Home
Chapter Home
Jobs
Conferences
Fellowships
Books
Advertisement
Leukemia - Acute
Reviewer: Syed Zaidi, M.D. (see Reviewers
page)
Revised: 30 December 2011, last major update December 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.
Table of contents
Recurrent genetic abnormalities: t(8;21), inv(16) or t(16;16), APL with t(15;17), APL with t(V;17), APL-therapy related, 11q23 abnormalities, FLT3 mutations, t(6;9), multilineage dysplasia, therapy related AML not
otherwise categorized: minimally differentiated, without
maturation, with maturation, M3, myelomonocytic, monoblastic and
monocytic, erythroid, megakaryoblastic,
CD13/CD33 negative, basophilic, myeloid sarcoma, acute
panmyelosis with myelofibrosis, with Philadelphia
chromosome, with pseudo Chediak-Higashi anomaly,
hypocellular ALL: general, WHO classification, with eosinophilia PreB ALL: general, t(9;22), t(v;11q23), t(1;19), t(12;21), hyperdiploidy,
hypodiploidy, mature B cell
ALL/Burkitt’s Other ALL: preT, bilineal, biphenotypic See also Chronic leukemia topics in other chapters: B
cell leukemias: chronic lymphocytic,
hairy cell, preB lymphoblastic,
prolymphocytic
leukemia, leukemic
phase of mantle cell lymphoma T/NK
cell leukemias: NK cell, adult T cell,
preT
lymphoblastic, T cell large
granular, T cell
prolymphocytic, Sezary
syndrome Myelodysplastia
/ myeloproliferative disorders: chronic
myelomonocytic (CMML), juvenile
myelomonocytic, chronic
myeloid (CML), chronic
neutrophilic, chronic
eosinophilic Bone
chapter: plasma cell
leukemia
top AML with inv(16)(p13;q22) or
t(16;16)(p13;q22) Also
called M4Eo 8% of
adult AML, 25% of acute myelomonocytic leukemia (AML M4) cases Associated
with more frequent hepatosplenomegaly, lymphadenopathy and granulocytic sarcoma
than AML in general Longer
median survival than other AML (AJCP 2003;119:672); complete remission rates are 76% to 92% If
translocation present, consider as AML even if initial blast count is < 20% FISH
recommended if suggestive cell morphology but negative cytogenetics (J Mol Diagn 2004;6:271) Poorer
prognostic factors are high initial WBC count for complete response and age
> 35 years for disease free survival (Blood 2003;102:462) Peripheral
blood: monocytosis, high blast
counts Micro: usually AML M4 (acute myelomonocytic leukemia)
features plus marrow eosinophilia with dysplastic eosinophils containing large basophilic
staining granules in addition to usual eosinophilic granules; usually >10%
dysplastic forms in at least one lineage (AJCP 2003;120:236) Micro
images: bone
marrow smears (Wright-Giemsa): eosinophil
precursors show prominent basophilic staining granules #1; #2; H&E,
cytogenetics and FISH; immature
cells with folded, monocytoid nuclei mixed with abnormal eosinophils (arrow)
containing large basophilic granules and more normal eosinophil granules;
various
eosinophil precursors; various
images #1; #2;
#3;
#4;
#5
(some images associated with cytogenetic changes); H&E,
RT-PCR and FISH Virtual
slides: bone
marrow smear-AML with inv(16) Positive
stains: granules are positive for
chloroacetate esterase and nonspecific esterase; high Ki-67, CBFbeta-SMMHC
(nuclear stain with microgranular or fine-speckled pattern, AJSP
2006;30:1436) Molecular: inversion(16) or t(16;16)(p13;q22) are due to breaks
in smooth muscle myosin heavy chain gene (SMMHC) producing MYH11 at 16p13 and
core binding factor beta (CBF-beta) gene at 16q22, creating CBF-beta - MYH11
protein (Science
1993;261:1041, Proc Natl Acad Sci USA 1998;95:11863); multiple fusion transcripts exist (J Mol Diagn 2004;6:22); fusion transcripts appear to upregulate NF-kappaB
signaling pathway (Mod
Path 2007;20:811) Molecular
images: two G banded
chromosome 16 pairs show pericentric inversion at #16, arrowheads point to
breakpoints on abnormal chromosome; diagram;
karyotype Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) Either
hypergranular (this section) or microgranular (section below) 8% of
AML cases, 15% of adult AML Formerly
called AML M3 Median
age 35-40 years Decreased
WBC count at presentation with abnormal promyelocytes; usually severe
