Acute Myelogenous Leukemias Flashcards
What are some general features
of AML?
- most adult and infantile leukemias are myeloid
- only 10% of leukemias in children are myeloid
- median age is 65
- AML usually presents with a very high WBC and abundant circulating blasts
- sometimes will present with a soft tissue mass
- chloroma, myeloid sarcoma
How is the diagnosis of
AML made?
- 2 ways to arrive at the diagnosis:
- blast >20%
- < 20% blasts if there is a myeloid sarcoma or characteristic genetic abnormalities
How many cells must be counted
in order to determine blast percentage?
- Bone marrow: 500 cells
- Peripheral blood: 200 cells
Note: in APML, promyelocytes are included in the blast percentage while in Monocytic leukemia promonocytes are included
What is the classic immunophenotype seen
for AML by Flow cytometry?
- CD34
- CD13, CD33
- HLA-DR
- CD45
IMP: APL usually negative for HLA-DR and CD34
** negative for lymphoid markers but some may express CD7 and CD19
What is the gene that is coded
for in AML with t(8;21)(q22;q22)?
- RUNX1 gene
- encodes the alpha chain of core binding factor (CBFa)
- represents 8-10% of de novo AML
- affects young adults and is relatively chemosensitive
What is the morphology of the
blasts in AML with t(8;21)?
- pronounced azurophilic granules
- sometimes large pseudo-Chediak Higashi granules and Auer rods
- Dysplastic mature granulocytes are present in the blood and bone marrow
- display pseudo-Pelger-Huet nuclei with homogeneous pink cytoplasm
What marker, when positive by flow,
should make you consider AML with t(8;21)?
- CD19
- it’s expression should make you consider AML with t(8;21)
What immunomarker expression by
flow should suggest monoblasts?
- expression of CD33 and CD11b
In AML with t(8;21) what is associated
with a poor prognosis ?
- lack of or decreased expression of CD19
- with retention of CD56 expression
- this correlates with a KIT mutation
- poor prognosis
What is the gene that is coded for
in AML inv (16)(p13q22) or
t(16;16)(p13;q22)?
- it is a translocation resulting in the apposition of the MYH11 (myosin) and CBFB genes
- affects younger adults
- relatively chemosensitive
What is the morphology of the blasts in
AML with inv(16) or t(16;16)?
- myelomonocytic differentiation
- usually found in association with eosinophils
- eosinophils usually have abnormal granules that look basophilic (eos-basos)
- stain + with Naphthyl acetate esterase
- this stain is negative in normal eosinophils
What is the immunophenotype of
AML with inv(16) or t(16;16)?
- CD13, CD33
- CD14, CD64
- CD11b, HLA-DR, lysozyme
- also can express CD2
What is the morphology and prognosis for
AML with inv(3) or t(3;3) ?
- genes involved: GATA2-MECOM
- can occur de novo or following MDS
- morphology:
- blasts seen in association with dysmorphic, small, hypolobated megakaryocytes
What is the clinical presentation of
AML t(15;17)(q22;q21)?
- tendency to present in DIC and highly responsive to ATRA
- bimodal distribution
- late teen years and over age 60
What is the morphology of the blasts
for APL?
- abnormal promyelocytes with kidney shaped or bilobed nuclei
- cytoplasm varying from intensely granulated to agranular (microgranular variant)
- microgranular variant can resemble acute monocytic leukemia
- MPO reaction is quite strong in both variants
- weak or negative in monoblasts
How do the hyper and hypogranular
variants present in peripheral blood?
- Hypergranular variant
- very few leukemic cells
- Hypogranular variant
- presents with a high blast count in blood
What is the immunohistochemical finding
for APL?
- Positive:
- CD33, CD13 (both strong)
- CD15 (weak)
- normal promyelocytes will be CD15 strong +
- Negative:
- HLADR and CD34
- Note: these markers can be positive in the hypo/microgranular variant
- also CD2
What are the translocation variants of
APL that are resistant to ATRA?
- t(11;17)
- t(5;17)
What are the three major RARa
breakpoints (for APL)?
