Transcript Acute lymphoblastic leukemia/lymphoma (ALL)

Acute lymphoblastic
leukemia/lymphoma (ALL)
• A group of neoplasms of B or T lymphoblasts
• Pre-B cell (85%): childhood acute leukemias
• Pre-T cell: lymphomas in adolescent males,
50~70% with mediastinal (thymic) masses
• B & T : similar histology, immunophenotype
• Chromosome anomaly (90%): hyperdiploidy,
pseudodiploid, t(12;21), t(9;22), and t(4;11)
Diagnosis
Cell of
Origin
Genotype
Salient Clinical
Features
Precursor B- Bone
Diverse
Predominantly
cell acute
marrow
chromosom
children with
lymphobla
precursor
al
symptoms
stic
B-cell
translocatio
relating to
leukemia/l
expressin
ns; t(12;21)
pancytopenia
ymphoma
g TdT and
involving
secondary to
lacking
CBFαand
marrow
surface Ig
ETV6 most
involvement;
aggressive
common
rearrangem
ent
Precursor Precursor T- Diverse
T-cell
cell (often
chromosomal
acute
of thymic
translocations,
lympho
origin)
many involving
blastic
expressin
T-cell receptor
g TdT
leukem
loci;
ia/lymp
rearrangements
homa
of TAL1 most
common
Predominantly
adolescent
males with
thymic
masses;
variable
splenic,
hepatic, and
bone
marrow
involvement;
aggressive
BM smear: lymphoblasts
Flow cytometry immunophenotype
Clinical features of ALL
• Blasts in BM suppress hematopoiesis by physical
crowding: anemia, neutropenia, thrombocytopenia
• Abrupt stormy onset
• Bone pain and tenderness
• Generalized lymphadenopathy (LAP),
splenomegaly, hepatomegaly
• CNS manifestations
• Treatment (Tx) & prognosis (Px)
Myeloid Neoplasms
• This heterogeneous group of neoplasms is an
origin in a progenitor cell that normally gives rise
to terminally differentiated cells of the myeloid
series (erythrocytes, granulocytes, monocytes, and
platelets).
• Bone marrow (BM) and other MPS
• AML: immature myeloid cells in the BM
• MDS: ineffective hematopoiesis & cytopenia
• MPD: increased production of terminally
differentiated myeloid cells
Acute myelogenous leukemia
(AML)
• Primarily in adult: peak age, 15~39 y/o
• Pathophysiology: acquired genetic alteration 
inhibition of terminal differentiation  physical
replacement pancytopenia
• Tx: clear the BM leukemic clone (cytotoxic drugs),
overcome the block in differentiation
• Classification
• Diagnosis: >20% myeloid blasts in BM, variable
number of leukemic cells in PB (aleukemic
leukemia)
Revised FAB Classification of AML
Class
M0 Minimally
differentiated
AML
Incidence (%
of AML)
2-3%
20%
M1 AML
without
Differentiation
M2 AML with
maturation
30-40%
Marrow Morphology/Comments
Blasts lack definitive cytologic and
cytochemical markers of myeloblasts
(e.g., myeloperoxidase negative) but
express myeloid lineage antigens and
resemble myeloblasts ultrastructurally.
Very immature, but =3% of blasts are
peroxidase positive; few granules or
Auer rods and little maturation beyond
the myeloblast stage.
Full range of myeloid maturation through
granulocytes; Auer rods present in
most cases; often associated with the
t(8;21).
5-10%
M3 Acute
promyelocytic
leukemia
Most cells are hypergranular
promyelocytes, often with
many Auer rods per cell;
patients are younger (median
age 35 to 40 years); high
incidence of DIC; strong
association with the t(15;17).
15-20% Myelocytic and monocytic
M4 Acute
myelomonocy
differentiation evident;
tic leukemia
myeloid elements show
range of maturation;
monoblasts are positive for
nonspecific esterases; subset
associated with the inv(16).