disseminated intravascular coagulation (DIC) and hemorrhage before or during
induction chemotherapy, which may cause early death; organomegaly or
extramedullary disease is unusual Rarely
has skin involvement, detected with FISH (Mod Path 2005;18:1569) Criteria
for diagnosis: most cells
(>50%) are abnormal promyelocytes with heavy cytoplasmic granulation, often
reniform nucleus; cells with multiple Auer bodies usually present Note: if t(15;17) present, diagnose as AML even if initial
blast count is < 20% Prognostic
factors: in children, age < 10
years is favorable (Cancer 2006;106:2495) Case
reports: 45 year old man with fatigue Treatment: (1) all trans retinoic acid (ATRA) causes neoplastic
promyelocytes to rapidly differentiate into bizarre maturing neutrophils, but
patients eventually relapse; (2) arsenic trioxide (ATO) for ATRA-refractory
patients; induces differentiation at low doses, marrow necrosis at high doses (Mod Path 2000;13:954); (3) combination chemotherapy required for
sustained remissions (Hematology Am Soc Hematol Educ Program 2006;147) Survival: excellent if DIC and hemorrhage are adequately
controlled; excellent in adults with complete remission Micro: most cells are hypergranular promyelocytes (abundant
cytoplasm, round/oval and frequently eccentric nuclei with occasional clefts or
indentations, moderately condensed chromatin, indistinct nucleoli) with heavy
red/purple cytoplasmic granulation that may obscure nuclear borders; 90% have
multiple Auer rods in some cells, which may be intertwined (“faggot” cell-word
is derived from Middle English/Old French term for bundle
of twigs, sticks, or branches bound together); reniform (kidney shaped)
nucleus; may have basophilic cytoplasm, <20% myeloblasts post-treatment: may be difficult to differentiate residual disease
(promyelocytes not in any particular location) from regenerating marrow
(promyelocytes are perivascular and endosteal) Acute promyelocytic leukemia (APL) with t(15;17)(q22;q12) -
continued Micro
images: bone
marrow smears (Wright-Giemsa): abundant
azurophilic granules #1, also two microgranular promyelocytes with basophilic
cytoplasm and lobulated nuclei; #2;
numerous
Auer rods in bundles bone
marrow biopsy: bone marrow is
almost completely replaced by promyelocytes with abundant cytoplasm, oval/round
nuclei that are often eccentrically located, with occasional indentations/clefts,
somewhat condensed chromatin and indistinct nucleoli; promyelocytes are
relatively uniform with abundant cytoplasm containing dense azurophilic
granules and multiple Auer rods, nuclei are round, oval and lobulated treatment
related: before
and after arsenic trioxide; post-chemotherapy
smear shows single “faggot” cell with numerous Auer rods in bundles other
sites: skin
infiltration-various H&E and FISH stains: CD99
(figures 3C/3D); H&E
and CD99 (fig A1/A2) Positive
stains: CD9, CD11a, CD11b
(post-treatment only-ATRA: Archives 2003;127:e4 or arsenic trioxide: Mod Path 2000;13:954),
CD13, CD33, CD79a (86% but varies by clone, AJCP
2007;128:306),
myeloperoxidase (strong), CD2 (23%), CD64 (27%), HLA-DR (9%); variable CD34, CD71, CD99 Negative
stains: CD11b (but post-treatment is
positive), CD11c (AJCP
1998;109:211), CD14, CD34, CD36,
CD41, CD61, glycophorin A Molecular: t(15;17) translocation not found in other AML
subtypes; breakpoints at PML gene on #15q22 and retinoic acid receptor alpha
(RARa) gene on #17q21; hybrid mRNA produces abnormal retinoic acid receptor
that blocks myeloid differentiation Cases
without Auer rods usually have additional chromosomal abnormalities besides
t(15;17) (AJCP
1999;112:113) Cytogenetic
images: t(15;17)-arrowheads
at breakpoints on abnormal chromosomes; karyotype Molecular
images: FISH
- negative and positive control of t(15;17) EM: Auer rods have tubular substructure, markedly
dilated endoplasmic reticulum, stellate complexes of rough ER, nucleus has
dispersed chromatin and prominent nucleolus EM
images: cytoplasm has
numerous dense granules and several Auer rods, nucleus has dispersed chromatin
and prominent nucleolus; cross section of
Auer rod shows characteristic tubular structure References: Atlas
