Transcript Acute Myeloid Leukemia & Related Precursor Neoplasms

Acute Myeloid Leukemia with
cytogenetic abnormality
PARDIS NEMATOLLAHI,MD,ACP
Acute myeloid leukemia (AML) is a heterogeneous group of
diseases that represent clonal proliferations of immature,
nonlymphoid, bone marrow–derived cells that most often
involve the bone marrow and peripheral blood and may
present in extramedullary tissues
the FAB classification remained the primary system used by
most pathologists and hematologists for many years. The
terminology of the FAB classification continues to be used,
but this system is now considered obsolete owing to its
inability to accurately identify many prognostically
significant disease types.
Acute Myeloid Leukemia & Related
Precursor Neoplasms
1. Acute myeloid leukemia with recurrent genetic abnormalities
2. Acute myeloid leukemia with myelodysplastic-related changes
3. Therapy-related myeloid neoplasms
4. Acute myeloid leukemia,NOS
5. Myeloid sarcoma
6. Myeloid proliferation related to Down syndrome
7. Blastic plasmacytoid dendritic cell neoplasms
Epidemiology
The incidence of AML is approximately 3.5 cases per 100,000 per
year. The median age at diagnosis is 67 years, and there is a slight
male predominance. The frequency of AML increases with age, with
approximately 6% of cases occurring in children and adults younger
than 20 years and more than 50% of cases occurring in patients 65
years of age and older.
Etiology
The cause of many cases of AML is unknown, particularly those
arising in children and young adults.
A subset of AML arises from a preexisting myelodysplastic syndrome
(MDS) or is a secondary leukemia related to prior therapy for a
nonleukemic disorder.
AML occurs more commonly in patients with some preexisting
genetic disorders, including Fanconi’s anemia and Down syndrome.
Current Approach to Diagnosis of ALs:
Practice of Multidisciplinary Correlations
Clinical history
Morphology (architecture and cytology)
Immunophenotyping
FC(Multiparameter flow cytometric methods), IHC, and
cytochemistry
Cytogenetic/ FISH
Molecular genetic
Acute Myeloid Leukemia & Related
Precursor Neoplasms
1. Acute myeloid leukemia with recurrent genetic abnormalities
2. Acute myeloid leukemia with myelodysplastic-related changes
3. Therapy-related myeloid neoplasms
4. Acute myeloid leukemia , NOS
5. Myeloid sarcoma
6. Myeloid proliferation related to Down syndrome
7. Blastic plasmacytoid dendritic cell neoplasms
Acute myeloid leukemia with recurrent
genetic abnormalities
This group is characterized by recurrent genetic abnormalities of prognostic significance
The most common:
t(8,21)
inv(16) or t(16,16)
t(15,17)
t(9,11)
t(6,9)
inv(3)
t(1,22)
Are considered as acute leukemia without regard to blast cell count
Many of these diseases have characteristic morphological &
immunophenotypic features
Acute myeloid leukemia with t(8,21)
AML with t(8;21)(q22;q22) has distinctive morphologic and
immunophenotypic findings that correlate well with a specific
cytogenetic abnormality
 Generally show maturation in neutrophilic lineage
meeting the criteria for M2 AML in the FAB classification(Found in
10% of the prior acute myeloblastic leukemia with maturation (M2)
of FAB classification)
Acute myeloid leukemia with t(8,21),cont
*Morphology & Cytochemistry:
Large blasts with abundant basophilic cytoplasm , often containing azurophilic granules(The
blasts in the bone marrow have cytoplasmic hofs , occasional Auer rods, and occasional large,
salmon-colored granules)
Some blasts show very large granules(pseudo-chediak-higashi )
Auer rods frequently found
Variable dysplasia is noted in myeloid series , uncommon in other cell lines
Eosinophil precursors frequently increased but not abnormal
Basophils and/or mast cells sometimes increased
Monocytic series usually minimal or absent
Acute myeloid leukemia with t(8;21)A, Blasts show a variable number of
granules, suggesting cell maturation. One blast contains thin Auer rods.
B, Perinuclear hofs (green arrows) and large pink granules (black arrows)
are characteristic features of this type of AML.
