Hemepath: Acute Myeloid Leukemia

Front 1

Gingival hyperplasia may be the presenting sign in __ leukemias

Back 1

monocytic

Front 2

In AML, the blood cell counts are usually __

Back 2

decreased in at least 2 lineages, but usually all three
- anemia is usually NCNC, but may be macrocytic
- in >50% pts, the WBC is increased due to circulating blasts and immature myeloid cells
- BUT: WBC count usually not greater than 100 (seen in only about 20% pts)

Front 3

clues that may suggest AML vs ALL

Back 3

AML:
- blasts are a little larger and more uniform
- nucleoli are more prominent
- more cytoplasm w/ granules
- Auer rods (60-70%)
- dysplasia in the maturing meyleoid cells

Front 4

The only morphologic feature that allows distinction between AML and ALL is

Back 4

- Auer rods

Front 5

In making a diagnosis of possible AML, you first must __

Back 5

1. rule out reactive processes or other non-neoplastic disorders

2. distinguish AML vs ALL

3. classification of AML

Front 6

AML PB smear

Back 6

1. variable blast count
- >100 to rare or none!!
2. hypogranular and hyposegmented neutrophils (dysgranulopoiesis)
3. large atypical platelets (dysmegakaryopoiesis)
4. RBC anisopoikilocytosis and NRBCs

Front 7

AML with sparse circulating blasts in the PB, may require __ to make the diagnosis

Back 7

BM biopsy
- should always be done when AML is considered

Front 8

BM in AML

Back 8

- usually hypercellular and consists predominantly of blasts and other immature and abnormal cells

- 60-70% cases, Auer rods can be found in some blasts

- blast nuclei can be round, irregular, or convoluted in shape

- nucleoli are often prominent

Front 9

For a diagnosis of AML, there has to be at least __% blasts or the presence of __ despite <__% blasts!

Back 9

- 20% blasts
- or AML specific cytogenetic abn such as t(8;21), inv(16), 11q23 abn

Front 10

In myelomonocytic and monocytic leukemias, ___ are considered comparable to blasts

Back 10

- promonocytes = blasts

Front 11

Myeloperoxidase (primary granules), Sudan black B, and specific esterase (chloroacetate esterase) stains are all useful for __

Back 11

- identifying granulocytic differentiation (nonreactive in lymphocytes)

- MPO: has the best sensitivity and specificity of the three

Front 12

Non-specific esterases (alpha-naphthyl acetate and alpha-naphthyl butyrate) are useful for ___

Back 12

- identifying monocytic differentiation
- AMML, acute monoblastic leukemia, acute monocytic leukemia

Front 13

Sudan black B stains __ in granulocytes

Back 13

- lipids
- useful in the event that the leukemic myeloblasts are MPO deficient

Front 14

specific esterase (chloroacetate esterase) is __ sensitive than Sudan black B and MPO

Back 14

- less sensitive, but is useful for distinguishing granulocytic from lymphoid in paraffin-embedded tissue sections (the others are done on air dried smears)

Front 15

non-specfic esterase (alpha-naphthyl acetate or alpha-naphthyl butyrate) are useful for __

Back 15

- identifying monocytic leukemias
- stains monocytes and histiocytes diffusely
- negative in myeloblasts and neutrophil precursors

Front 16

PAS staining in AML

Back 16

- not useful in distinguishing from ALL (+ in 75% of ALL)

PAS stianing can be seen in:
- monocytic leukemia
- erythroid leukemia
- megakaryoblastic leukemia

Front 17

If dealing with an acute lymphoblastic leukemia, myeloid dysplasia is __

Back 17

absent!

Front 18

Granules seen in the cytplasm of blasts of ALL?

Back 18

Can be seen!
- usually scant
- coarse granules seen in 7%!

So, granules do not help distinguish AML from ALL, but finding Auer rods does!