of Genetics and Cytogenetics Microgranular
variant of acute promyelocytic leukemia Formerly
called AML-M3v Note:
“variant” APL without further description may mean microgranular variant or cytogenetic
variant (see below) Peripheral
blood white blood count usually elevated, in contrast to hypergranular form Diagnosis: cytogenetics recommended, because other AML cases
may appear similar (AJCP 2002;117:651) Case
reports: 5 year old girl with Down’s
syndrome (J Med Case Reports 2007;1:147), post-chemotherapy with atypical
breakpoints for translocation (Cancer
Genet Cytogenet 2002;138:143), occuring after untreated essential thrombocythemia (Am J Hematol 2002;71:114) Micro: leukemic cells have fewer and smaller cytoplasmic
granules, usually multiple Auer rods but less than classic (hypergranular)
promyelocytic leukemia; nuclei is folded, convoluted, markedly irregular Micro
images: promyelocytes
have abundant fine, azurophilic cytoplasm with variable size and basophilia,
markedly lobulated and invaginated nuclei #1; #2;
small
hyperbasophilic promyelocytes with prominent cytoplasmic budding, most cells
have sparsely granular cytoplasm and lobulated nuclei #1; #2 Positive
stains: CD34 (more common than
hypergranular variant, Haematologica
2006;91:311),
CD13, CD33, myeloperoxidase (strong), usually CD2 (Leukemia
1995;9:1461) Molecular: associated with FLT-3 aberrations (Br
J Haematol 2004;125:463) and different gene expression profile than
hypergranular APL (Genes
Chromosomes Cancer 2005;43:113) EM: stellate array of endoplasmic reticulum is
characteristic EM
images: smaller granules
than hypergranular variant, granules are more uniform in size, endoplasmic
reticulum is prominent; small granules
and stellate array of endoplasmic reticulum DD: other AML (AJCP 2002;117:651) References:
Blood 1980;55:253 Acute promyelocytic leukemia with
t(V;17)(V;q12) Note:
“variant” APL without further description may mean microgranular (morphologic)
variant or cytogenetic variant other than t(15;17) Uncommon,
involves retinoic acid receptor alpha on #17 but not PML gene on #15 t(11;17)
is most common DIC
common; may NOT respond to all-trans retinoic acid; may be more aggressive than
classic acute promyelocytic leukemia (Blood 1995;85:1083) Recommended
to combine cytogenetics, FISH and molecular biology to document presence /
absence of PML-RARalpha fusion gene in complex cases (Cancer
Genet Cytogenet 2005;159:69) Case
reports: with PRKAR1A gene (Blood
2007;110:4073), t(17;20) masking t(15;17) (Cancer
Genet Cytogenet 2006;168:73) Micro: features are intermediate between hypergranular
acute promyelocytic leukemia (M3) and acute leukemia with maturation (M2) -
most cells have many granules, usually no Auer rods, regular nuclei but
increased pseudo Pelger-Huet cells Micro
images: cells
with many granules, no Auer rods, regular nuclei Molecular: involves RAR alpha and either PLZF (11q23), NUMA
(11q13), NPM (5q31) or STAT5b genes (Leukemia 2002;16:1927) DD: t(11;17) may resemble AML with 11q23 abnormality (Cancer
Genet Cytogenet 2005;159:168) References: Atlas
of Genetics and Cytogenetics-t(11;17) Acute promyelocytic leukemia-therapy
related Not a
WHO diagnosis Prior
tumor is usually breast carcinoma, other solid tumor or non-Hodgkin’s lymphoma,
treated with radiation or chemotherapy (J Clin Oncol 2003;21:2123) Usually
develops within 3 years, with no preleukemic phase Mitoxantrone
and etoposide or its metabolites stimulate topoisomerase II to cleave
different sites in PML and RARA (N Engl J Med 2005;352:1529) Case reports: microgranular variant developing post-chemotherapy
for breast cancer (Cancer
Genet Cytogenet 2002;138:143), post-radioactive iodine for thyroid cancer (J
BUON 2007;12:129), developing post-chemotherapy in 8 year old girl with non Hodgkin’s
lymphoma (J
Pediatr Hematol Oncol 2004;26:427) Micro: classic findings of APL plus dyserythropoiesis and
dysmegakaryopoiesis Molecular: t(15;17)(q22;q12), often with additional
abnormalities; PML-RARa in most cases; FLT-3 gene mutations in 42% References: AJCP 2005;123:840 AML with 11q23 (MLL) abnormalities 3-5%
