Acute leukemias 1-csbrp

LeukemiasLeukemiasDr.CSBR.Prasad, M.D.,

CSBRP-SDUMC-Oct-2014

Terms • Dysplasia• Clone• Malignancy• Leukemia• Lineage• CD antigens• Immunophenotyping• Flow cytometry• Acute & Chronic• Gp IIb/IIIa• Oncogenes

Myeloid neoplasms

All have common origin from hemopoietic progenitor cells

They primarily involve BM and to a lesser degree the secondary hemopoietic organs (spleen, liver and LNs)

and Present with altered hematopoiesis

Three broad categories:

1. Acute myelogenous leukemia2. Myelodysplastic syndromes3. Chronic myeloproliferative disorders

Myeloid neoplasms

Leukemias

Main groups:

1-Myeloid (acute / chronic)2-Lymphoid (acute / chronic)3-Mixed lineage leukemias

Leukemias

Pathogenesis:Normal hemopoiesis is finely tuned by

hemostatic feedback mechanisms involving cytokines and growth factors that modulate the marrow output of red cells, granulocytes and platelets.

These mechanisms are deranged in marrows involved by myeloid neoplasms.

Loss of control on growth & survival and suppressor fuctions.

Leukemias

Leukemias – clinical features• Anemia• Fever• Fatigue• Bleeding• Gum hypertrophy• Hepatosplenomegaly• Lymphadenopathy• Mediastinal mass• CNS symptoms

Gum bleeding

Gum hypertrophy

Hepatosplenomegaly

Cervical lymphadenopathy

Cerebral hemorrhage

What do you call this?

Acute Myeloid Leukemia

Definition: Acute myeloid leukemia (AML) is a clonal

expansion of myeloid blasts in bone marrow, blood or other tissue.

AML is a quite heterogeneous disease, reflecting the complexities of myeloid cell differentiation

Acute Myeloid Leukemia

Definition: Acute myeloid leukemia (AML) is a tumor of

hematopoietic progenitors caused by acquired oncogenic mutations that impede differentiation, leading to the accumulation of immature myeloid blasts in the marrow.

AML is a quite heterogeneous disease, reflecting the complexities of myeloid cell differentiation

Differentiation of blood cells

Classification of AMLClassification of AMLTwo types of classificationsTwo types of classifications:

1- 1- FABFAB classification classification- degree of maturation & lineage of blasts- usage of cytochemistry & IHC

2- 2- WHOWHO classification classification - degree of maturation & lineage of blasts- Immunophenotyping- cytogenetic & molecular features- clinical outcome

WHO classificationWHO classification

1. AML with recurrent genetic abnormalities2. AML with multilineage dysplasia3. AML and MDS 4. AML - Tx related5. AML not otherwise categorised6. AML of ambiguous lineage

AMLAMLGenetic Genetic

abnormalityabnormality FAB typeFAB type Out comeOut come

AML t(8,21) M2 Favorable

AML t(15,17) M3 Intermediate

AML t(11q, 23) Poor

AML Rx related Very poorCSBRP-SDUMC-Oct-2014

Very large, immature myeloblasts with many nucleoli. A distincitve feature of these blasts is a linear red "Auer rod" (red arrow) composed of crystallized granules.

Leukemias typically fill up the marrow with abnormal cells, displacing normal hematopoiesis. CSBRP-SDUMC-Oct-2014

At high power, the bone marrow of a patient with acute myelogenous leukemia is seen here. There is one lone megakaryocyte (arrow) at the right center.

Cells Cells

TYPE I AND II MYELOBLASTSAND PROMYELOCYTE

Type-III blastsCSBRP-SDUMC-Oct-2014

Requisits for diagnosis of AMLThe diagnostic requisite of 20 percent type I and II myeloblasts

in the bone marrow or blood cannot be applied uniformly to all types of AML.

BLAST Equivalents:

1. In AML (M3), the predominant leukemic cell is promyelocyte 2. In AML (M5A), the predominant proliferating cell is the

monoblast3. In AML (M5B), the predominant cell is the promonocyte.4. The megakaryoblasts of acute megakaryoblastic leukemia vary

in morphology but uniformly lack the cytochemical properties of myeloblasts.

Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. pp.23-25.