- bcr1 - located within intron 6
- bcr2- (exon 6)
- bcr3- (intron 3)
- bcr 3 may have microgranular features
What is Differentiation Syndrome
in APL?
- called Retinoic acid syndrome
- potentially life threatening complication of treatment with ATRA
- Present with:
- fever, weight gain, anasarca
- effusions, hypotension, renal failure
- Risk correlates with initial WBC > 5 x 10^9
- Dexamethasone treatment can prevent or ameliorate it
What is AML with t(6;9) associated with?
- genes: DEK-NUP214
- there is basophilia and multilineage dysplasia
- often in younger adults and children
What age group is AML t(9;11)(p22;q23)
usually seen in and what genes are involved?
- common in children
- AML with KMT2A (MLL) gene anomalies
- FISH is significantly more sensitive for detection
What is the immunohistochemical profile
for AML with t(9;11)?
- monoblastic FAB M4-M5
- CD4, CD14, CD64
- CD11b and lysozyme
IMP:
- CD34 usually negative
What gene fusion is common in
infants with AML containing the MLL gene?
- t(4;11)
- produces MLL/AF4 gene fusion
What is the prognosis of AML with
t(9;11)?
- usually a poor prognosis
- BUT this AML has a better prognosis than other 11q23 aberrations
What is true about AML with t(9;22)?
- de novo AML with t(9;22)
- p210 BCR-ABL translocation
What is classic about AML
with t(1;22)?
- gene fusion: RBM15-MKL1
- often in infants without trisomy 21
- female predominance
- megakaryoblastic differentiation
- express CD41, CD61 and CD42b
What is true about AML with
mutated NPM1?
- favorable prognosis
- in the absence of FLT3-ITD
- normal cytogenetics
- “cup-shaped” nuclei in the blasts
- often CD34 negative
What is the prognosis for AML with
biallelic CEBPA mutation?
- favorable prognosis
- must have absence of FLT3-ITD
- normal cytogenetics
- often in children and young adults
What is the prognosis of AML
with mutated RUNX1?
- poor prognosis
- not therapy related or MDS related AML
What is the morphology, age and prognosis
for AML with t(8;21) ?
- abundant grey-blue cytoplasm
- Auer rods
- large granules (M2 like)
- young adults affected
- Favorable prognosis
Molecular:
- RUNX1/RUNX1T1 (AML1/ETO)
What is the immunophenotype of
AML with t(8;21)?
- Positive
- CD34
- HLA-DR
- CD13
- CD33
- CD19 ( can also be negative sometimes)
What is the morphology, age, and prognosis
for AML with inv(16) or t(16;16)?
- M4-like with increased eosinophils (abnormal)
- eos-basos
- seen in young adults
- Favorable prognosis
Molecular:
- MYH11/CBFB
What is the immunophenotype for
AML with inv(16) or t(16;16)?
- Positive
- CD34
- HLA-DR
- CD13
- CD33
- CD11b
- CD14
- CD64
What is the morphology, age, and prognosis
for AML with t(15;17)?
- promyelocytes
- middle age individuals
- Favorable prognosis
Molecular:
- PML/RARA
What is the immunophenotype of
AML with t(15;17)?
- Positive:
- CD13
- CD33
- CD15 and CD2 (can also be negative)
- Negative:
- CD34
- HLA-DR
What is the morphology, age and prognosis
of AML with t(9;11)?
- M5-like morphology (monocytic)
- children
- Intermediate prognosis
Molecular:
- MLLT3/MLL
What is the immunophenotype of
AML with t(9;11)?
- Negative:
- CD34
- Positive
- HLA-DR
- CD13 and CD33
- CD56 (can also be negative)
- CD14, CD64
- CD11b
What is the morphology, age, and prognosis of
AML with t(6;9) ?
- any morphology, especially myelomonocytic (M4) with basophilia
- seen in children and adults
- poor prognosis
Molecular:
- DEK/NUP214
What is the immunophenotype of
AML with t(6;9)?
- Positive:
- CD34
- HLA-DR
- CD13
- CD33
- Tdt
What is the morphology, age, and prognosis
of AML with t(1;22)?