Front 19

normal cells with MPO+

Back 19

neutrophil series
+/- monocytes
eosinophils (cyanide resistant)

Front 20

normal cells with Sudan Black B stianing

Back 20

neutrophil series
+/- monocytes

Front 21

normal cells with non-specific esterase staining

Back 21

monocytes (inhibited by sodium floride)

Front 22

MPO and Sudan Black B are useful for the diagnosis of __

Back 22

AML without maturation
AML with maturation
microgranular APL

Front 23

Non-specific esterase is useful for the diagnosis of __

Back 23

AMML
Monoblastic leukemia
acute monocytic leukemia

Front 24

AML vs ALL
MPO
SBB
CAE (specific esterase)
NSE (nonspecific esterase)
PAS
AP (alkaline phosphatase)

Back 24

AML:

MPO +
SBB +
CAE +
NSE + (monocytic) diffuse
PAS +/- (monocytic, erythroid, and megakaryoblastic)
AP +/-

ALL:

MPO -
SBB -
CAE -
NSE -/+ (focal)
PAS + (75%)
AP + (T-ALL focal paranuclear)

Front 25

If leukemic myeloblasts have an acquired myeloperoxidase deficiency, the __ would be a useful cytochemical stain

Back 25

SBB

Front 26

MPO staining is seen in __

Back 26

normal and leukemic myeloblasts and developing neutrophils

increased intensity of reaction with maturation

positive: diffuse granular cytoplasmic staining

monocytes are variably positive for MPO

Front 27

NSE(with alpha-naphthyl butyrate substrate) shows a __ reaction in __

Back 27

- diffuse cytoplasmic reaction in normal monocytes and monocytic leukemias

NOTES:
- most mature T lymphocytes show dense dot-like cytoplasmic positivity with NSE! Can also see this in some ALL cases!!

- can see NSE + in some caricnomas!!

- can see NSE + erythroblasts in megaloblastic anemia!!!

Front 28

NSE(with alpha-naphthyl acetate substrate) stains megakaryoblastic leukemic cells __

Back 28

with a focal cytoplasmic staining

- less commonly seen with NSE(with alpha-naphthyl butyrate substrate)

Front 29

PAS staining in ALL is ___

Back 29

coarse granular cytoplasmic staining

NOT specific for ALL
- 60% of erytholeukemic blasts
- monoblastic
- megakaryoblastic

Front 30

APL is HLA-DR __ and CD34__

Back 30

HLA-DR-
(most AML's are HLA-DR+)
CD34-

Front 31

Monocytic leukemias can be detected by __

Back 31

flow - coexpression of:
CD64+
CD36+
sometimes CD11b, CD15, CD14

IHC (paraffin-embedded tissue)
CD68+
lysozyme+

Front 32

AML can be stratified into low, intermediate and high grade disease based on __

Back 32

bone marrow cytogenetics (done on every case!)

Front 33

Favorable cytogenetics in AML

Back 33

inv(16) or t(16;16)
t(8;21)
Single misc defects

Front 34

Intermediate grade cytogenetics in AML

Back 34

t(15;17) (due to hemorrhagic ocmplications [DIC], but if complete remission achieved, then good prognosis)

+8
t(6;9)
t(9;11) in children
Normal cytogenetics

Front 35

High grade cytogenetics in AML

Back 35

-7
-5
del(7q)
abn of 11q23
Complex abn`

Front 36

Corresponding molecular genetic abnormalities
t(8;21)(q22;q22)
inv(16)(p13;q22)
t(15;17)(q22;q21)
t(6;9)(p23;q23)
t(9;11)(p22;q23)

Back 36

Corresponding molecular genetic abnormalities
t(8;21)(q22;q22)
- ETO/AML1 fusion

inv(16)(p13;q22)
- MYH11/CBF-Beta fusion

t(15;17)(q22;q21)
- PML-RAR-Alpha fusion

t(6;9)(p23;q23)
- DEK/CAN fusion

t(9;11)(p22;q23)
- MLL/AF9 fusion

Front 37

WHO classification of AML, major categories (5)

Back 37

- AML with recurrent genetic abn
- AML with multilineage dysplasia
- AML and MDS, therapy related
- AML (NOS)
- Acute leukemia of ambiguous lineage

Front 38

AML with recurrent genetic abn (4)

Back 38

- AML with t(8;21)(q22;q22);(AML1/ETO)

- AML with abnormal bone marrow eosinophils inv(16)(p13;q22) or t(16;16)(p13;q22);(CBF-beta/MYH11)

