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Hematopathology WHO MPN, Mastocytosis, MPN/MDS, & MDS > Myeloid/Lymphoid Neoplasms with Eosinophilia and Gene Rearrangement > Flashcards

Myeloid/Lymphoid Neoplasms with Eosinophilia and Gene Rearrangement Flashcards

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
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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
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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
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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
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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

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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

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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

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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
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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
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10
Q

What is the etiology of

FIPIL1-PDGFRA disorders ?

A
  • cause is unknown but some have recurred following cytotoxic chemotherapy
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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
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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)

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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
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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
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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
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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
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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
Q

What is the postulated cell

of origin in PDGFRB cases ?

A
  • pleuripotent stem cell that can give rise to many different cell types including B cell lineage lymphoblasts in some cases
26
Q

What is the genetic profile of

PDGFRB myeloid and lymphoid neoplasms ?

A
  • 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
Q

What are the prognostic and predictive

factors for PDGFRB myeloid/lymphoid neoplasms ?

A
  • Imatinib as greatly improved survival
    • median 65 months
  • important to start therapy prior to cardiac damage
28
Q

What is the definition of

myeloid/lymphoid neoplasms with FGFR1 rearrangement ?

A
  • 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
Q

What is the epidemiology of

FGFR1 rearranged neoplasms ?

A
  • generally presents in younger patients
    • median age ~30
  • moderate to small male predominance
30
Q

What is the tissue localization of

FGFR1 rearranged cases ?

A
  • primarily involves the bone marrow, PB
  • LN
    • lymphadenopathy mostly occurs due to infiltration by lymphoblasts or myeloid cells
  • liver
  • spleen
31
Q

What are the clinical features of

FGFR1- rearranged neoplasms ?

A
  • 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
Q

What are the microscopic features

of FGFR1 rearranged neoplasms ?

A
  • 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
Q

What is the genetic profile of

FGFR1 rearranged neoplasms ?

A
  • 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
Q

What are the prognostic and predictive

factors for FGFR1 rearranged neoplasms ?

A
  • 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
Q

What is the definition of myeloid/lymphoid

neoplasms with PCM1-JAK2 ?

A
  • 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
Q

What gene fusion can be considered

a variant of PCM1-JAK2 neoplasms ?

A
  • 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
Q

What is the epidemiology of PCM1-JAK2

neoplasms ?

A
  • marked male predominance (27:1)
  • wide age range, but again median age is 47 years
38
Q

What are the localization and the

clinical features of PCM1-JAK2 ?

A
  • peripheral blood and bone marrow are involved
  • patients often have hepatosplenomegaly
39
Q

What are the microscopic features of

PCM1-JAK2 neoplasms ?

A
  • 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
Q

What is the postulated cell

of origin fo PCM1-JAK2 neoplasms ?

A
  • pluripotent stem cell
41
Q

What are the genetics of

PCM1-JAK2 neoplasms ?

A
  • 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
Q

What are the prognostic and predictive

factors seen in PCM1-JAK2 neoplasms?

A
  • survival is highly variable for patients presenting in chronic phase
    • days to years

Hematopathology WHO MPN, Mastocytosis, MPN/MDS, & MDS (17 decks)

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