of AML (Anticancer
Res 2005;25:1931) Usually
children or young adults Present
in high percentage of topo II inhibitor, therapy related AML (Blood 2003;102:2395); also ALL and biphenotypic leukemia More
than 50 chromosomal loci have been identified as 11q23 partners, but most
common are t(9;11)(p21;q23) [AF9-MLL] and t(4;11) [AF4-MLL] FISH
is more sensitive than conventional cytogenetics in detecting MLL; may also
detect 11q22-25 rearrangements that are MLL negative (AJCP 2004;122:298) PCR is
more sensitive than conventional cytogenetics in detecting MLL/ENL [t(11;19)]
fusion transcripts (AJCP
2007;127:24) Typically poor prognosis MLL partial tandem duplication: present in 93% of normal cord blood
samples at low levels (Leuk
Res 2006;30:1091); associated with normal karyotype or trisomy 11; typically poor
prognosis in AML (Br
J Haematol 2006;135:438), but recent study showed similar outcome (Blood
2007;109:5164) Micro: blasts resemble monoblasts, monocytes or
myelomonocytes (AML M4, M5) Positive
stains: nonspecific esterase Molecular: involves MLL-mixed lineage or myeloid/lymphoid
leukemia gene, present in both AML and ALL; is also called HTRX1, HRX and ALL1;
translocations occur in AML (intermediate prognosis) and ALL (poor prognosis, Blood
Cells Mol Dis 2007 Sep 28 [Epub ahead of print]) Molecular
images: partner
genes; diagram
of MLL/ALL1 duplication Cytogenetics
images: t(4;11)(q21;23)
in bilineal leukemia References: OMIM
159555, Atlas of
Genetics and Cytogenetics Not a
WHO diagnosis Mutations
of FMS-like tyrosine kinase 3 (FLT3) occur in 20-30% of de novo AML Most
frequent molecular abnormality in AML Usually
peripheral leukocytosis and normal cytogenetics Mutations
include internal tandem duplication/juxtamembrane domain (ITD) and tyrosine
kinase domain (TKD) FLT3-ITD
associated with poor prognosis (Blood 2002;100:1532), FLT3-TKD doesn’t affect prognosis (Blood
2007 Oct 26 [Epub ahead of print]) Diagrams: FLT3
structure Micro: monocytic differentiation Molecular: usually normal cytogenetics; most common mutation is
internal tandem duplication mutation (ITD) Molecular
images: activating
ITD mutations (diagram) Not a
WHO diagnosis 1% of
AML Usually
women, median age 51 years, range 20-76 years Often
DIC, basophilia Poor
prognosis Treatment: allogeneic hematopoietic stem cell transplantation;
monitor by real time RQ-PCR (Leukemia
2005;19:1338) Micro: intermediate features between AML with maturation
(AML M2), acute promyelocytic leukemia and acute myelomonocytic leukemia; often
ringed sideroblasts (AJCP
1997;107:430) Positive
stains: CD9, CD13, CD33, CD34 (92%),
CD38, CD117, HLA-DR, TdT (64%) Molecular: produces DEK-CAN fusion protein; 88% have FLT3 gene
mutations, often additional chromosomal abnormalities Cytogenetic
images: karyotype
#1; #2;
karyotype-bottom
row References: AJCP 2004;122:348, Atlas of Genetics
and Cytogenetics AML with multilineage dysplasia Arises
either as de novo AML or from existing myelodysplastic syndrome Includes
what was previously called refractory anemia with excess blasts in
transformation Usually
presents with severe pancytopenia Children: occurs in 3% with de novo AML, good response to
treatment (Int
J Hematol 2007;86:358) Adults: median age 61 years; higher incidence in AML in older individuals Prognosis: controversial - poorer (AJCP 2003;119:672) versus no independent prognostic
value (Blood
2007 Dec 4 [Epub ahead of print]) versus poor only with adverse cytogenetics (Eur
J Haematol 2002;68:203) Micro: dysplasia in 50% of cells of 2 or more lineages;
often panmyelosis, usually dysplastic megakaryocytes Micro
images: prior MDS - various
images #1; #2 no
prior MDS - various
images #1; #2;
#3;
#4;
#5;
#6 Positive
stains: CD34, CD117, HLA-DR Molecular: trisomy 8, abnormalities of #5 or #7 are common;
also t(3;5)(q25;q34-35) involving MLF1 and NPM (Hum
Path 2003;34:809) DD: acute erythroid leukemia, AML M2, AML
M6a AML and myelodysplastic syndrome -
therapy related May
occur post-chemotherapy or post-radiation therapy Rarely
occurs after therapy for de novo AML (Leuk