Chediak-Higashi–like granules
On this high-power view, blasts are seen with some maturing myeloid elements as
demonstrated by the appearance of granules. There is, however, a maturation arrest
as PMNs and bands are not present
Centrosomes are evidence of myeloid differentiation
Acute myeloid leukemia with t(8,21),cont
Immunophenotyping:
Characteristic immunophenotype : high intensity expression of CD34,HLADR,MPO,CD13,weak CD33
Sometimes population of blasts showing maturation asynchrony(co expression
of CD34,CD15)
Frequently express lymphoid markers CD19,PAX5,cCD79a
Some cases weak TdT expression
Sometimes CD56 expression
Acute myeloid leukemia with t(8,21),cont
Prognosis and predictive factors:
Good response to chemotherapy
High complete remission rate and long term disease-free survival
CD56 with adverse prognosis
The differential diagnosis
1-APL
2- mixed phenotype acute leukemia
3-MDS
4- Regenerative changes that include the effects of growth factors
Acute myeloid leukemia with t(16,16) or inv(16)
Definition:
Is an AML that usually shows monocytic and granulocytic
differentiation
Characteristically with abnormal eosinophil component in
the BM, meeting the criteria for AML M4EO in the FAB
classification
Acute myeloid leukemia with t(16,16) or inv(16),cont
Morphorphology and Cytochemistry:
In addition to usual morphological features of acute myelomonocytic leukemia,variable number
of eosinophilia at all stages of maturation
The eosinophilic granules are often larger than those normally present in immature
eosinophils,purple violet in color,some obscure the cell morphology,mature eos show nuclear
hyposegmentation
Auer rods may observed in myeloblast
At least 3% of blasts show MPO reactivity
PB such as acute myelomonocytic leukemia , abnormal and increased eos
Acute myeloid leukemia with inv(16): A and B, Both cases show blasts with
monocytoid nuclear features and abundant cytoplasm. One leukemia (A) exhibits
numerous eosinophil precursors, some of which have the characteristic large
basophilic granules. The other (B) shows only one abnormal eosinophil.
AML with inv(16)
The dysplastic eosinophil precursors are shown at a higher magnification. Note both eosinophilic and
basophilic granules are present in the cytoplasm of these cells.
Acute Myeloid Leukemia with inv 16
Acute myelomonocytic leukemia with abnormal eosinophils (arrow).
Acute Myeloid Leukemia with inv( 16 )
The arrow marks an abnormal immature eosinophil found in the bone marrow of a
patient with an acute myeloid leukemia with inv (16)
Acute myeloid leukemia with t(16,16) or inv(16),cont
Immunophenotype:
Complex immunophenotype with multiple blast population:
1-Immature blasts with CD34 and CD117
2-blasts differentiating towards granulocytes(CD13,CD15,CD56,MPO)
3-blasts differentiating towards monocytes(CD14,CD4,CD64,CD11b,CD11c)
4-Maturation asynchrony
5-Aberrant expression of CD2
The differential diagnosis
1-myelomonocytic types of AML, NOS
2-Reactive monocytic proliferations
3-CMML
Acute myeloid leukemia with t(16,16) or inv(16),cont
Prognosis and predictive factors:
Longer complete remission
Older patients have decreased survival
Acute promyelocytic leukemia with t(15,17)
Definition:
APL is an AML in which abnormal promyelocytes predominate
Both hypergranular or typical and microgranular or hypogranular types exist
Epidemiology:
5-8% of all AML
Can occur in any age , dominantly adults in mid life
Acute promyelocytic leukemia with t(15,17),cont
Clinical features:
Frequently associated with DIC
In microgranular APL,the leukocyte count is very high
Acute promyelocytic leukemia with t(15,17),cont
Morphology and Cytochemistry:
Nuclear size and shape
Cytoplasmic granules,Faggot cells are characteristic
MPO reaction
Cases of microgranular APL are characterized by distinct morphological features such as
paucity or absence of granules, and predominantly bilobed nuclear shape
Cases of microgranular may misdiagnosed as acute monocytic leukemia:
1-small number of typical promyelocytes and faggot cells
2-marked elevated leukocyte count
3-strong MPO reaction
Acute promyelocytic leukemia (FAB M3), bone marrow aspirate. The blasts are relatively
monomorphous and show heavily granulated cytoplasm without Auer rods (compare with acute
myeloid leukemia with maturation). Karyotyping showed t(15;17).
