Transcript the leukemias

Chicago Medical School
The Leukemias
Arthur S. Schneider, M.D.
2012
Department of Pathology
Chicago Medical School at
Rosalind Franklin University of Medicine and Science
THE LEUKEMIAS
• acute leukemias
– acute lymphoblastic leukemia (ALL)
– acute myeloblastic leukemia (AML)
• chronic leukemias
– chronic lymphoid leukemia (CLL)
– chronic myelogenous leukemia (CML)
THE LEUKEMIAS
• malignancies involving lymphoid or
hematopoietic cell lines
• increase in circulating leukocytes (not
invariable)
• bone marrow always involved
• replacement/hypoproliferation of normal
hematopoietic cells
– anemia, infection, hemorrhage
– leukemic infiltration in liver, spleen, lymph
nodes, and other tissues
THE LEUKEMIAS
• acute leukemias
• chronic leukemias
Blast cell in acute leukemia
ACUTE LEUKEMIAS
• predominance of blasts
• aleukemic leukemia
– WBC count normal or decreased
– no blasts in peripheral blood
– leukemic cells in marrow
ACUTE LEUKEMIAS
• most common malignancy in childhood
• second age peak after age 60
• short clinical course (without treatment)
• anemia, infection, thrombocytopenic
bleeding
• lymph nodes and spleen variably enlarged
ACUTE LEUKEMIAS
• two major classes: acute lymphoblastic
and acute myeloblastic leukemia
• blast cells often clearly identifiable as
myeloid or lymphoid
• special stains, immunologic markers, gene
rearrangement studies often useful
• cytogenetic abnormalities frequent
Acute lymphoblastic leukemia
ACUTE LYMPHOBLASTIC
LEUKEMIA (ALL)
• lymphoblast predominant cell type
• most frequent in children
• better prognosis than AML
• FAB classification L1-L3
– not used as a diagnosis, just as a descriptor
– entirely based on morphology
ACUTE LYMPHOBLASTIC
LEUKEMIA (ALL)
• cytogenetic changes frequent
– hyperdiploidy associated with better prognosis
– Ph1 chromosome associated with poorer
prognosis
– t (8;14) associated with B-ALL
FAB L1 type of ALL
FAB L2 type of ALL
FAB L2 type of ALL
FAB L3 type of ALL
FAB L3 type of ALL
OLDER IMMUNOLOGIC
CLASSIFICATION
• This classification is no longer used as
such, but is helpful to understanding.
– common (CALLA) - positive) ALL
(CALLA=CD10)
– null ALL
– T-ALL
– B-ALL
CLP, common lymphoid precursor
DN, CD4/CD8 double
negative pre-T cell
BLB, pre-B lymphoblast
DP, CD4/CD8 double
positive pre-T cell
NBC, naive B cell
PC, plasma cell
MC, mantle B cell
PTC,
peripheral
T cell
GC, germinal center
B cell
MZ, marginal zone B cell
(Early B-precursor, Pre-B ALL)
• 70% of childhood leukemia
• best prognosis
• cells react with common acute
lymphoblastic leukemia antigen (CALLA,
CD10)
• early B precursor - surface Ig absent
• CD19, CD20 positive
(Early B-precursor, Pre-B ALL)
• Ig heavy chain rearrangement
• Ig light chain rearrangement in some
• often positive for terminal deoxynucleotidyl
transferase (TdT)
• FAB L1 or sometimes L2
B-ALL
• 2-5% of ALL
• FAB L3 morphology
• t(8;14)
• sig positive, cig (Cµ) negative
• leukemic analog to Burkitt lymphoma
FAB L3 type of ALL
AML (note Auer rod)
AML (note Auer rod)
ACUTE MYELOBLASTIC
LEUKEMIA (AML, ANLL)
• myeloblasts and early promyelocytes
predominant cells
• most frequent in adults
• poorer response to therapy than ALL
• Auer rods, when present, are
pathognomonic of leukemic myeloblasts
• positive staining for myeloperoxidase
AML (myeloperoxidase stain)
FRENCH-AMERICAN-BRITISH
(FAB) CLASSIFICATION OF AML
M0 - myeloblastic leukemia with minimal
differentiation; CD13 or CD33 positive