CYTOLOGIC FEATURES OF BLASTS IN ACUTE MYELOID & ACUTE LYMPHOBLASTIC LEUKEMIAS

AMLAML ALLALLBlast sizeBlast size Medium to large, uniform Variable Small to

medium

CytoplasmCytoplasm Fine granules may be present

Usually scant, a few coarse granules may be seen

Auer rodsAuer rods Present in 60-70% of cases absent

Nuclear chromatin Nuclear chromatin Finely dispersed Fine to coarse

NucleoliNucleoli 2-4, prominent 1-3, indistinct

Other cell typesOther cell types Often dysplastic changes in maturing myeloid cells

Myeloid cells are not dysplasticCSBRP-SDUMC-Oct-2014

Auer rods

AML M3 case-3 Bone marrow smear, May-Giemsa stain, x1000 CSBRP-SDUMC-Oct-2014

Auer rodsAuer rodsPresent in the leukemic cells of approximately 60 to 70 percent of

cases of AML, The Auer rod is an azurophilic linear structure of varying length

and WidthAuer rods may be present in numerous blasts or only in rare cells Single or multiple Auer rods may be present. They are generally MPO, SBB, and CAE positive Ultrastructurally, the Auer rod is an alignment and crystallization

of azurophilic granules. The presence of an Auer rod in one or more blasts is

definitive evidence of AML. The finding is not specific for any one type of AML.Auer rods do not occur in cells of erythroid or megakaryocyte

lineage.

Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. pp.26-27.

Auer rodsAuer rods

CYTOCHEMICAL PROFILES OF ACUTE LEUKEMIASCYTOCHEMICAL PROFILES OF ACUTE LEUKEMIAS

MPOMPO/ SBB/ SBB

CAECAE NSENSE PASPAS APAP

ALL _ _ + / -Focally

+ / -Focal in T-

AML + + +Monocytic-

diffuse- / + +

MPO-myeloperoxidase, SBB-Sudan balck B, CAE-chloracetate esterase, NSE-non specific esterase, PAS-periodic acid schiff, AP-acid phosphatase

MPO positivity CSBRP-SDUMC-Oct-2014

SBB positivity AML M1CSBRP-SDUMC-Oct-2014

AML M2 (with trileneage myelodysplasia) Bone marrow smear, alpha-naphthyl butyrate esterase and chloroacetate esterase stains, x1000 case-8. CSBRP-SDUMC-Oct-2014

AML M0, M1, M2

AML M0AML M0

20% blasts < 3% blasts reactive for MPO, SBB or NSEAuer rods are not foundImmunophenotyping:

– 20% blasts express one or more myeloid antigens: CD13, CD14, CD33

– may be TdT positive; – Blasts are negative for lymphocyte antigens

AML-M0 Bone marrow smear, May-Giemsa stain, x1000 CSBRP-SDUMC-Oct-2014

AML M0 Bone marrow smear, cyMPO stain, x1000CSBRP-SDUMC-Oct-2014

AML- M1AML- M120% blasts>3% blasts reactive for MPO or SBB.<10% of marrow nucleated cells are

promyelocytes or more mature neutrophils

Immunophenotyping: Blasts express myeloid antigens: CD13, CD14, CD33.

AML M1 case-1

Bone marrow smear, May-Giemsa stain, x1000CSBRP-SDUMC-Oct-2014

AML M1 CASE-4 PEROXIDASE 1000X BMCSBRP-SDUMC-Oct-2014

AML- M2AML- M2=/>20% Blasts Evidence of maturation to promyelocytes and

more mature neutrophils in 10 percent or more of the cells.

Immunophenotyping: myeloid antigen positive in blasts.

In t(8,21) associated cells: 40-80% are positive for CD19 20% are TdT positive

AML M2 CASE 1 Bone marrow smear, MGG x200 CSBRP-SDUMC-Oct-2014

AML M2 CASE-2 Bone marrow smear, MGG, x1000 CSBRP-SDUMC-Oct-2014

AML M2(with eosinophilia) CASE-7 BM, MGG, x1000 CSBRP-SDUMC-Oct-2014

AML M2 CASE-1 BM Peroxidase stain, x1000 CSBRP-SDUMC-Oct-2014

AML- M3AML- M3

AML M3AML M3A form of AML characterized primarily by a proliferation of

abnormal promyelocytes.

It is usually accompanied by DICt(15;17)

The disease presents in two morphologic types: -- hypergranular APL in which the predominant cell is an

abnormal promyelocyte with markedly increased and coarse azurophilic granules and

-- microgranular or hypogranular APL in which the predominant cell is an abnormal promyelocyte with diminished or small azurophilic granules.

Brunning, RD and McKenna, RW. Tumors of the bone marrow. Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington

D.C.:Armed Forces Institute of Pathology, 1993. p.43.