Faggot" cell in acute promyelocytic leukemia
A "faggot" cell present on the peripheral smear from a patient with acute promyelocytic leukemia is shown. The
cytoplasm contains multiple Auer rods, singly and in bundles.
“Flaming” promyelocyte .
Abnormal promyelocyte with disintegrating cytoplasm which, in turn, liberates Auer rods and granules
into the surrounding marrow. These "flaming" promyelocytes are one of the characteristic cells found in
APL.
Acute promyelocytic leukemia (FAB M3), bone marrow aspirate. Numerous blasts are
present, showing folded and lobated nuclei and abundant cytoplasm containing Auer
rods and granules. Karyotyping showed t(15;17).
APL
Some abnormal promyelocytes have a distinct folding pattern to the nucleus as shown by the cell
marked with the arrow.
AML-M3, Hypogranular Variant
At higher magnification of the cells shown on the previous slide, the nuclear convolutions are more
apparent. Azurophilic granules are present in the cell on the left. A peinuclear hof can not be seen in
any of the hypogranular promyelocytes.
Acute promyelocytic leukemia (FAB M3), bone marrow aspirate. The blasts are very
large, with lobated nuclei, fine dust-like cytoplasmic granules, and numerous Auer
rods. Karyotyping showed t(15;17).
Acute promyelocytic leukemia (FAB M3), bone marrow clot. The marrow
is replaced by a diffuse infiltrate of blasts with abundant, heavily
granulated cytoplasm.
Acute promyelocytic leukemia with t(15,17),cont
Immunophenotyping:
Absence of HLA-DR and CD34(microgranular may express dim HLA-DR and
commonly dim CD34
Bright expression of CD33
Heterogenous expression of CD13
Many cases CD117
Commonly CD64
Microgranular shows CD34 & CD2 expression
Differential diagnosis:
Hypergranular variant:
Agranulocytosis and maturation arrest at promyelocyte
Regenerative hyperplasia
AML without maturation with negativity for CD34 and HLA-DR(next
slide)
Microgranular variant:
AML with monocytic differentiation
HLA-DR and CD34 negative AML without maturation,shows
fish mouth deformity or cup like nuclear inclusion
Arrow marks "thumbprinting" which is characteristic of myeloid blasts.
Acute promyelocytic leukemia with t(15,17),cont
Prognosis & predictive factors:
APL has a particular sensitivity to ATRA which acts as a
differentiating agent
Prognosis in APL treated optimally with ATRA is more favourable
than for any other AML cytogenetic subtype
Acute myeloid leukemia with t(9,11),MLL
Is usually associated with monocytic differentiation
May occur in any age ,but is more common in children
May presented with DIC or extramedullary myeloid sarcoma
Acute myeloid leukemia with t(9,11),MLL,cont
Morphology & cytochemistry:
There is a strong association with acute monocytic and acute
myelomonocytic leukemia
Monoblasts and promonocytes show strong positivity for non
specific esterase
Monoblasts are negative for MPO
Promonocytes may show weak reactivity with MPO
Acute myeloid leukemia with t(9;11)
The morphologic appearance is variable. A, This case shows abundant basophilic cytoplasm, suggestive of
monocytic differentiation. B, This case shows blasts with a more myeloblastic appearance, including some cells with
granules. Although myelomonocytic or monocytic features are most common, there are no specific morphologic
features of this translocation.
