Module 6 Path

Front 1

General features of acute leukemia?

Back 1

First defined:
Cases of leukemia in which death occurred w/in days to a few weeks w/o treatment

Now Used:
-- designate leukemis in which there is little to no cellular maturation
-- predom cell in the periph blood and BM is a blast

Front 2

Dx of acute leukemia requires...?

Back 2

presence of at least 20% blasts in the BM

Front 3

Etiology of leukemia?

Back 3

heredity
toxic exposures - radiation, chemicals, drugs
possibly viruses

Front 4

Which acute leukemia occurs predominantly in children? adults?

Back 4

ALL is seen most often in children w/ 75% of cases under age 6

AML occurs predom in adults at median age of 60

Front 5

Clinical findings in acute leukemia?

Back 5

1. DECREASED ERYTHROPOIESIS
-- decreased RBC, Hb, and HCT
-- pts almost always anemic at time of presentation w/ various levels of severity

2. DECREASED NORMAL MYELOPOIESIS
-- peripheral count of normal WBC is low, although total WBC is increased due to leukemic cells
-- decreased normal WBC leads to infections
-- pts may present w/ various infectious d/o including perirectal abcess, bacterial pneumonia, etc

3. DECREASED MEGAKARYOPOIESIS
-- leads to thrombocytopenia of varying severity
-- pt may present w/ bleeding d/o's such as increased bruising, nose bleeds, etc

4. TISSUE INFILTRATION BY BLASTS
-- localized symptoms and signs as blasts infiltrate various organ sites
-- ALL more likely to involve CNS
-- AML more likely to involve gingiva

Front 6

How are leukemias classified?

Back 6

LYMPHOCYTIC
- ALL, acute lymphocytic leukemia, acute lymphoblasic leukemia

MYELOCYTIC
- AML, acute myelocytic leukemia, acute myeloblastic leukenia
- ANLL, acute non-lymphocytic leukemia

Within the categories of ALL and AML, subclassif are determined based on:
-- morphology
-- cytochemical stains
-- cell surface markers (immunophenotypes)
-- cytogenetics
-- molecular DNA studies

Front 7

List the cytochemical stains used in subclassifying AML and ALL.

Back 7

sudan black

myeloperoxidase

specific esterase

non-specific esterase

PAS

TdT

Front 8

Sudan black

Back 8

stains the mbrn of the primary granule
--myeloid, monocytic

Front 9

Myeloperoxidase

Back 9

stains the content of the primary granule
-- myeloid, monocytic

Front 10

Specific esterase

Back 10

stains enxyme specific to myeloid series

Front 11

Non-specific esterase

Back 11

stains enzyme presnet in monocytes

Front 12

PAS

Back 12

periodic-acid-Schiff

Stains glycogen in the cytoplasm
-- many types of blasts will stain
-- lymphoblasts tend to have a "chunky" positivity
-- other blasts tend to have finely granular or diffuse staining

Front 13

TdT

Back 13

terminal deoxynucleotide transferase
-- enzyme present in the nucleus of T and B lymphoblasts

Front 14

Myeloid cell markers

Back 14

CD13, 33, 11c, 34

Front 15

Pre-B-lymphoblastic cell markers

Back 15

CD19, 20, 10, 34

Front 16

T-lymphoblastic cell markers

Back 16

CD2, 5, 7

Front 17

B-lymphoblastic cell markers

Back 17

CD19, 20, 10, monoclonal SIg

Front 18

Three main categories of AML classification?

Back 18

1. AML w/ recurrent genetic abnormalities

2. AML w/ multilineage dysplasia

3. AML and myelodysplastic syndromes, therapy related

Also: AML not otherwise categorized

Front 19

Incidence of AML w/ t(18;21)(q22;122)?

Back 19

approx 5-12% of all AML cases

usually occurs in younger patients

Front 20

Morphology of AML w/ t(18;21)(q22;122)?

Back 20

BM shows maturation of myeloid series w/ at least 10% of cells being:
-- promyelocytes
-- myelocytes
-- metamyelocytes

Auer rods are infrequent

Front 21

Genetics of AML w/ t(18;21)(q22;122)?