AML M3AML M3The most common presenting symptoms,

occurring in 90 percent of patients, relate to hemorrhagic manifestations and include easy bruisability, bleeding gums, hemoptysis, epistaxis, petechiae, and symptoms of gastrointestinal bleeding and intracranial hemorrhage.

Basic pathology is DIC.

Brunning, RD and McKenna, RW. Tumors of the bone marrow.

Atlas of Tumor Pathology, 3rd Series, Fascicle 9. Washington D.C.:Armed Forces Institute of Pathology, 1993. p.43.

AML M3 case-3 BM, MGG x1000 CSBRP-SDUMC-Oct-2014

AML M3 Case-8 Bone marrow smear, May-Giemsa stain, x1000CSBRP-SDUMC-Oct-2014

Hypogranular variant – AML-M3 may be mistaken

for AML-M5

AML M3 case-3 BM, Proxidase stain, x1000 CSBRP-SDUMC-Oct-2014

AML- M4AML- M4

AML M4AML M4• Acute myelomonocytic leukemia• Proliferation of both neutrophil and monocyte precurssors• BM blast >20%• >3% of blasts MPO +• >20% of the BM cells are monocytes and their precurssors• Monocytes and their precursors are NSE +• Express CD 13, 33 (myeloid Ag), CD64, 36, and Lysozyme (Monocyte differentiation)• A high number of circulating Monocytes (~5000cells/cumm)

AML M4AML M4Monoblast:• Monoblasts are large cells with abundant cytoplasm

with only moderate basophilia and may show pseudopod formation

• Scattered azurophilic granules and vacuoles in the cytoplasm

• Round nucleus with delicate lacy chromatin• 0ne or more prominent nucleoliPromonocyte:• More irregular, convoluted nucleus• Granularity and vacuolations are more obvious

AML M4 Case-1 Bone marrow smear, May-Giemsa stain, x1000 CSBRP-SDUMC-Oct-2014

AML M4 CASE-1 Bone marrow smear, Peroxidase stain, x1000 CSBRP-SDUMC-Oct-2014

AML M4 Case-1 Bone marrow smear, alpha-naphthyl butyrate esterase and chloroacetate esterase stains, x1000

AML M4( with eosinophilia ) Case-4 , BM< MGG x1000

AML- M5AML- M5

AML M5AML M5• Acute monoblastic leukemia

• >80% of leukemic cells are monocytic lineage (Mb, PMc, Mc)

• Neutrophil component may constitute <20%

• Acute monoblastic Vs monocytic leukemias:

• Monoblasts >80% in monoblastic leukemia

• Promonocytes are predominant in monocytic leukemias

Presentation:

Extramedullary masses

Cutaneous & gingival infiltrations

CNS involvement is common

Gum hypertrophy

Soft tissue masses

AML M5 Case-5 Bone marrow smear, May-Giemsa stain, x1000

AML M5B Case-2 Bone marrow smear, alpha-naphthyl butyrate esterase

and chloroacetate esterase stains, x1000 CSBRP-SDUMC-Oct-2014

AML- M6AML- M6

AML M6AML M6• Def: Erythroleukemia by definition involves both the

granulocytes and erythroid cells.– BM shows >50% are erythroid precurssors (of all

nucleated cells)– >20% myeloblasts in non-erythroid cell population

• PURE erythroleukemia: >80% are erythroid lineage No significant myeloid cells• No myeloid markers in erythroid precurssors• Glycophorin A +• HGB A +• Myeloid precurssors CD13, CD33, CD117, MPO

AML M6 Case-2 Bone marrow smear, May-Giemsa stain, x1000 CSBRP-SDUMC-Oct-2014

AML M6 Case-4 Bone marrow smear, PAS stain, x1000CSBRP-SDUMC-Oct-2014

History: 47year old man with a history of renal transplant as well as refractory anemia with ringed sideroblasts diagnosed 1 year back.

Now he has fatigue and loss of weight. He is on cyclosporin and prednisolone.

Source: CAP

AML M6b AML M6b case-5

Investigations:Blood count revealed anemia and thrombocytopenia and rare blasts. BM revealed 51% erythroid precursors, marked dysplastic changes and “block-and-blush” PAS positivity of erythroid lineage. There were 22% myeloblasts and minimal dysplasia of granulocytic cell line. Diagnosis:Acute erythroleukemia-M6b (pure erythroleukemia).