- megakaryocytic (M7-like)
- infants
- intermediate prognosis
Molecular:
- RBM15/MKL1
What is the immunophenotype of
AML with t(1;22) ?
- Negative:
- CD34
- HLA-DR
- Positive:
- CD13
- CD33
- CD41
- CD61
What is the morphology, age, and prognosis of
AML with inv(3) or t(3;3)?
- M0, M1 or M7-like
- thrombocytosis
- giant, agranular platelets
- adults
- poor prognosis
Molecular:
- RPN1/EVI1
What is the morphology, age, and progonisis of
therapy-related AML ?
- multilineage dysplasia
- often increased eosinophils
- usually occurs 5 years after therapy
- poor prognosis
Molecular:
- Topoisomerase II associated:
- 11q23 (MLL) or
- 21q22 (RUNX1)
What is the immunophenotype of
therapy-related AML?
- Positive:
- CD34
- HLA-DR
- CD13
- CD33
- CD56
What is the morphology, age, and prognosis of
AML with MDS related changes?
- variable morphology, immunophenotype
- elderly
- slowly progressive, unresponsive to treatment
Molecular:
- MDS-like
What are the criteria for AML
with MDS related changes?
- at least 20% blasts
- and one of the following:
- history of MDS
- MDS related cytogenetic abnormality
- multilineage dysplasia ( >50% of 2 cell lines)
- Absence of the following:
- prior cytotoxic therapy
- any of the known recurrent genetic abnormalities of AML
What are the clinical, IHC and prognisis
for AML with MDS related changes?
- affects mainly the elderly
- follows a period of antecedent MDS
- or can arise de novo
- Positive IHC
- CD34, CD13, CD33
- Prognosis
- relatively poor
- leukemias are slowly progressive and do not respond to chemotherapy
What are some of the drugs that can
lead to therapy related AML?
- Topoisomerase II inhibitors
- Alkylating agents
- Ionizing radiation
Note: the response to treatment is poor
What is the latency period for the different
drugs / treatments that can cause AML?
- Topoisomerase II inhibitors
- 1-5 years
- may have KMT2A (MLL) gene rearrangements
- Alkylating agents and radiation
- 5-10 years
IMP: the incidence IS DOSE dependent
How many categories of AML, NOS
are there?
- 7 categories- all do NOT have cytogenetic abnormalities
- M0
- M1
- M2
- M4
- M5
- M6
- M7
- M3 was APL
What is the morphology and prognosis
for AML, NOS M0 ?
- undifferentiated blasts
- < 3% positvie for SBB or MPO or NSE
- agranular cytoplasm
- blasts usually > 30%
- often seen in infants and adults
- poor prognosis
What is the immunohistochemical profile
for AML, NOS M0 ?
- blasts usually express myeloid markers
- Positive:
- CD34
- HLA-DR
- CD13
- CD33
- CD117
Note: myeloid antigens indicating greater degree of maturation are negative: CD14, CD15, CD11b
What is the morphology and prognisis for
AML, NOS M1 ?
- > 3% of blasts are positive for SBB or MPO or CAE (chloroacetate esterase)
- still considered without maturation
- > 90% show no maturation
- prognosis is poor
What are the immunohistochemical findings
for AML, NOS M1 ?
- Positive
- CD34
- HLA-DR
- CD13
- CD33
- CD117
What is the morphology and prognosis of
AML, NOS M2 ?
- with maturation –> must have maturation in >10% blasts
- undifferentiated myeloblasts <89%
- Monocytic differentiation is present in < 20% of nonerythroid cells (know)
- or else M4/M5 must be considered
- abundant grey-blue cytoplasm, Auer rods and large granules
- eos and basos may be increased
- Frequently responds to therapy
What is the immunohistochemical profile
of AML, NOS M2 ?
- Positive:
- CD34 –> may not be expressed
- HLA-DR
- CD13
- CD33
- CD117
- CD15
What is the morphology and prognosis for
AML, NOS M4 ?
