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Acute Myeloid Leukemia with cytogenetic abnormality. Pardis Nematollahi,md,acp.
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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 • Acute myeloid leukemia with recurrent genetic abnormalities • Acute myeloid leukemia with myelodysplastic-related changes • Therapy-related myeloid neoplasms • Acute myeloid leukemia,NOS • Myeloid sarcoma • Myeloid proliferation related to Down syndrome • 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 • Acute myeloid leukemia with recurrent genetic abnormalities • Acute myeloid leukemia with myelodysplastic-related changes • Therapy-related myeloid neoplasms • Acute myeloid leukemia , NOS • Myeloid sarcoma • Myeloid proliferation related to Down syndrome • 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, Perinuclearhofs (green arrows) and large pink granules (black arrows) are characteristic features of this type of AML.
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
Acute myeloid leukemia with t(8,21),cont Immunophenotyping: • Characteristic immunophenotype : high intensity expression of CD34,HLA-DR,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 microgranularAPL,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 promyelocyticleukemia 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 peinuclearhof can not be seen in any of the hypogranularpromyelocytes.
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