoplasms with FGFR1 rearrangement ?
- very heterogeneous group derived from a pluripotent stem cell
- in different patients at different stages neoplastic cells can be precursor cells or mature cells
- can present as:
- MPNs in transformation
- AML
- T or B-ALL
- Mixed phenotype AML
- atypical CML
- mastocytosis with another neoplasm
What is the epidemiology of
FGFR1 rearranged neoplasms ?
- generally presents in younger patients
- median age ~30
- moderate to small male predominance
What is the tissue localization of
FGFR1 rearranged cases ?
- primarily involves the bone marrow, PB
- LN
- lymphadenopathy mostly occurs due to infiltration by lymphoblasts or myeloid cells
- liver
- spleen
What are the clinical features of
FGFR1- rearranged neoplasms ?
- some cases present as lymphoma others with features of an MPN or AML or myeloid sarcoma
- systemic symptoms often present
- fever
- weight loss
- night sweats
What are the microscopic features
of FGFR1 rearranged neoplasms ?
- variable presentations (read p. 78)
- if presenting in chronic phase
- usually have eosinophilia and neutrophilia with occasional monocytosis
- >90% of patients have peripheral blood or BM eosinophilia
- KEY: eosinophils belong to neoplastic clone as do the myeloblasts
- basophilia is uncommon except in BCR-FGFR1 fusion
IMP: cases with t(8;13) present with lymphoblastic lymphoma!
What is the genetic profile of
FGFR1 rearranged neoplasms ?
- variety of translocations with an 8p11 breakpoint can underlie the syndrome
- secondary cytogenetics can occur
- mostly trisomy 21
- all fusions with FGFR1 encode a tyrosine kinase
What are the prognostic and predictive
factors for FGFR1 rearranged neoplasms ?
- high rates of transformation in these cases lead to a poor prognosis for patients presenting in the chronic phase
- no established treatment
- Midostaurin has show to be effective in one case
- Interferon has induced cytogenetic responses in a few cases
IMP: if presenting in chronic phase….should do stem cell transplant since no effective therapy
What is the definition of myeloid/lymphoid
neoplasms with PCM1-JAK2 ?
- they have unifying characteristics and present as MPNs or MPN/MDS overlap syndromes
- there is t(8;9) or PCM1-JAK2 fusion
- these cases can have acute transformation
- usually myeloid
- reports of B-ALL
- also reports of T-ALL
What gene fusion can be considered
a variant of PCM1-JAK2 neoplasms ?
- t(9;12) ETV6-JAK2
- tends to be even more heterogeneous than PCM1-JAK2
- B and T-ALL have been more common
- myeloid neoplasms also have been reported
- eosinophilia has NOT been commonly observed
What is the epidemiology of PCM1-JAK2
neoplasms ?
- marked male predominance (27:1)
- wide age range, but again median age is 47 years
What are the localization and the
clinical features of PCM1-JAK2 ?
- peripheral blood and bone marrow are involved
- patients often have hepatosplenomegaly
What are the microscopic features of
PCM1-JAK2 neoplasms ?
- PB
- eosinophilia and neutrophil precursors are present
- monocytosis is uncommon
- basophils may rarely be increased
- Dyserythropoiesis and dysgranulopoiesis can be seen
- Increased erythropoiesis
- sheets of erythroblasts can be seen
What is the postulated cell
of origin fo PCM1-JAK2 neoplasms ?
- pluripotent stem cell
What are the genetics of
PCM1-JAK2 neoplasms ?
- t(8;9) PCM1-JAK2 (dominant type)
- other types of fusions seen:
- t(9;12) ETV6-JAK2
- t(9;22) BCR-JAK2
- some of these cases are BCR-ABL like B-ALL and are better categorized as such
What are the prognostic and predictive
factors seen in PCM1-JAK2 neoplasms?
- survival is highly variable for patients presenting in chronic phase
- days to years