Res 2007 Dec 17 [Epub ahead of print)) Includes therapy related myelodysplastic syndrome, which has close
relationship to therapy related AML Similar genetic abnormalities as de novo myelodysplasia and AML,
although different frequencies (Hematology Am Soc Hematol Educ Program 2007;392) Survival
varies by cytogenetics (Hematology Am Soc Hematol Educ Program 2007;453,
Pediatr
Blood Cancer 2008;50:17) Risk is children and adults may actually be similar (J
Toxicol Environ Health B Crit Rev 2007;10:379) References: Haematologica 2007;92:1389 Alkylating
agents as cause of therapy related AML and myelodysplastic syndrome Occurs
median 5 years after initiation Risk
is associated with patient age and cumulative dose of alkylating agent Typically
presents with myelodysplastic syndrome and bone marrow failure May
progress to AML or may die without progression Poor
prognosis; median survival is 7-8 months Micro: hypocellular marrow; often severe dysplastic changes
in blood and marrow; myelofibrosis and ringed sideroblasts common; <5%
myeloblasts Molecular: abnormalities of chromosomes 5 or 7 or complex
cytogenetic abnormalities Topoisomerase
II inhibitors as cause of therapy related AML and myelodysplastic syndrome Occurs
mean 2-3 years after initiation of etoposide or teniposide with doxorubicin Usually
presents as acute monocytic or myelomonocytic leukemia Poor
prognosis Molecular: 11q23 and 21q22 abnormalities Other
agents as cause of therapy related AML and myelodysplastic syndrome Case
reports: t(4;11) post-rituximab and
fludarabine for SLL (Cancer
Genet Cytogenet 2007;177:143) AML not otherwise categorized Acute myeloblastic leukemia, minimally differentiated
(M0) 5% of
AML cases Typically
presents with thrombocytopenia, neutropenia and marrow failure No
definitive evidence of myeloid differentiation by morphology and cytochemistry;
need immunohistochemistry or EM to characterize as myeloid Criteria
for diagnosis: nongranular blasts;
less than 3% of blasts are positive for myeloperoxidase or Sudan Black B by
enzyme cytochemistry, although blasts may express myeloperoxidase by EM or
immunohistochemistry; blasts do not express classic lymphocyte antigens, but
may aberrantly express some lymphocyte antigens Children (Blood
2007;109:2314) and adults (Br
J Haematol 2001;113:737) may have poorer outcome than other AML subtypes Micro: nongranular, medium sized-blasts, no Auer rods,
dispersed chromatin; small blasts may resemble lymphoblasts Micro
images: bone
marrow smear (Wright-Giemsa): no
differentiated features #1; #2 bone
marrow biopsy: complete
replacement of marrow by blasts without differentiation stains: myeloblasts are
negative for myeloperoxidase by cytochemistry with positive staining in
neutrophil; blasts are
positive for myeloperoxidase by IHC; CD99 Enzyme
cytochemistry: negative for
myeloperoxidase, Sudan Black B, chloroacetate esterase, nonspecific esterase Positive
stains: CD13, CD33 (AJCP 2001;115:876), CD34, CD117 (AJCP 2002;117:380), HLA-DR, CD38; variable expression of myeloperoxidase, Sudan Black B,
TdT, CD2, CD4, CD7 and CD71 Negative
stains: CD14 (usually), CD36
(usually), CD41, CD61, CD64 (usually, Archives 2007;131:748), most lymphocyte antigens; glycophorin A Flow
cytometry: pediatric AML-M0 is
usually CD33 bright, TdT-, CD34-, CD13-/weak (AJCP 2000;113:193) EM: resembles myeloblasts; may show focal
myeloperoxidase+ granules EM
images: granules
are myeloperoxidase positive #1; #2 Molecular: often complex chromosomal abnormalities; 31% have
AML1/RUNX1/core binding factor alpha mutation, associated with trisomy 13 and
FLT3 mutation (Haematologica
2007;92:1123);
tend to have more 5-, trisomy 21 and hypodiploidy than other AML, although
outcome is similar (Blood
2007;109:2314) DD: ALL, M7, biphenotypic leukemia Acute myeloblastic leukemia without maturation (M1) 10-20%
of AML cases, 44% in one Brazil hospital (Sao Paulo Med J 2006;124:45) 4% of
childhood AML (Orphanet) Usually
adults presenting with anemia, thrombocytopenia and neutropenia Criteria
for diagnosis: at least 90% of
nonerythroid cells in marrow are myeloblasts; if no Auer rods, at least 3% of
