Transcript leukemiax







Blasts characteristically express TdT,
cytoplasmic CD22 and CD79a, CD19, and
HLA-DR
CD10 (common ALL antigen) is expressed
Expression of CD34 is variable
Cytoplasmic μ immunoglobulin heavy chain
(cyt-μ) indicates a slightly more mature state
but surface immunoglobulin is negative
Myeloid-associated antigens CD13, CD33, and
CD15 may be expressed.


Cytogenetic findings are increasingly
important in diagnosis and prognostication in
ALL and have been previously reviewed
The current WHO classification divides B-ALL
into groups based on frequently found
(recurrent) cytogenetic findings.







in about 30% of cases of adult (20% detected at
karyotyping)
6% of cases of childhood ALL
Poor prognosis
210 kD fusion protein, occurring in half of adult
cases
190 kD protein occurs in most childhood Ph′positive cases
Ph′-positive ALL is most often of precursor B cell
lineage
May present with biphenotypic myeloid
differentiation





5%–7% of cases of ALL
as well as in AML
ALL with t(4;11)(q21;q23) is associated with poor
prognosis, high WBC count, and immature Blineage phenotype with lack of CD10 but with
CD15 expression
Translocation t(11;19)(q23;p13.3) is the next most
frequent MLL abnormality in ALL
Overall, 11q23 (MLL) abnormalities, with the
possible, confer poor prognosis.





25% of B-ALL,
Correlates with high-density CD10 and HLADR expression with negative CD20
Good prognosis
The abnormality is difficult to detect by karyotyping
can be detected by RT-PCR analysis for the chimeric
mRNA or by FISH.

associated with decreased response to therapy.


This rare variant of B-ALL is associated with
eosinophilia
Immunophenotype is CD19+, CD10+.




B-ALL with multiple trisomies and between 50
and 66 chromosomes (normal = 46) is referred
to as hyperdiploid
This usually occurs in children and implies
favorable prognosis
Trisomies of chromosome 4,10, and 17 are
considered markers for low-risk disease in
pediatric leukemia protocols
Blasts usually express CD19, CD10, and CD34
but often are CD45 negative.


Hypodiploid B-ALL shows fewer than the
normal 46 chromosomes
Prognosis is unfavorable, especially when
chromosomes are fewer than 45, and even
more so when fewer than 44.

B Lymphoblastic Leukemia/Lymphoma, Not
Otherwise Specified (Refers to All Other BALL)


AML with Balanced Translocations/Inversions
AML with Gene Mutations






The morphology usually corresponds to acute
myeloid leukemia with neutrophilic maturation,
5%–12% of AML, with predominance in young
patients.
Blasts are 20% or greater in the marrow (or blood),
Monocytosis is not prominent, and monocytes are
less than 20% of the marrow
Eosinophilia is common, and basophils or mast
cells may be increased
One or more B cell markers—CD19, PAX5, and
cytoplasmic CD79a—are often coexpressed.


The presence of t(8;21) is diagnostic of AML,
even when blasts appear to be less than 20%
The outcome of AML with t(8;21) is generally
more favorable than AML without recurrent
genetic abnormalities, or with MDSassociated abnormalities




These correspond to acute myelomonocytic
leukemia with abnormal eosinophils
Occurrence and outcome are similar to AML
with t(8;21)
These cases show >20% blasts in marrow
and/or blood with differentiation to monocytic
and neutrophilic lineages (≥20% each).
Eosinophils are characteristically increased

Secondary genetic abnormalities are common,
including trisomy 22, which is relatively
specific for this disease, and KIT mutations.




Promyelocytes instead of myeloblasts predominate
in the marrow in hypergranular promyelocytic
leukemia
Azurophilic granules are abundant and intensely
stained
Auer rods are found in most cases and frequently
are multiple (10 or more) in a given cell
Hemorrhagic complications are frequent as the
result of disseminated intravascular coagulation
(DIC), apparently initiated by procoagulant
material from leukemic cell granules.




The characteristic chromosomal abnormality
t(15;17)(q22;q21) shows fusion of the retinoid
acid receptor gene-α (RARA) on chromosome 17
with the PML gene on chromosome 15
Leukemia usually responds to therapy with all-trans
retinoic acid (ATRA), which is usually given in
addition to chemotherapy
prognosis is relatively favorable
The molecular genetic abnormality may be detected
in the laboratory by cytogenetics, RT-PCR, or FISH





Variant translocations include
t(11;17)(q23;q21),
t(5;17)(q32;q12),
and t(11;17)(q13;q21)
Some variants, such as t(11;17)(q23;q21), do
not respond to ATRA



cytoplasmic granules appear sparse by light
microscopy, and numerous but smaller by
electron microscopy
Nuclei of most leukemic cells are bilobed or
reniform, and confusion with an atypical
monocytic leukemia is frequent.
Auer rods, single or multiple, and typical
hypergranular promyelocytes are found in
variable numbers, and there appears to be a
spectrum between typical and hypogranular
types.