Back 21

t(18;21) results in fusion of genes AML1 and ETO
-- few cases have been described that show the gene rearrangement w/o cytogenetic evidence of translocation

Front 22

Prognosis of AML w/ t(18;21)(q22;122)?

Back 22

usually good response to chemo w/ high rate of first remission and long-term remissions

Front 23

Incidence of AML w/ abnormal BM eosinophils w/ inv(16)(p13;q22) or t(16;16)(p13;q22)?

Back 23

approx 10-12% of all AML

usually younger patients

Front 24

Morphology of AML w/ abnormal BM eosinophils w/ inv(16)(p13;q22) or t(16;16)(p13;q22)?

Back 24

leukemic blasts show evidence of monocytic and PMN maturation

BM shows increased numbers eosinophils and precursors w/ abnormal granules

Front 25

Genetics of AML w/ abnormal BM eosinophils w/ inv(16)(p13;q22) or t(16;16)(p13;q22)?

Back 25

chromosome abnormalities result in rearrangements of:
-- gene CBFβ (core binding factor β) at 16q22 TO
-- MYHII (smooth muscle myosin heavy chain) at 16p13

Front 26

Prognosis of AML w/ abnormal BM eosinophils w/ inv(16)(p13;q22) or t(16;16)(p13;q22)?

Back 26

relatively better w/ high rates of complete remission and long-term remission

Front 27

Incidence of AML w/ t(15;17)(q22;q12), acute promyelocytic leukemia?

Back 27

approx 5-8% of all AML cases

predominantly middle aged adults

Front 28

Morphology of AML w/ t(15;17)(q22;q12), acute promyelocytic leukemia?

Back 28

-- malignant promyelocytes have a variable shaped nucleus, "kidney bean" shape

Hypergranular form:
-- cytoplasm full of numerous, priminent primary granules,
-- some cells w/ multiple Auer rods

Microgranular variant:
-- "dusty" cytoplasm and inapparent granules w/ typical stain
-- easily demonstrated w/ cytochemistry studies

Front 29

Genetics of AML w/ t(15;17)(q22;q12), acute promyelocytic leukemia?

Back 29

Translocation results in fusion of:
-- the gene retinoic-acid-receptor-α (RARα) on 17q12 with
-- a nuclear regulatory gene, PML (promyelocytic leukemia) on 15q22

Front 30

Prognosis of of AML w/ t(15;17)(q22;q12), acute promyelocytic leukemia?

Back 30

Patients are at high risk of DIC due to pro-coag activity of granules

Response is favorable to all-trans-retinoic-acid followed by chemo

Front 31

Incidence of AML w/ 11q23 abnormalities?

Back 31

approx 5-6% of all AML cases

Front 32

Morphology of AML w/ 11q23 abnormalities?

Back 32

-- most show monocytic differentiation, w/ or w/o PMN differentiation

-- Monocytic differentiation can be detected by morphology, cytochem,and immunophenotype

Front 33

Genetics of AML w/ 11q23 abnormalities?

Back 33

Most common translocations are:
-- t(9;11)(p21;q23)
-- t(11;19)(q23;p13.1)
Results in rearrangement of gene MLL (developmental regulator) at 11q23

Front 34

Prognosis of AML w/ 11q23 abnormalities?

Back 34

Intermediate survival

Front 35

Incidence of acute myeloid leukemia w/ multilineage dysplasia?

Back 35

mainly occurs in elderly

Front 36

Morphology of acute myeloid leukemia w/ multilineage dysplasia?

Back 36

Dysplastic features are apparent in ≥ 50% of marrow cells in at least 2 different cell lines

Front 37

Genetics of acute myeloid leukemia w/ multilineage dysplasia?

Back 37

cytogenetic abnormalities are seen in most cases, and tend to be similar to those seen in MDS such as:
-- -5/del(5q)
-- -7/del(7q)
-- +8
-- +11

Front 38

Prognosis of acute myeloid leukemia w/ multilineage dysplasia?