blasts must be positive for myeloperoxidase or Sudan Black B by enzyme
cytochemistry Case
reports: large and small blasts (Archives 2004;128:448), presenting with arterial thromboembolism (Leuk
Res 2007;31:869); t(6;9) and basophilia (Ann
Biol Clin (Paris) 2003;61:352) Micro: very immature cells, usually round with few
cytoplasmic granules or Auer rods; nuclei are round or indented; little
maturation beyond myeloblast stage; cells may not appear myeloid cytologically;
typically markedly hypercellular marrow Micro
images: bone
marrow smears (Wright-Giemsa): blasts show mild
size variation, have pale to slightly basophilic agranular cytoplasm, uniform
nuclei with fine chromatin and prominent nucleoli; blasts show more
variation in size and number of nucleoli, four blasts have Auer rods;
myeloblasts
have irregular nuclei with folding and invagination, one myeloblast has
numerous azurophilic granules; myeloblasts have
marked size variation, irregular nuclei with condensed chromatin, no nucleoli,
one blast has a thin Auer rod; some variation in
size, two myeloblasts have more intense basophilic cytoplasm and coarse nuclear
chromatin; myeloblasts are
large with abundant eosinophilic cytoplasm, two cells have prominent Auer rods,
one cell has numerous azurophilic granules, 2 post-mitotic erythroblasts are
also present; agranular
myeloblasts have variation in size, cytoplasmic volume and cytoplasmic
basophilia; various
images #1; #2 bone
marrow biopsy: marrow is
completely replaced by blasts with variable cytoplasm, round/oval nuclei with
mild irregularities and small/indistinct nucleoli; biphasic
morphology (large and small blasts) blood
smear: case with
inv(3)(q21q26) shows large and smaller blasts and normal appearing platelets stains: myeloblasts are
myeloperoxidase+; numerous
granules are Sudan Black B+; H&E
and CD99 (figures B1 & B2) Acute myeloblastic leukemia without maturation (M1) -
continued Enzyme
cytochemistry: at least 3% of blasts
are positive for myeloperoxidase or Sudan Black B (confirm by
immunohistochemistry if only 3-10% positive for MPO by enzyme cytochemistry);
chloroacetate esterase positive Positive
stains: at least two myelomonocytic
antigens (CD13, CD33, CD117); CD34, CD99 (Mod Path 2000;13;452);
variable CD15, CD71 and HLA-DR Negative
stains: CD14 (usually), CD36
(usually), CD41, CD61, CD64 (usually), glycophorin A EM: may have heterogeneous features (Ultrastruct
Pathol 1995;19:9) Molecular:
associated with t(8;21); FLT3 ITD in
22% (Ai
Zheng 2007;26:58), FLT3 mutations associated with HLA-DR negative patients (Leuk
Res 2007;31:921) DD: ALL, AML-M0, AML-M2 Acute myeloblastic leukemia with maturation (M2) 30-45%
of AML cases; 5% of childhood leukemias (Orphanet) Any
age, 20% are < 25 years and 40% are 60 years+ Variable
prognosis Criteria
for diagnosis: 20%+ nonerythroid
cells in peripheral blood or bone marrow are myeloblasts; monocytic precursors
are < 20%, granulocytes are >10% of cells Case
reports: with t(5;11) (Cancer
Genet Cytogenet 2007;172:154) Micro: usually hypercellular marrow; full range of myeloid
maturation through maturing neutrophils, often with abnormal segmentation; Auer
rods in 70% of blasts; variable azurophilic granules; erythroid and
megakaryocyte precursors may have dysplastic changes; often increased
eosinophil precursors; rarely mast cell hyperplasia (Indian
J Pathol Microbiol 2007;50:655) Micro
images: bone
marrow smears (Wright-Giemsa):
type III
myeloblasts (>20 azurophilic granules); several
myeloblasts, promyelocytes, myelocytes and neutrophils, also several
erythroblasts; several blasts have prominent nucleoli and
Auer rods, also a promyelocyte and myelocyte; several
myeloblasts and maturing forms, also neutrophils with agranular cytoplasm;
large
myeloblasts have pseudopods, usually abundant cytoplasm, some with prominent
Auer rods; various
images #1; #2;
#3;
#4;
#5;
#6;
#7;
#8; promyelocytes bone
marrow biopsy: markedly
hypercellular marrow has predominantly blasts, also scattered erythroid
precursors and eosinophils stains: myeloperoxidase+
blasts, neutrophils are intensely positive; myeloperoxidase+