M1 - myeloblastic leukemia without
maturation; myeloperoxidase positive
M2 - myeloblastic leukemia with
maturation
M3 - hypergranular promyelocytic
leukemia
M4 - myelomonocytic leukemia
M5 - pure monocytic leukemia
M6 - erythroleukemia
M7 - megakaryocytic leukemia
PROPOSED WHO
CLASSIFICATION OF AML
• I. AML with Recurrent Chromosomal
Rearrangements
– AML with t(8;21)(q22;q22); CBFα/ETO fusion gene
• favorable prognosis
– AML with inv(16)(p13;q22); CBFβ/MYH11 fusion gene
• favorable prognosis
– AML with t(15;17)(q22;11-12); RARα/PML fusion gene
• intermediate prognosis
– AML with t(11q23;v); diverse MML fusion genes
• poor prognosis
PROPOSED WHO
CLASSIFICATION OF AML of
AML
• II. AML with Multilineage Dysplasia
– with prior myelodysplastic syndrome
• very poor prognosis
– without prior myelodysplastic syndrome
• poor prognosis
PROPOSED WHO
CLASSIFICATION OF AML
• III. AML, Therapy Related
– alkylating agent related
• very poor prognosis
– epipodophyllotoxin (a topoisomerase II inhibitor)
related
• very poor prognosis
• IV. AML, not Otherwise Specified
– sub-classes defined by extent of differentiation and
FAB classification (e.g., M0-M7)
• Intermediate prognosis
FAB M1
FAB M1
AUER
ROD
AML
FAB M2
FAB M2
FAB M3
FAB M3
FAB M3
FAB M3 t(15;17)
FAB M3 ACUTE
MYELOBLASTIC LEUKEMIA
• also known as acute promyelocytic leukemia
• t(15;17)
– retinoic acid receptor- (RAR- ) on chromosome 17
– PML on chromosome 15
• better prognosis than other FAB types of AML
• frequently associated with disseminated
intravascular coagulation (DIC)
• cells can be induced to mature by treatment with
ALL-trans-retinoic-acid (ATRA), a vitamin A
analogue
FAB M4
FAB M4
Double esterase
stain
FAB M5
FAB M5
FAB M5
FAB M6
FAB M6
FAB M6
FAB M6
PAS Stain
CHROMOSOMAL CHANGES IN
AML
• t(9;22): poor prognosis (also in ALL)
• t(15;17): M3 AML; intermediate prognosis
• t(8;21): favorable prognosis
REMINDER OF EARLIER
PROJECTION OF PROPOSED
NEW WHO CLASSIFICATION
• I. AML with Recurrent Chromosomal
Rearrangements
– AML with t(8;21)(q22;q22); CBFα/ETO fusion gene
• favorable prognosis
– AML with inv(16)(p13;q22); CBFβ/MYH11 fusion gene
• favorable prognosis
– AML with t(15;17)(q22;11-12); RARα/PML fusion gene
• intermediate prognosis
– AML with t(11q23;v); diverse MML fusion genes
• poor prognosis
CASE THIRTEEN
A 20-year-old woman, a marathon runner,
presented with fever, anemia, and
hemorrhagic phenomena all of two weeks
duration.
Physical examination revealed a fever of 40°
C. Pallor and multiple scattered purpuric
hemorrhages were apparent as well as
oozing bleeding of the oral mucosae and
gingiva.
CASE THIRTEEN
A few scattered cervical and inguinal nodes
were palpable but were not considered
impressive. The spleen was palpable 1
cm below the left costal margin on deep
inspiration.
The total WBC was 30,000/µl, and on the
peripheral smear 100% of the white cells
were undifferentiated blast forms. The
hemoglobin was 8 gm/dl, and the platelet
count was 10,000/µl.
CASE THIRTEEN
1. What is your initial working diagnosis?
2. Can the diagnosis be defined more
closely? What laboratory procedures may
be of value?
3. What is the significance of positive or
negative staining of the blast cells for
myeloperoxidase?
CASE THIRTEEN
What is meant by immunophenotyping?
What help might you get from this
procedure?
What is the role of gene rearrangement
studies in this group of disorders?
Do any of these studies have anything to do
with prognosis or with management?