Back 38

poor response to chemo

Front 39

Incidence of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 39

When related to alkylating agents/radiation exposure, usually occurs 5-6yrs post exposure

When related to topoisomerase II inhibitor, interval from exposure is 12-130 months

Front 40

Morphology of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 40

May present as MDS or AML w/ 20% blasts

Involves all 3 cell lines w/ dysplastic features

Cases assoc w/ topoII inhibitors show monocytic component

Front 41

Genetics of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 41

Most cases will have clonal cytogenetic amnormalities, frequently:
-5/5del(q)
-7/7del(q)

Cases assoc w/ topoII inhibitors will have t(9;11)

Front 42

Prognosis of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 42

Little or no response to therapy

Cases assoc w/ topoII inhibitors may have prognosis similar to primary acute leukemia

Front 43

What are the AML's not otherwise categorized?

Back 43

-- AML, minimally differentiated
-- AML, w/o maturation
-- AML, w/ maturation
-- Acute myelomonocytic leukemia (AMML)
-- Acute monoblastic leukemia, acute monocytic leukemia
-- Acute erythroid leukemia
-- Acute megakaryoblastic leukemia
-- Acute basophilic leukemia
-- Acute panmyelosis w/ myelofibrosis
-- Myeloid sarcoma

Front 44

AML, minimally differentiated

Back 44

≥ 20% blasts in the BM that have:
-- no Auer rods
-- negative cytochem stains
-- have myeloid markers by immunophenotyping

Approx 50-75% of cases will have clonal chrom aberrations, but no distinctive cytogenetic or molecular DNA abnormalities are seen

Front 45

AML, w/ maturation

Back 45

≥20% blasts and >10% of cells showing maturation to:
-- promyelocytes
-- myelocytes
-- metamyelocytes

Frequent Auer rods seen

Approx 30-45% of all cases of AML

Occurs more often in younger age groups and has relatively better prognosis

Front 46

Incidence of AML w/ 11q23 abnormalities?

Back 46

approx 5-6% of all AML cases

Front 47

Morphology of AML w/ 11q23 abnormalities?

Back 47

-- most show monocytic differentiation, w/ or w/o PMN differentiation

-- Monocytic differentiation can be detected by morphology, cytochem,and immunophenotype

Front 48

Genetics of AML w/ 11q23 abnormalities?

Back 48

Most common translocations are:
-- t(9;11)(p21;q23)
-- t(11;19)(q23;p13.1)
Results in rearrangement of gene MLL (developmental regulator) at 11q23

Front 49

Prognosis of AML w/ 11q23 abnormalities?

Back 49

Intermediate survival

Front 50

Incidence of acute myeloid leukemia w/ multilineage dysplasia?

Back 50

mainly occurs in elderly

Front 51

Morphology of acute myeloid leukemia w/ multilineage dysplasia?

Back 51

Dysplastic features are apparent in ≥ 50% of marrow cells in at least 2 different cell lines

Front 52

Genetics of acute myeloid leukemia w/ multilineage dysplasia?

Back 52

cytogenetic abnormalities are seen in most cases, and tend to be similar to those seen in MDS such as:
-- -5/del(5q)
-- -7/del(7q)
-- +8
-- +11

Front 53

Prognosis of acute myeloid leukemia w/ multilineage dysplasia?

Back 53

poor response to chemo

Front 54

Incidence of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 54

When related to alkylating agents/radiation exposure, usually occurs 5-6yrs post exposure

When related to topoisomerase II inhibitor, interval from exposure is 12-130 months

Front 55

Morphology of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 55

May present as MDS or AML w/ 20% blasts

Involves all 3 cell lines w/ dysplastic features

Cases assoc w/ topoII inhibitors show monocytic component

Front 56

Genetics of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 56

Most cases will have clonal cytogenetic amnormalities, frequently:
-5/5del(q)
-7/7del(q)

Cases assoc w/ topoII inhibitors will have t(9;11)

Front 57

Prognosis of acute myeloid leukemias and myelodysplastic syndromes, therapy related?

Back 57

Little or no response to therapy

Cases assoc w/ topoII inhibitors may have prognosis similar to primary acute leukemia

Front 58

What are the AML's not otherwise categorized?