Acute myeloid leukemia with t(9,11),MLL,cont
Immunophenotype:
Cases of AML with MLL in children:
Strong CD33, CD4 , HLA-DR
Low CD 13 , CD 14 ,CD34
Cases of AML with MLL in adults:
Express some markers of monocytic differentiation CD4 , CD14 , CD64 ,CD11b
,CD11c
Variable expression of immature markers,CD34 , CD117
Acute myeloid leukemia with t(9,11),MLL,cont
Prognosis and predictive factors:
Has intermediate survival
Acute myeloid leukemia with t(6;9)
Is an AML with or without monocytic features
is often associated with basophilia and multilineage dysplasia
Acute myeloid leukemia with t(6;9),cont
Morphology and cytochemistry:
May shows morphologic and cytochemical features of any type of FAB subtype
of AML other than APL and acute megakaryoblastic leukemia
Marrow and PB basophilia
Most cases show granulocytic and erythroid dysplasia and less common
megakaryocytic dysplasia
Ring sideroblast may be seen
Acute myeloid leukemia with t(6;9)
Blast cells exhibit variable morphology but are often associated with
admixed basophils (arrows). A, Blasts with monocytic features. B,
Myeloblasts without maturation and dysplastic erythroid precursors.
Acute myeloid leukemia with t(6;9),cont
Immunophenotype:
Blasts consistently express MPO,CD13,CD33,CD38,HLA-DR
Most cases express CD117 , CD34 ,
Half are TdT positive
Differential diagnosis:
1-AML with myelodysplastic related changes
2-Blast transformation of CML
Acute myeloid leukemia with t(6;9),cont
Prognosis and predictive factors:
Poor prognosis
Elevated WBC
Increased BM blast
Shorter overall survival
Acute myeloid leukemia with inv(3)
May present de novo or from prior MDS
Normal or elevated plt count
BM atypical hypermegakaryosis
Multilineage dysplasia
Morphological findings
Acute myeloid leukemia with inv(3),cont
Clinical features:
Anemia and normal to elevated plt count
May have HSM
LAP is uncommon
Acute myeloid leukemia with inv(3),cont
Morphology and cytochemistry:
May show any type of FAB classification of AML other than APL
Blood findings: normal to elevated plt count

Giant and hypogranular plt

bare megakaryocyte nuclei

Hypogranular PMN with pseudo pelger huet anomaly
BM findings:
Atypical hypermegakaryosis

Dyserythropoietic and dysgranulopoiesis are common

Marrow eos , bas & mast cells may increased
Acute myeloid leukemia with inv(3)(q21q26.2) .
A, Increased blasts with mono- and bilobed megakaryocytes are typical of this
disorder. B, Distinctive hypolobated megakaryocytes are apparent on the biopsy
specimen.
Acute myeloid leukemia with inv(3),cont
Immunophenotyping:
Blast cells express CD13 , CD33 , HLA-DR , CD34 , CD38
Some aberrantly express CD7
Some express CD41 , CD61
Acute myeloid leukemia with inv(3),cont
Prognosis and predictive factors:
Is an aggressive disease
Acute myeloid leukemia(megakaryoblastic) with t(1;22)
Is an AML showing maturation in the megakaryocyte lineage
Is uncommon(<1% of all AML)
Most commonly occurs in infants without Down syndrome
F>M
Acute myeloid leukemia(megakaryoblastic) with t(1;22),cont
Morphology & cytochemistry:
Similar to acute megakaryoblastic leukemia , NOS
Small and large megakaryoblast(cytoplasm is basophilic , often agranular,may
show bleb or pseudopod)
Micromegakaryocytes are common
Reticulin and collagen fibrosis
Blasts are negative for MPO
Acute myeloid leukemia (megakaryoblastic) with t(1;22).
A, Hemodilute aspirate shows rare blasts with basophilic cytoplasm and
blebbing. B, Core biopsy shows blasts and atypical megakaryocytes.
Acute myeloid leukemia(megakaryoblastic) with t(1;22),cont
Immunophenotyping:
CD41 , CD61
Myeloid associated markers may be positive,CD13 , CD33
Often negative:CD34 , CD45 , HLA-DR
Negative MPO , TdT
Prognosis and predictive factors:
Poor
References
1-WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues,4th Edition,2008
2-Pathology of Bone marrow and Blood cells,Diane C.Farhi,2nd Edition,2009
3-Flowcytometry in evaluation of hematopoietic neoplasms,Sindhu Cherian,2012
4-Hematopathology,Elaine S. Jaffe ,2011
5-Henry,s Cinical Diagnosis and Management by Laboratory Methods,22nd Edition 2011