- acute myelomonocytic leukemia
- monocytic cells > 20% (amongst non-erythroid cells)
- granulocytic cells >20 %
- Frequently responds to therapy!
What is the immunohistochemical profile for
AML, NOS M4 ?
- Positive
- CD34 -/+
- HLA-DR
- CD13
- CD33
- CD117
- CD14
- CD11b, CD64
- CD4
What is the morphology and prognosis of
AML, NOS M5 ?
- > 80% show monocytic differentiation
- Acute monocytic/monoblastic leukemia
- Non-erythroid cells
- monoblasts, promonocytes, and monocytes
- Manifests with bleeding disorders and soft tissue infiltration
- Gingival enlargement, CNS infiltrate
- Poor prognosis
- t(8;16)
- associated with hemophagocytosis
What is the immunohistochemical profile
for AML, NOS M5 ?
- IMP: usually CD34 negative
- Positive:
- HLA-DR
- Monocytic markers
- CD4, CD14, CD64, CD11b, lysozyme
- Myeloid markers
- CD13, CD33, CD117
What is the morphology and prognosis for
AML, NOS M6 (erythroleukemia) ?
- > 20% show erythroid differentiation
- undifferentiated/proerythroblastic
- erythroid cytoplasm may contain vacuoles and display PAS positivity (like ALL blasts)
- respond poorly to treatment, poor prognosis
Note:
- also called diGuglielmo Syndrome
What are the immunohistochemical findings
for AML, NOS M6 ?
- Positive:
- CD34 -/+
- HLA-DR
- CD13
- CD33
- CD117
- CD235 (glycophorin)
- Note: CD7 can be dim positive sometimes
What is the morphology and prognosis for
AML, NOS M7 ?
- megakaryoblastic, blasts with blebbing
- > 50% of blasts should show megakaryotic differentiation
- Associated with:
- Mediastinal germ cell tumors
- i(12p)
Note: AMLs and transient myeloproliferative disorders associated with Down’s Syndrome often are M7 type
What is the immunohistochemical profile for
AML, NOS M7 ?
- CD34 and HLA-DR -/+
- Postivie
- CD13
- CD33
- CD117
- CD41
- CD61
What is Acute panmyelosis
with myelofibrosis?
- acute neoplastic proliferation of panmyeloid elements, in conjunction with marrow fibrosis
What disorders is acute panmyelosis with
myelofibrosis associated with?
- end stage MPN, AML with MDS related changes
- M7 AML must be excluded
What is the clinical presentation of
acute leukemia in Down Syndrome?
- shows increased chemosensitivity
- especially with Methotrexate
- relatively favorable prognosis
- Megakaryoblastic differentiation
- Down syndrome associated AML arises at an early age (1-5 years)
- in 1-2 % of children
What is Transient abnormal myelopoiesis (TAM) ?
- can cause hydrops
- arises in the first week of life, presenting with a very high WBC and hepatosplenomegaly
- complete clinicopathological resolution without therapy
IMP: ~30% of children with TAM can develop true Down Syndrome associated AML during childhood
What somatic gene mutation can be seen in blasts in
both TAM and Down Syndrome associated AML ?
- GATA-1 gene somatic mutation
Note:
- both Down syndrome associated AML and TAM, the blast type is megakaryoblastic or mixed megakaryoblastic-erythroblastic
What mutations are seen in myeloid neoplasms
without a pre-existing disorder or organ dysfunction?
- CEBPA and DDX41 mutations
What mutations are seen in myeloid neoplasms
with pre-existing platelet disorders?
- RUNX1
- ANKRD26
- ETV6 mutations
What mutations are seen in myeloid neoplasms
with other organ dysfunction?
- GATA2
- associated with bone marrow failure syndromes
- telomere biology disorders
- neurofibromatosis
- Noonan syndrome
- Down syndrome
When should a genetic predisposition syndrome
be suspected in someone who presents with
a myeloid neoplasm ?
- personal history of multiple cancers
- thrombocytopenia or bleeding propensity
- preceding MDS/AML
- Family history
- other features of bone marrow failure syndromes