Acute promyelocytic leukemia with t(15;17)(q22;q12);(PML/RAR-alpha) and variants

AML with 11q23(MLL) abnormalities

Front 39

AML with multilineage dysplasia (2)

Back 39

1. AML with multilineage dysplasia [following MDS]
2. AML with multilineage dysplasia [without antecedant MDS]

Front 40

therapy related AML and MDS

Back 40

- alkylating agent related
- topoisomerase type II inhibitor related
- other

Front 41

AML (NOS)(10 types)

Back 41

Similar to prior FAB classificaton of AML with additional types added

- AML minimally differentiated
- AML without maturation
- AML with maturation
- Acute myelomonocytic leukemia (AMML)
- Acute monoblastic and monocytic leukemia
- Acute eythroid leukemia
- Acute megakaryoblastic leukemia
- Acute basophilic leukemia
- Acute panmyelosis with myelofibrosis
- Myeloid sarcoma

Front 42

Acute leukemia with ambiguous lineage (3)

Back 42

- undifferentiated acute leukemia
- bilineal acute leukemia
- biphenotypic acute leukemia

Front 43

In monocytic cells, NSE (alpha-naphthyl acetate esterase) will be __ by sodium fluoride

Back 43

Nonspecific esterase (alpha-naphthyl acetate esterase) stains both monocytic and megakaryocytic cells, but only the monocytic cells will be quenched by sodium fluoride. Additionally, megakaryocytic cells are not stained by alpha-naphthyl butyrate, whereas monocytic cells are stained by either esterase stain

Front 44

Change in the pecentage of blasts in blood and bone marrow required for a diagnosis of AML from FAB to 2001 WHO classification

Back 44

- went from 30% (FAB) to 20% (WHO) effectively getting rid of the MDS classificaiton RAEB-T

RAEB-T behave clinically like AML and should be managed as an acute leukemia

Front 45

AML with t(8:21)(q22;q22)

Back 45

- AML1 (8q22)
- ETO (21q22)
- AML1/ETO fusion protein

8% of AMLs

Morphology:
- features of AML w/ maturation (FAB-M2):
= large blasts
= frequent and often large Auer rods
= neutrophilic dysplasia (striking)
= strong MPO+

Flow:
- CD34+
- CD13+ CD33+
- often CD19+ (aberrant B cell antigen)
- often CD56+
- +/- TdT+

Front 46

AML with t(8:21) with <20% should be classified as __

Back 46

AML with t(8:21)(q22;q22) and NOT as an MDS

Front 47

AML with t(8:21)(q22;q22) has a relatively ___ prognosis

Back 47

favorable

Favorable cytogenetics in AML included:
- inv(16) or t(16;16)
- t(8;21)
- Single misc defects

Front 48

AML with inv(16)(p13;q22) or t(16;16)(p13;q22)

Back 48

- beta subunit of CBF factor (16q22)
- smooth muscle mysoin heavy chain gene (MYH11) (16p13)
- CBF-beta/MYH11 fusion

Morphology:
- features of acute myelomonocytic leukemia (AMML) with abnormal bone marrow eosinophils (FAB-M4e):
= dypslasitc eosionphils with abundant large irregular basophilic granules

10% of AMLs

Higher incidence of extramedullary involvement than other AMLs
- 50% with extramedullary disease
- lymphadenoapthy and hepatomegaly common

Myeloid sarcoma (concurrent or proceeding bone marrow involvement) is more common than with other leukemias

- a/w CNS relapse with intracerebral myeloblastomas

Px:
- longer median survival than other AMLs
- complete remission rates of 76% and 92% reported

Front 49

inv(16) is a ___ inversion of chromosome 16

Back 49

- pericentric inversion
- the genes at the breakpoint junction are CBF-beta (16q22) and MYH11 (16p13)

Front 50

Myeloid sarcoma is more likely to be associated with which AML type

Back 50

AML with inv(16)(p13;q22) or t(16;16)(p13;q22)

Front 51

CNS relapse, with intracerebral myeloblastomas, is more likely with whihch AML type

