Myeloid/Lymphoid Neoplasms with Eosinophilia and Gene Rearrangement Flashcards
(42 cards)
1
Q
What is a common feature
of these neoplasms ?
A
- 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
2
Q
How do PDGFRA disorders
often present ?
A
- 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
3
Q
How do PDGFRB disorders
often present ?
A
- 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
4
Q
FGFR1 related diseases
often present how ?
A
- lymphomatous presentations are common, especially T-ALL with accompanying eosinophilia
- other presentations
- CEL
- B-ALL
- AML
5
Q
Why is it important to recognize
these disorders?
A
- 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
6
Q
What type of analysis needs to be
performed on most PDGFRA related diseases
and why?
A
- must be analyzed by molecular
- Most cases result from a cryptic deletion
cytogenetics can be done for cases with PDGFRB, FGFR1 or JAK2
7
Q
What is the definition of myeloid/lymphoid
neoplasms with PDGFRA rearrangement ?
A
- 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
8
Q
What is the clinical presentation ?
A
- 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
9
Q
What is the epidemiology of
the FIP1L1-PDGFRA ?
A
- rare syndrome
- more common in men (17:1)
- median age of involvement is late 40s
10
Q
What is the etiology of
FIPIL1-PDGFRA disorders ?
A
- cause is unknown but some have recurred following cytotoxic chemotherapy
11
Q
What is the localization of
CEL (FIPIL1-PDGFRA) ?
A
- multisystem disorder (PB, BM, and other tissues)
- release of cytokines and other humoral factors
12
Q
What are the clinical features
of FIPIL1-PDGFRA disorders ?
A
- 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)
13
Q
What are the microscopic findings
for FIPIL1-PDGFRA ?
A
- 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
14
Q
What is a recognized feature of
FIPIL1-PDGFRA disorders?
A
- mast cell proliferation
- can be scattered or form clusters
- can have increased/spindle shaped mast cells
- may mimic mastocytosis
- reticulin is increased
15
Q
What is the immunophenotype
of FIPIL1-PDGFRA ?
A
- 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
16
Q
What is the genetic profile
of FIPIL1-PDGFRA ?
A
- 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
17
Q
What are the prognostic and
predictive factors ?
A
- 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
18
Q
What is the definition of myeloid/
lymphoid neoplasms with PDGFRB rearrangement ?
A
- 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
19
Q
What is the presentation of cases of
ETV6-PDGFRB MPNs?
A
- 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
20
Q
What is necessary for diagnosis
of PDGFRB MPNs ?
A
- 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
21
Q
What is the epidemiology
of PDGFRB MPNs ?
A
- more common in men than women
- 2:1
- peak incidence in middle age but there is a wide age range
22
Q
What is the localization of the
MPNs associated with t(5;12) ?
A
- multisystem disorder
- peripheral blood and bone marrow are always involved
- spleen is enlarged in most cases
- tissue infiltration with eosinophils
23
Q
What are the clinical findings of
PDGFRB MPNs ?
A
- most patients have splenomegaly
- some with hepatomegaly
- some have skin infiltration and cardiac damage
- Imatinib can successfully treat
24
Q
What are the microscopic features of
PDGFRB MPNs ?
A
- 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%
25
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
26
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)
27
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
28
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
29
What is the epidemiology of
FGFR1 rearranged neoplasms ?
* generally presents in younger patients
* median age ~30
* moderate to small male predominance
30
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
31
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
32
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!
33
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
34
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
35
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
36
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
37
What is the epidemiology of PCM1-JAK2
neoplasms ?
* marked male predominance (27:1)
* wide age range, but again median age is 47 years
38
What are the localization and the
clinical features of PCM1-JAK2 ?
* peripheral blood and bone marrow are involved
* patients often have hepatosplenomegaly
39
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
40
What is the postulated cell
of origin fo PCM1-JAK2 neoplasms ?
* pluripotent stem cell
41
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
42
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