Back 58

-- AML, minimally differentiated
-- AML, w/o maturation
-- AML, w/ maturation
-- Acute myelomonocytic leukemia (AMML)
-- Acute monoblastic leukemia, acute monocytic leukemia
-- Acute erythroid leukemia
-- Acute megakaryoblastic leukemia
-- Acute basophilic leukemia
-- Acute panmyelosis w/ myelofibrosis

Front 59

AML, minimally differentiated

Back 59

≥ 20% blasts in the BM that have:
-- no Auer rods
-- negative cytochem stains
-- have myeloid markers by immunophenotyping

Approx 50-75% of cases will have clonal chrom aberrations, but no distinctive cytogenetic or molecular DNA abnormalities are seen

Front 60

AML, w/ maturation

Back 60

≥20% blasts and >10% of cells showing maturation to:
-- promyelocytes
-- myelocytes
-- metamyelocytes

Frequent Auer rods seen

Approx 30-45% of all cases of AML

Occurs more often in younger age groups and has relatively better prognosis

Front 61

AML, w/o maturation

Back 61

≥20% blasts in BM w/ <10% cells of myeloid maturation

Auer rods may be seen

Approx 50-75% of cases will have clonal chromosome abnormalities, but no distincive cytogenetic or molecular DNA abnormalities are seen

Front 62

Acute myelomonocytic leukemia (AMML)

Back 62

leukemic blasts show myeloid and monocytic differentiation w/ >20% but <80% monocytic cells

No specific clonal aberrations, but many cases involve 11q

Approx 15-20% of cases of AML

Front 63

Acute monoblastic leukemia

Acute monocytic leukemia

Back 63

Leukemic blasts show >80% with monocytic differentiation

Monoblastic:
-- predom of monoblasts

Monocytic:
-- some maturation with promonocytes and monocytes

No specific chromosome aberration, but 11q is frequently involved

Approx 5-8% of cases of AML

Clinically, this type of leukemia more often has tissue infiltration, particularly gingival hypertrophy

Front 64

Acute erythroid leukemia

Back 64

Rare type of acute leukemia that has a predominance of erythroblasts

Poor prognosis

No specific type of chrom aberration

Front 65

Acyte megakaryoblastic leukemia

Back 65

Prolif of megakaryoblasts and abnormal mature megakaryocytes

Freq assoc w/ fibrosis in the BM hampering diagnosis

Front 66

Acute lymphocytic leukemia (ALL) general info

Back 66

May occur at any age, but more often in pediatric age groups w/ peak indidence of 4yrs.

WHO classification based on cell surface markers

Front 67

Types of ALL?

Back 67

Precursor B lymphoblastic leukemia/lymphoma

Precursor T lymphoblastic leukemia/lymphoma

Front 68

Incidence of precursor B lymphoblastic leukemia/lymphoma?

Back 68

Most cases of ALL are precursor-B, and most cases of lymphoma are precursor-T

Front 69

Morphology of precursor B lymphoblastic leukemia/lymphoma?

Back 69

Two distinctive morphologies:

1. BLASTS -- small w/ minimal cytoplasm; homogenous in appearance
NUCLEUS -- immature but slightly course chromatin, no nucleoli

2. BLASTS - somewhat larger w/ moderate cytoplasm; more heterogenous in appearance
NUCLEUS - usually 1 to 2 nucleoli

Front 70

Genetics of precursor B lymphoblastic leukemia/lymphoma?

Back 70

Cytogenetics are very important for prognosis and determining high-risk vs. low-risk cases

Good prognosis:
-- hyperdiploid >50 chrom
-- normal
-- t(12;21)(p13;q22)

Intermediate to Poor Prognosis:
-- t(9;22)(q34;q11.2)
-- t(v;11)(q23)
-- t(1;19)(q23;p13.3)
-- hypodiploid, <46 chrom

Front 71

Incidence of precursor T lymphoblastic leukemia/lymphoma?

Back 71

few cases of ALL, but most cases of lymphoblastic lymphoma are precursor T

Front 72

Morphology of precursor T lymphoblastic leukemia/lymphoma?

Back 72

Same as for precursor B

Some cases may show convolutions of the nucleus

Front 73

Genetics of of precursor T lymphoblastic leukemia/lymphoma?

Back 73

Many will have abnormal chrom at loci of T-cell receptor genes: 14q11.2, 7q35, 7p14-15

Front 74

Prognosis of precursor T lymphoblastic leukemia/lymphoma?

Back 74

Most cases are considered high-risk