blasts and immature neutrophils, erythroid cells are negative; Sudan black B+ and chloroacetate
esterase+ diagnosed
as AML with maturation because no t(15;17) and no DIC, but FISH not done, so
may actually be acute promyelocytic leukemia: abundant coarse
azurophilic granules #1; #2 with specific
granules resembling Chediak-Higashi anomaly; #3 with numerous
promonocytes Enzyme
cytochemistry: most blasts are
positive for myeloperoxidase or Sudan Black B, and chloroacetate esterase Positive
stains: CD13, CD33, CD34, HLA-DR,
CD71 (variable), CD99 Negative
stains: CD14 (usually), CD36
(usually), CD41, CD61, CD64 (usually), glycophorin A EM
images: numerous primary
granules and fusion of Auer rods Molecular:
associated with t(8;21) (Cytometry
B Clin Cytom 2008;74:25); FLT3 mutations associated with HLA-DR negative
patients (Leuk
Res 2007;31:921) DD: leukemoid reaction, AML with multilineage dysplasia,
refractory anemia with excess blasts, AML-M1, M3, M4 Acute promyelocytic leukemia (M3) See
Acute promyelocytic leukemia with t(15;17)(q22;q12) Acute myelomonocytic leukemia (M4) See
also AML with inv(16)(p13;q22) or t(16;16)(p13;q22)-M4eo 15-25%
of AML cases, 3% of childhood leukemia (Orphanet) Children
and adults Often
markedly elevated WBC with anemia and thrombocytopenia, organomegaly,
lymphadenopathy and other tissue infiltration (monocytes infiltrate) May
occur post-therapy (myeloma-Sichuan
Da Xue Xue Bao Yi Xue Ban 2007;38:347) Criteria
for diagnosis: myeloblasts,
monoblasts and promonocytes are 20% or more of nonerythroid cells; myeloblasts
and granulocytes are 80% or less of nonerythroid cells; monocyte lineage cells
are 20% or more of nonerythroid bone marrow cells If
less than 20% of bone marrow cells are monocyte lineage, still M4 if blood
monocyte count is 5000/mm3 or more Additional
criteria (if cannot distinguish early monocytes and early granulocytes):
nonspecific esterase reactivity in 20% or more cells or serum lysozyme of 3
times normal Case
reports: leukemic ascites (Archives 2005;129:262), pregnant woman (Internet J of Hematology 2003; Vol 1, No. 1), 30 year old woman with gingival
hyperplasia, catastrophic antiphospholipid antibody syndrome (J
Pediatr Hematol Oncol 2004;26:327) Micro: myelocytic and monocytic differentiation evident;
myeloid cells resemble M2 (60% of myeloblasts have Auer rods) but at least 20%
of nonerythroid cells are large, monocyte lineage cells with abundant pale
gray-blue cytoplasm and prominent nucleoli; promonocytes have abundant
cytoplasm containing fine azurophilic granules and delicately folded nuclei Micro
images: bone
marrow smears (Wright-Giemsa): mixture of
monocytes and neutrophils at different stages of maturation, also several
promonocytes with abundant cytoplasm containing fine azurophilic granules and
delicately folded nuclei; promonocytes on
left have basophilic cytoplasm with coarse azurophilic granules, those in upper
right have abundant pale cytoplasm with delicate nuclear folds; three
promonocytes have abundant cytoplasm with fine azurophilic granules, also
dysplastic neutrophil with pseudo-Pelger-Huet nucleus in upper left; five promonocytes
and two myelocytes (center), one containing numerous azurophilic granules and
an Auer rod; various
images #1; #2 Acute myelomonocytic leukemia (M4) - continued bone
marrow biopsy: markedly
hypercellular marrow with heterogeneous cells, including immature monocytes
(irregular nuclei and prominent nucleoli) and neutrophils; resembling
sarcomatoid carcinoma other
sites: leukemic
ascites stains: chloroacetate
esterase stains neutrophils blue, and nonspecific esterase stains monocytes
red-brown; non-specific
esterase; CD68; lysozyme; peroxidase (myeloid
marker) Enzyme
cytochemistry: monoblasts are positive
for nonspecific esterase; if negative, confirm monocyte lineage with
immunohistochemistry or EM Positive
stains: may vary between monocyte
and myeloid populations; CD4, CD11, CD13, CD14 (possibly), CD33, CD36, CD64,
CD68, CD71 (variable), HLA-DR, lysozyme, myeloperoxidase; variable CD56, CD34,
CD117 (AJCP 2004;122:865) Negative
stains: CD41, CD61, glycophorin A,