10%
M5 Acute
monocytic
leukemia
In M5a subtype, monoblasts
(peroxidase-negative,
nonspecific esterase-positive)
and promonocytes
predominate in marrow and
blood;
In M5b subtype, mature
monocytes predominate in
the peripheral blood; M5a
and M5b occur in older
patients; characterized by
high incidence of
organomegaly,
lymphadenopathy, and tissue
infiltration.
5% Dysplastic erythroid precursors
M6 Acute
erythroleukemia
(some megaloblastoid, others with
giant or multiple nuclei)
predominate, and within the nonerythroid cells, >30% are
myeloblasts; seen in advanced
age; makes up 1% of de novo AML
and 20% of therapy-related AML.
1% Blasts of megakaryocytic lineage
M7 Acute
megakaryocytic
predominate; blasts react with
leukemia
platelet-specific antibodies
directed against GPIIb/IIIa or vWF;
myelofibrosis or increased marrow
reticulin seen in most cases.
Proposed WHO Classification of AML
Class
Prognosis
I. AML with Recurrent Chromosomal
Rearrangements
AML with t(8;21)(q22;q22); CBFα/ETO Favorable
fusion gene
AML with inv(16)(p13;q22);
CBFβ/MYH11 fusion gene
Favorable
AML with t(15;17)(q22;11-12);
RARα/PML fusion gene
Intermediate
AML with t(11q23;v); diverse MML
fusion genes
Poor
II. AML with Multilineage Dysplasia
With prior myelodysplastic syndrome
Very poor
Without prior myelodysplastic syndrome
Poor
III. AML, Therapy Related
Alkylating agent related
Very poor
Epipodophyllotoxin related
Very poor
IV. AML, not Otherwise Specified
Sub-classes defined by extent of
differentiation and FAB classification
(e.g., M0-M7)
Intermediate
BM smear: myeloblasts (M1)
Flow cytometry immunophenotype
Acute promyelocytic leukemia (M3)
Acute monocytic leukemia (M5b)
Chromosomal Abnormalities of
AML
• 90% AML, with prognostic implication
• Ch 5 or 7 deletion: AML after MDS of CT/RT
• AML M3 (APL): t(15;17)  RAR-α/PML fused
gene  hybrid mRNA  abnormal retinoic acid
receptor  block myeloid cell differentiation =>
all-trans-retinoic acid causing neoplastic
promyelocytes  neutrophils (differentiation
therapy), but all patients ultimately relapse
Clinical Features of AML
• Weeks or a few months of the onset of symptoms
with findings related to pancytopenia, similar to
that of ALL
• APL: DIC (disseminated intravascular coagulation)
• M4 &M5: infiltration of the skin (leukemia cutis)
and the gingiva
• localized mass composed of myeloblasts:
granulocytic sarcoma (myeloblastoma, chloroma)
Myelodysplastic Syndrome (MDS)
• A group of clonal stem cell disorders characterized
by maturation defects resulting in ineffective
hematopoiesis and an increased risk of
transformation to AML
• BM replaced by the clonal progeny of a mutant
multipotent stem cell that retains the capacity to
differentiate into RBC, WBC, PLT, but in an
ineffective and disordered manner
• BM: hyper-/normo-cellular, PB: pancytopenia
• Idiopathic (primary) or therapy-related (t-MDS)
MDS
• Pathogenesis: unknown (? Stem cell damage)
• monosomy 5/7, 5q/7q deletions, trisomy 8, 20q
deletion
• MF: dysplastic differentiation & <30% blasts
–BM: ring sideroblasts, megaloblastoid maturation,
nuclear budding; pseudo-Pelger-Huet cells, hypoor hyper-lobated nucleated megakaryocytes
– PB: pseudo-Pelger-Huet cells, giant PLT,
macrocyte, poikilocyte, monocytosis
BM smear: myelodysplasia
Clinical Course of MDS
• Adult >60 y/o
• S/S: pancytopenia, asymptomatic (half)
• multiple chromosomal abnormalities and severity