Back 51

AML with inv(16)(p13;q22) or t(16;16)(p13;q22)

Front 52

Flow: AML with inv(16)(p13;q22) or t(16;16)(p13;q22)

Back 52

CD34+
CD11b+
CD33+
CD45+
CD56+

CD15-
MPO-
CD16-

Front 53

Acute promyelocytic leukemia (APL) with t(15;17)(q22;q21)

Back 53

- PML (15q22)
- first intron of RAR-alpha (17q12-21)
- PML/RAR-alpha fusion

Morphology (characteristic)
- abnormal promyelocytes NOT myeloblasts (myeloblasts actually make up a minor component, usually <20%)
- for APL, abn promyelocytes are considered comparable to myeloblasts for purposes of diagnosis!!

- larger, dark numerous red to purple granules (may obscure nucleus)
- may see deeply basophilic cytoplasm
- Auer rods multiple (may be numerous and intertwined) 90% of cases!
- Nuclei: reniform or bilobed

hypergranular and microgranular(hypogranular) types (only a morphologic difference between these two)

8-10% of AMLs

Front 54

Acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) should be distinguished from ____(DDX)

Back 54

agranulocytosis with arrested maturation at the promyelocyte stage

- platelet and hemoglobin normal
- BM not hypercellular
- promyelocytes lack nuclear features of APL
- no Auer rods
- lacks t(15;17)

Front 55

microgranular variant of Acute promyelocytic leukemia (APL) with t(15;17)(q22;q21)

Back 55

- high WBC counts (higher)
- sparse/fine granules
- markedly irregular nuclei
- Auer rods present, but less abundant

Front 56

Acute promyelocytic leukemia (APL) with t(15;17)(q22;q21)
Immunophenotype

Back 56

Differs from other AMLs by:
- increased side scatter
- dim-partial HLA-DR+
- CD34-

Front 57

Acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) occurs at __ age

Back 57

- any age, but mostly middle age adults (median age 35-40 yo)

Front 58

Most clinically important feature of APL is the association with ___

Back 58

- DIC and hemorrhage
- most pts have severe DIC and hemorrhage prior to or during induction chemotherapy

- if controlled, there is a good chance for complete remission and long survival

Front 59

Acute promyelocytic leukemia (APL) with t(15;17)(q22;q21) treatment includes

Back 59

- standard chemotherapy induction plus ATRA
- ATRA induces maturation of leukemic cells

Front 60

Features of APL but FISH studies negative for t(15;17)?

Back 60

APL variant
t(V;17) V/RAR-alpha

uncommon

cytogenetics would likely reveal abn

t(11;17) is one of the more common variants

Can have similar morphology to APL or intermediate between APL and AML

Important:
- patients still present with DIC!!
- DO NOT respond to ATRA!!!

Front 61

AML with 11q23 abnormality is found in __% of AML

Back 61

6% AML

also seen in:
- topoisomerase II inhibitor therapy-related AMLs
- ALL
- biphenotypic acute leukemias

Front 62

de novo AML with 11q23 abnormality typically have __, ___ or __ morphology

Back 62

- monoblastic
- monocytic
- myelomonocytic

Front 63

de novo AML with 11q23 abnormality is most consistently seen in what age group?

Back 63

Children with monoblastic leukemia
- t(9;11)
- t(11;19)

Front 64

Most leukemias with 11q23 abnormalities typically have a __ prognosis

Back 64

poor

EXCEPTION: children with acute monocytic leukemia with t(9;11) - good response to therapy

Front 65

AML with multilineage dysplasia can present as __ or as a __

Back 65

- de novo AML with mulilineage dysplasia

- AML secondary to MDS

Morphologically they can be the same (history)

Front 66

AML with multilineage dysplasia requires dysplasia in __

Back 66

at least 50% of cells of at least 2 lineages

Front 67

acute leukemia with 11q23 abnormality with the following immunophenotype:

CD45+
CD14+/-
CD13+/-
CD33+
CD15+
CD64+
CD36+

CD4+

CD34-
CD5-

Back 67

acute monoblastic/monocytic leukemia

the blasts lack expression of CD34 and CD5

Front 68

Hypcellular AML or MDS is defined as __

Back 68

bone marrow cellularity <30% or <20% in pts over 60 yo

Front 69

AML with multilineage dysplasia morphology

Back 69

- often borders between morphologic classes
- often features of AML with maturation or AMML