CHRONIC LEUKEMIAS
• longer clinical course
• chronic lymphocytic (lymphatic)
leukemia (CLL)
– mature-appearing lymphocytes
• chronic myelocytic (myeloid,
myelogenous, granulocytic) leukemia
(CML, CGL)
– segs, bands, metamyelocytes, and
myelocytes
CLL
CML
CML
CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)
• most common in persons over age 60
• no relation to ionizing radiation or
alkylating agents
• rare in Asia
• "indolent" clinical course
• hypogammaglobulinemia
• generalized lymphadenopathy and
moderate hepatosplenomegaly
• WBC count markedly elevated
• mature lymphocytosis
CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)
• anemia as disease progresses, sometimes
thrombocytopenia
• almost always B-CLL
• T-CLL quite rare
• sig positive
• frequent chromosomal abnormalities:
trisomy 12, structural abnormalities of
chromosome 13 or 14
CHRONIC LYMPHOCYTIC
LEUKEMIA (CLL)
• CD19, CD20, CD21, CD23, CD24 positive
• CD5 positive, CD10 negative
CLL
CLL
CLL in lymph node
CAUSES OF ANEMIA IN CLL
• "packed marrow"
• erythroid hypoplasia due to drug therapy
• autoimmune hemolytic anemia
• other causes (blood loss, iron deficiency,
etc.)
HAIRY CELL LEUKEMIA
• middle aged men
• prominent splenomegaly and
pancytopenia
• dramatic response to several therapeutic
agents: alpha interferon (alpha IFN), 2chlorodeoxyadenosine (2-CdA),
deoxycoformycin
HAIRY CELL LEUKEMIA
• B-cell disease
• characteristic hair-like filamentous
projections of tumor cells
• tartrate resistant acid phosphatase (TRAP)
Hairy cell leukemia
Hairy cell leukemia
Hairy cell leukemia (positive TRAP
stain)
CHRONIC MYELOGENOUS
LEUKEMIA
• neoplastic clonal proliferation of myeloid
stem cells
• one of the myeloproliferative syndromes
• peak age incidence 35-50
• survival 3-5 years
• WBC count greatly elevated
CHRONIC MYELOGENOUS
LEUKEMIA
• myelocytes, metamyelocytes, bands, and
segs are predominant cells
• only a few blasts and promyelocytes
• increase in basophils
• anemia late in course
• platelets often increased at first
CHRONIC MYELOGENOUS
LEUKEMIA
• prominent splenomegaly
• liver and lymph nodes only modestly
enlarged
• acceleration late in course accounts for
most deaths
• 25% of blast crises are lymphoblastic
CML
CML
CHRONIC MYELOGENOUS
LEUKEMIA
• t(9;22) and Ph1 chromosome
• hybrid bcr-abl neogene codes for protein
p210
• rarely Ph1 chromosome absent - poorer
prognosis
• leukocyte alkaline phosphatase markedly
decreased
• Ph1 chromosome and leukocyte alkaline
phosphatase important in differential
diagnosis
CML t(9;22)
t(9;22) and bcr-abl in CML
Strongly positive stain for leukocyte
alkaline phosphatase in a normal
neutrophil
CASE ELEVEN
A 64-year-old man was referred to a
hematologist because of an abnormal
CBC which had been discovered during a
routine insurance examination. Physical
examination revealed slight pallor and
generalized lymphadenopathy and
hepatosplenomegaly.
CASE ELEVEN
The WBC was 90,000/µl, RBC 2.5 million/µl,
hemoglobin 7.3 gm/dl, and hematocrit
2l.8%. MCV was 87 µ3, MCH 29 pg, and
MCHC 33.5%.
Examination of the peripheral blood smear
revealed the presence of many
microspherocytes, as well as abundant
polychromatophilic erythrocytes.
CASE ELEVEN
The differential count revealed l00% matureappearing lymphocytes. The reticulocyte
count was l5%, and the direct Coombs’
test was positive.
1. What is the underlying hematologic
diagnosis?
2. What is the cause of the anemia?
3. The patient asks you what can he expect.
How would you counsel him?
CASE TWELVE
A 45-year-old man was seen because of
massive splenomegaly. The white count
was elevated to 200,000--with 2%
myeloblasts, l0% promyelocytes, 20%
myelocytes, 20% segs, l5% basophils, 5%
eosinophils, and 8% monocytes.
CASE TWELVE
1. What is the most likely diagnosis? What
are some other diagnostic possibilities?
2. Name two laboratory tests and their
expected results that will allow you to
confirm the most likely possibility.
3. Are there any newer laboratory
procedures that might also be of value?
Describe the expected results.
CASE TWELVE
4. You begin therapy and continue to
closely monitor the patient. After three
years of relatively uneventful followup, the
percentage of blasts and promyelocytes
on the peripheral smear begins to
increase. What is happening?
Is this an expected finding?