of cytopenia
• median survival: 9~29 months (may >5 yrs)
• 10~40%: AML transformation
• t-MDS: 4~8 months, more grim prognosis
• Tx: allogeneic BMT for younger patients;
supportive treatment for the older
Chronic Myeloproliferative
Disorders (MPD)
• A group of disorders of multipotent progenitor cell
capable of terminal differentiation =>
hypercellular BM and increased hematopoiesis &
PB counts, extramedullary hematopoiesis &
splenomegaly, later in spent phase (may progress
to AML, especially in CML)
• CML, PCV (PV), ET, IM
• non-specific pathologic findings, overlap with one
another and some reactive hyperplasia
• Dx: clinical+morphologic+cytogenetic
Chronic Myelogenous Leukemia
• Age: 25~60 y/o (peak 30+~40+y/o)
• Genetics: Philadelphia chromosome (Ph1)>90%
• MF: hypercellular BM with sea-blue histiocytes;
leukocytosis, eosinophilia, and basophilia in PB;
neoplastic extramedullary hematopoiesis (splenomegaly)
• S/S: anemia, hypermetabolism, LUQ distension or pain,
lack of leukocyte alkaline phosphatase
• Course: slow progression (median survival 3 yrs);
accelerated phase (50%)  6-12 m blast crisis  70%
AML, 30% ALL (most early B lineage)
• Tx: low-dose CT, allogeneic BMT (75% cure)
Fluorescence in situ hybridization (FISH)
FISH
FISH
PB smear: chronic myeloid leukemia
Spleen in CML
PCV: polycythemia vera
•
•
•
•
•
A multipotent myeloid stem cell neoplasm
absolute increase in red cell mass (Hb, Hct…)
serum erythropoietin: virtually undetectable
BM: hyperplasia  fibrosis (spent phase)
Age: 60 y/o; S/S: increased red cell mass 
hematocrit  total blood volume  vascular
stasis (hypertensive, cyanotic, pruritus, gout…)
• risk of bleeding and thrombotic episodes
• Px: 10 yrs, spent phase (M with MM), 2~15% to
AML; Tx: phlebotomy
Spleen in PCV
ET: essential thrombocytosis
•
•
•
•
The least common form of MPD
Megakaryocytic hyperplasia: PLT>600K
Dx: by exclusion of other MPDs or reactive
BM: mild to moderate hyperplasia with marked
megakaryocytic hyperplasia
• PB: giant PLT, mild leukocytosis
• S/S: thrombosis and hemorrhage
• Px: indolent disorder, long asymptomatic periods,
median survival: 12~15 yrs
PB smear: ET
IM: myelofibrosis with myeloid
metaplasia (MMM)
• Hallmark: early marrow fibrosis (myelofibrosis)
• neoplastic megakaryocytes release PDGF & TGF- 
 fibrosis  hematopoietic stem cells seed the
spleen, liver, LNs  EMH (MM)
• BM: early hypercellularity, megakaryocytic
hyperplasia and dysplasia, minimal fibrosis 
hypocellularity, diffuse fibrosis or osteosclerosis
• Spleen: huge, EMH with large, clustered megaK
• PB: leukoerythroblastosis, dacryocytes
PB smear: normoblast &
dacryocytes
Clinical Course of MMM
• Age: 60 y/o or more
• S/S: progressive anemia or huge spleen,
hyperuricemia and secondary gout
• Lab: moderate to severe anemia (normochromic
and normocytic) with leukoerythroblastosis, WBC
(variable) & PLT (N or elevated, then decreased)
• median survival: 1~5yrs, complication: infection,
thrombosis, bleeding, 5~20% to AML
Langerhans cell histiocytosis
(Histiocytosis X)
• Clonal proliferation of the antigen-presenting
dendritic cells (normal in the skin and others)
• Three categories:
－ Letterer-Siwe disease: acute disseminated
－ Hand-Schuller-Christian disease: calvarial
defects, diabetes insipidus, and exophthalmos
－ Eosinophilic granuloma
• EM: HX bodies (Birbeck granules)
Spleen
Splenic infarcts
Thymoma, benign
Thymoma, invasive