Front 70

Therapy related AML or MDS is most often a/w __

Back 70

alkylating agents or topoisomerase II inihibitors

Pt presents with unexplained cytopenias after treatment
- alkylating agents: 5 years
- topo II inh: 2.5-3 years


Alkylating agents:
- may present with MDS with rapid progression to AML
- may PRESENT with myelofibrosis, hypocellularity, and ringed siderblasts (more often than de novo MDS or AML)
- MDSs often a/w abn of chr 5 and/or 7

Topo II inh:
- more often a/w monocytic or myelomonocytic leukemias with 11q23 abn
- RARELY present as an MDS

Front 71

If a pt presents with a post-treatment MDS, the associated drug was most likely a __

Back 71

alkylating agent
- topoisomerase II inhibitor-related disease rarely present as MDS

Front 72

AML, minimally differentiated

Back 72

5% of AMLs
- lack definitive cytologic and cytochemical critieria for dx of AML
- DX made based on immunophenotyping!!
- show 1 or more myeloid antigens (eg. CD13, CD33, CD117)
- may aberrantly exrpress lymphoid associated markers
- TdT+ (33%)
- CD34+
- HLA-DR+

Morphology
- blasts LACK granules and Auer rods
- may resemble lymphoblasts!

Poor px!

Front 73

AML, minimally differentiated: the blasts show MPO+ cytochemically in ___% of cells

Back 73

<3% of cells show cytochemical MPO+, however, more may show MPO expression by immunohistchemistry or ultracytochemical methods

Front 74

AML, without maturation
distinguished from AML, minimally differentiated by __

Back 74

10% of AMLs

Distinguished from AML, minimally diff by cytochemical evidence of MPO+ or SBB+ in >3% of cells!

BM myeloblast must be >/=90% of non-erythroid cells (remaining cells can be maturing granulocytic precursors or monocytes)

Front 75

AML, without maturation
PB smear

Back 75

variable myeloblasts in blood
- leukopenia with occasional blasts to leukocytosis with nearly 100% blasts!
- anemia
- neutropenia
- thrombocytopenia

Front 76

AML, without maturation
BM shows

Back 76

- hypercellular with predominance of blasts
- decreased megakaryocytic and erythroid precursors

Front 77

AML, without maturation
morphology

Back 77

variable!

90%+ myeloblasts in BM!!

+/- cytoplasmic granules
Auer rods+ (50%)
- minimal/absent maturation to promyelocytes
- myeloblasts often appear undifferentiated and its the MPO+ (>3$ cells) that makes the diagnosis

2 subtypes of AML, without maturation
1. 25% cases:
- leukocytosis
- blasts show nuclear cups (distinct nuclear invaginations that resemble large nucleoli - abn smooth ER tubules)
- STRONG MPO+
- may show some resemblance microgranular APL
- Immunophenotype:
myeloid antigens (CD13+, CD33+..)
CD56+
CD34-
HLA-DR-
Normal cytogenetics!!

2. 25% cases
- leukopenia
- dysplasia
- prominent nucleoli
- WEAK MPO+
- Immunophenotype
CD34+
HLA-DR+
Abnormal cytogenetics!!

Remaining 50-60% case of AML without maturation show NO distinctive features

Front 78

The most common category of AML is __

Back 78

AML with maturation
30-45% cf AMLs!

Front 79

AML with maturation

Back 79

- shows maturation beyond myeloblast stage

- Myeloblasts: 20-89% of non-erythroid BM cells
- Monocytes: <20% of non-erythroid BM cells

Auer rods+ (70%)

Dysplasia present commonly in granulocytic series, however, may be prominent in other lineages to suggest AML, with multilineage dysplasia

No problem recognizing the myeloid lineage (MPO merely confirms the morphologic impression)

px is variable

Front 80

Distinct type of AML with maturation with t( )

Back 80

t(6;9), DEK/CAN
- basophil component seen in 50% cases
- present with high WBC counts