AML M6b AML M6b case-5

Source: CAP

AML- M7AML- M7

AML M7AML M7

• >50% of the blasts are of MKc lineage• Occur in both adults and children• Uncommon (3-5% of all AMLs)• May be associated with mediastinal

germ cell tumors

AML M7AML M7• MK blast:

– 12-18µm– Round nucleus with reticular chromatin– 1-3 nucleoli– Cytoplasm is basophilic and agranular– Cytoplasmic blebs– May resemble Lymphoblast

• Circulating MKc fragments, abnormal platelets• Clustering of blasts• Immunophenotyping: CD41, CD61, Gp IIb/IIIa• No lymphoid markers

AML M7AML M7

• Frequently manifests in neonatal period• Marked leucocytosis• MPO, SBB, TdT are negative• Some scattered PAS positivity

AML M7 case-1 Bone marrow smear, CD41 x1000 CSBRP-SDUMC-Oct-2014

Malignant germ cell tumor of anterior mediastinum

Acute basophilic leukemiaAcute basophilic leukemia

Acute basophilic leukemia• Myeloid lukemia with differentiation to basophils• No Ph’• Constitute <1%• Metachromatic positivity with Toludene blue• PAS positivity in blocks• MPO, SBB are negative• Myeloid markers are positive (CD13, 33, 34)

OthersOthers

• Acute panmyelosis / myelofibosis• Myeloid sarcoma• Acute leukemia with ambiguous lineage

Specific PresentationsSpecific Presentations

• AML M0, M1, M2 : Chloromas• AML M3 : DIC• AML M4, M5 : Gum hypertrophy• AML M7 : Mediastinal mass

(germ cell tumors)

Clinical PresentationsClinical Presentations

The arrest in myeloid development leads to marrow failure and complications related to:– Anemia– Thrombocytopenia and – Neutropenia / Infections

Frequency of AML

AML M2, M4 are more common (30% each)

Common chromosomal Common chromosomal abnormalities in AMLabnormalities in AML

• t(15,17) in M3 (70-100%) unique to M3

• t(8,21) in M2 (20%) good prognosis

• inv 16 in M4 (~25%) good prognosis

• del 11q in M5 (30%)

SummarySummary

Summary – Acute leukemiasSummary – Acute leukemias

• Leukemias are clonal disorders• Mutations in oncogenes is the most

common underlying pathology• Present with: Anemia, Petichiae,

infections, hepatosplenomegaly, Lymphadenopathy

• There may be normal, low or elevated total white count

SummarySummary AML is a heterogeneous disease Blast count should be 20% in BM There are blast equivalents The presence of an Auer rod is

definitive evidence of AML WHO classification is well accepted Detection of genetic abnormalities dictates

Tx and PrognosisCSBRP-SDUMC-Oct-2014

What’s the best stain for Auer rods?

• What stain is used for demonstrating Auer rods in myeloblasts? Myeloperoxidase or PAS? A. The best stain for demonstrating Auer rods is the myeloperoxidase (MPO) stain. This stain highlights one of two main populations of granules in the neutrophil: the primary (or azurophilic) granules. Secondary (or specific) granules do not light up with MPO. [...]

If the chronic leukemias have lots of mature cells, and the acute leukemias have immature cells, then how come chronic myeloid

leukemia has lots of immature cells? Seems like it belongs in the acute leukemia category!

Are chronic myeloproliferative disorders really leukemias?

How do you diagnose ALL?

Patients with which of the following leukemias may go into DIC if given routine chemotherapeutic agents?

• A. Acute promonocytic leukemia • B. Acute promyelocytic leukemia • C. Acute lymphoblastic leukemia • D. Chronic myeloid leukemia • E. Chronic lymphocytic leukemia

Which of the following leukemias is likely to show a panmyelosis:

• A. Acute lymphoblastic leukemiaB. Acute monoblastic leukemiaC. Acute erythroblastic leukemiaD. Chronic lymphocytic leukemiaE. Chronic myeloid leukemia

A bone marrow biopsy shows 5% myeloblasts and some funny-looking neutrophils and precursors. The most likely diagnosis is:

• A. Acute myeloid leukemiaB. Acute lymphoblastic leukemiaC. Myelodysplastic syndromeD. Bacterial infectionE. Chronic myeloid leukemia

While looking around a blood smear, you notice a blast with an Auer rod in it. This

patient has:

• A. A bacterial infectionB. No disease, unless 20% of the nucleated cells have Auer rodsC. A myelodysplastic syndromeD. Acute myeloid leukemiaE. Acute lymphoblastic leukemia

Which of the following is a GOOD prognostic indicator in acute lymphoblastic leukemia?

• A. Age less than 1B. A WBC >10,000C. B-lineage immunophenotypeD. Normal cytogeneticsE. Age >10

AML-M3

How to differentiate mononucleosis from AML on a blood smear?

Acute leukemias 1-csbrp

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