Chromosome band 11q23 abnormalities, which
involve the MLL gene, are not specific for AML, but
are also found in ALL, mixed lineage leukemias, and
occasionally in lymphomas.
The most common translocation in AML involving
this region is t(9;11)(p22;q23).
Others include t(6;11)(q27;q23), t(10;11)(p12;q23),
t(11;17)(q23;q21), and t(11;19)(q23;p13)
Most cases of t(9;11) show monocytic differentiation
(monoblastic or myelomonocytic)
prognosis of AML with 11q23 abnormalities is less
favorable


This disease shows variable morphology and
granulocytic and/or monocytic differentiation
but is usually associated with multilineage
dysplasia and basophilia of marrow and
blood (>2%).
Prognosis is generally poor.




This disease show multilineage dysplasia,
increased atypical megakaryocytes with
monolobed or bilobed nuclei, and normal to
increased platelet counts
Pseudo–Pelger-Huët cells are common, and
differentiation may be granulocytic and/or
monocytic.
Marrow eosinophils, basophils, and/or mast
cells are often increased.
This is an aggressive disease with short
survival




This is an acute leukemia of infants and
young children, more often reported in girls,
presenting as acute megakaryoblastic
leukemia with hepatosplenomegaly
This form is not associated with Down
syndrome.
Micromegakaryocytes are often found, and
biopsy sections show reticulin fibrosis
Patients may respond well to chemotherapy.





Many have shown normal karyotype.
Most of these carry genetic mutations not
detectable by Giemsa banding morphology;
mutations
Also found in cases with karyotypic
abnormalities.
Several carry prognostic implications.
Specific categories of AML are certain to be
described.






Mutations of fms-related tyrosine kinase 3
Encoding a tyrosine kinase receptor
Involved in hematopoietic proliferation and
differentiation
Occur in about one third of cases of AML
Two types of FLT3 mutations have been noted:
internal tandem duplications (FLT3-ITD)




tyrosine kinase domain (FLT3-TK) at codon 835 or
836
FLT3 mutations are seen in any AML
but primarily those with t(6;9), t(15;17), and
normal karyotype.
FLT3-ITD mutations associated with less favorable
prognosis, particularly in cases with normal
karyotype.




This constitutes a provisional entity in the
WHO classification.
Most cases have monocytic or myelomonocytic
differentiation
cases with multilineage dysplasia and
erythroid differentiation are also found
In one half of cases with normal karyotype




Associated with better prognosis
This favorable association is especially noted in
cases with normal karyotype and without FLT3
mutation
NPM1 mutation may be detected by
immunohistochemical assay of sections, in which
affected cells show abnormal cytoplasmic
localization of NPM protein
or it may be detected by PCR assays.





CEBPA encodes the CCAAT/enhancer binding proteinα
hematopoietic proliferation- and differentiationinducing transcription factor
Similar to NPM1 mutation, it is associated with
improved prognosis in AML with normal karyotype and
without FLT3 mutation
It is found in less than 20% of cases of AML
Immunophenotype includes usually CD34, frequently
CD7, with myeloid markers HLA-DR, CD11b, CD13,
CD15, CD33, and CD65.



KIT mutations are also seen in cases of AML
In AML with t(8;21) and t(15;17), KIT mutation is
associated with diminished prognosis
Other AML-associated mutations include those
involving WT1, MLL, NRAS, and KRAS





These leukemias show morphologic features of
myelodysplasia
or history of prior MDS or MDS/MPN
or they have MDS-related cytogenetic
abnormalities.
Patients with a history of cytotoxic chemotherapy
or radiation for another malignancy are not
included.
These cases are characterized by 20% or more
blasts in blood and/or marrow, as well as
dysplasia in ≥50% of cells of at least two lineages.


The immunophenotype often includes
primitive blasts with myeloid phenotype and
CD34 expression, CD56, and/or CD7.
Prognosis is generally poor.



These disorders are related to prior radiation or
cytotoxic chemotherapy utilizing alkylating
agents or topoisomerase inhibitors.
They include cases of AML, MDS, and
MDS/MPN.
Most patients have been treated for prior
malignancies, but some have been treated for
nonneoplastic conditions.





Most commonly, disease is related to
mutagenic effects of alkylating agents or
radiation.
These effects usually occur 5–10 years post
exposure and most often present as MDS.
Cytogenetic features are similar to those of
MDS and AML with multilineage dysplasia.
Loss of portions of chromosome 5 or 7 is
common.
Response to therapy and outcomes are poor




Cases secondary to prior chemotherapy with
topoisomerase II inhibitors occur after a shorter
latency period of 1–5 years
associated with overt AML with balanced
chromosomal translocations involving 11q23
(MLL) or 21q22 (RUNX1).
These most often show AML with maturation,
monocytic or myelomonocytic morphology.
Response to therapy is possibly similar to de novo
AML



Some cases of acute leukemia have features
that are indeterminate between lymphoid and
myeloid lineage, or have features of more than
one lineage.
This is a controversial area of difficult-toclassify leukemia.
Many leukemias that appear to be of defined
lineage have one or more immunologic
markers which are aberrant, or show lineage
infidelity.





A single such marker is usually insignificant.
ALL with myeloid markers responds similarly to
other types of ALL
lymphoid markers in AML are clinically
important, mostly if they help suggest a subtype,
such as CD19 expression in AML with t(8;21).
CD117 has been proposed as a good indicator of
myeloid lineage
but CD117, CD13, and CD33 are not considered
adequate to assign myeloid lineage in an otherwise
lymphoid blast proliferation


Acute undifferentiated leukemia (AUL)
Mixed phenotype acute leukemia (MPAL)



These are rare acute leukemias in which the
predominant cells are blast forms that cannot
be classified using morphologic, cytochemical,
ultrastructural, immunologic, or DNA analytic
methods
CD34, CD38, and HLA-DR are frequently
expressed
CD7 and TdT may be expressed as well.







Bilineal acute leukemia
Biphenotypic leukemia
Mixed Phenotype Acute Leukemia with t(9;22)
(q34;q11.2); BCR-ABL1
Mixed Phenotype Acute Leukemia with t(v;11q23);
MLL Rearranged
Mixed Phenotype Acute Leukemia, B/Myeloid, NOS
Mixed Phenotype Acute Leukemia, T/Myeloid, NOS
Mixed Phenotype Acute Leukemia, NOS—Other Rare
Types



Clonal neoplasms of mature plasma cells are
common neoplasms that have been difficult to
treat and are greatly feared.
indolent and nonprogressive to highly
aggressive and refractory to therapy.
The best measures of disease course are the
clinical findings themselves, and treatments
using new agents are rapidly evolving to
increase efficacy and improve outcome.







monoclonal serum immunoglobulin is present but no
myeloma is detectable.
The condition consists of a monoclonal Ig (Mcomponent) of <30 g/L
<10% clonal plasma cells in the marrow
absence of lytic bone lesions
no melanoma-related organ or tissue impairment
(CRAB: hypercalcemia, renal insufficiency, anemia, or
bone lesions)
no evidence of other B cell lymphoproliferative
disorder
Cytogenetic and immunophenotypic abnormalities are
similar to those in myeloma, and none is known to be
predictive of progression





Smoldering myeloma shows M-protein at
myeloma levels (>30 g/L)
and/or 10% or more clonal plasma cells in the
marrow
no related organ/tissue impairment (CRAB).
Patients with solitary plasmacytoma and bone
lesions detected only by magnetic resonance
imaging (MRI) are included.
These asymptomatic patients differ from those
with MGUS primarily by a higher rate of
progression:









The BM shows the presence of plasma cells or myeloma
cells, ranging from less than 1% to over 90%, depending on
the degree of involvement at the site of the aspirated
marrow
Cytologically, the cells may be indistinguishable from
normal plasma cells
but they usually show abnormal chromatin
less clumping of nuclear chromatin
large nucleoli
lack of perinuclear clear zone
lighter blue cytoplasm
varying degrees of anaplasia
Immature, plasmablastic, and anaplastic variants are
described.






most typically with expression of CD38 and CD138
Loss of CD19 expression (normally present on
plasma cells)
Absence of CD20
Abnormal acquisition of CD56 and often CD117.
Immunohistochemical labeling or mRNA in situ
hybridization of BM sections for κ and λ usually
identifies monoclonal plasma cells
Cyclin D1 expression is associated with t(11;14).





divides myeloma into two main groups:
1-hyperdiploid with multiple trisomies
involving odd-numbered chromosomes and
associated with good prognosis
2-hypodiploid associated with adverse
prognosis
Karyotype and FISH studies show frequent
del13q14 (50% of cases), translocations t(4;14),
t(14;16) or t(14;20)
Losses of 8, 13, 14, and X are common.


These patients are similar to others with
myeloma, except that tumor cells do not
produce (15%) or secrete (85%)
immunoglobulin.
The incidences of renal insufficiency,
hypercalcemia, and depression of normal Ig
are less.




large numbers of plasma cells circulate (either
>20% of blood leukocytes, or >2 × 109/L) is
the term plasma cell leukemia used
Patients with plasma cell leukemia tend to
have tissue infiltration
advanced-stage disease, and poor survival
The immunophenotype varies from usual
myeloma in that CD56 is often absent




These patients show no clinical features of
myeloma
May have a monoclonal immunoglobulin
without suppression of normal
immunoglobulin.
Tumors are controlled by radiation
Two thirds of cases eventually progress to
myeloma.



Extramedullary solitary plasmacytomas occur
in GI tract, bladder, CNS, breast, thyroid,
testis, parotid gland, lymph nodes, or skin
and are irradiated
They recur in one quarter of patients
Progress to myeloma in only about 15%.