keratin Molecular: may have recurrent genetic abnormalities of inv(16)
or 11q23 rearrangement DD: leukemoid reaction, G-CSF related transient atypical
monocytosis (Clin
Lab Haematol 2004;26:359),
myelodysplastic syndrome, AML M2, M5, microgranular M3, sarcomatoid carcinoma Acute monoblastic and acute monocytic leukemia (M5) 10% of
AML cases High
incidence of bleeding disorders (including DIC), organomegaly, lymphadenopathy,
gingival hyperplasia, CNS and other tissue involvement (monocytes infiltrate) May
present with acute respiratory failure (Am
J Respir Crit Care Med 2003;167:1329) M5a
and M5b have similar immunophenotype, cytogenetics and clinical outcome (Leuk Res 2007 Aug 7 [Epub
ahead of print]), although M5a may have higher expression of CD68 and CD11c (Zhongguo Shi Yan Xue Ye Xue
Za Zhi 2006;14:1079); but see Zhongguo
Shi Yan Xue Ye Xue Za Zhi 2006;14:654 (cytogenetics are different) Similar
prognosis as other subtypes (J
Clin Oncol 2004;22:1276) Criteria
for diagnosis: 80% or more
nonerythroid bone marrow cells are monocyte lineage Micro
images: erythrophagocytosis
in AML M4/M5 (see cell in upper right) Enzyme
cytochemistry: monoblast granules
and monocytes are strongly positive for nonspecific esterase and lysozyme, but
negative for myeloperoxidase; more mature monocyte lineage cells may be weakly
myeloperoxidase positive Note: If NSE negative, confirm monocyte lineage with
immunostains Positive
stains: CD11b (80-90%, AJCP
1997;107:283), CD11c (50%),
CD13, CD33, CD64 (AJCP
1998;110:797), CD68, HLA-DR Cytogenetics: 11q23 translocations in 19%, trisomy
8 in 17% References: Orphanet Acute
monoblastic leukemia (M5a) 5-8%
of AML Children
and young adults Criteria
for diagnosis: 80% or more monocyte
lineage cells are monoblasts Case
reports: with mantle cell lymphoma (Leuk Lymphoma 2005;46:1813), erythropoietin-dependent
transformation of refractory anemia with ringed sideroblasts into acute
monoblastic leukemia (Blood 2001;98:3492) Micro: hypercellular marrow with large number of
monoblasts; monoblasts are large with moderately abundant cytoplasm, variably
basophilic and delicate azurophilic granules but no/rare Auer rods; may have
pseudopods or vacuoles; have round nuclei with prominent nucleoli but no folds;
promonocytes have abundant cytoplasm with fine azurophilic granules and nuclei
have delicate folds Micro
images: blood
smear (Wright-Giemsa): two monoblasts
(left) have abundant cytoplasm with numerous azurophilic granules, promonocyte
(right) has abundant cytoplasm with fine azurophilic granules, nuclei has
delicate folds bone
marrow smear (Wright Giemsa):
monoblasts are
large with abundant cytoplasm containing numerous fine azurophilic granules,
nuclei lack folds but have slightly coarse chromatin and 2-3 distinct nucleoli
#1; #2-some
monoblasts also show pseudopods; monoblasts have
variable cytoplasm with mild to intense basophilia, some vacuoles but no
granules; monoblasts are
larger cells with abundant cytoplasm and round nuclei, and promonocytes are two
cells with folded and creased nuclei next to monoblast in center; t(8;16)
with erythrophagocytosis; bone
marrow and skin; various
images #1; #2 bone
marrow biopsy: marrow
completely replaced by monoblasts-large cells with abundant cytoplasm,
round/oval nuclei with prominent nucleoli; monoblasts are
large with abundant pale cytoplasm, numerous vacuoles and prominent pseudopods,
nucleoli are distinct; monoblasts are
large with abundant cytoplasm, some nuclei are irregular, many blasts have
single prominent nucleoli stains: monoblasts are
intensely positive for nonspecific esterase #1; #2
(fig 4), case also has neoplastic plasma cells; monoblasts are
positive for CD68 #1 (KP-1); #2; buffy coat
smear-vacuoles are PAS+ Positive
stains: CD13, CD14 (most), CD68, PAS
(vacuoles), nonspecific esterase (strong), lysozyme Negative
stains: myeloperoxidase EM
images: monoblast
stained for nonspecific esterase shows scattered electron-dense deposits
indicating enzyme activity; cytoplasm
contains focal area of glycogen deposition, also scattered dense granules and a
paranuclear fibrillar array Molecular: 75% have cytogenetics abnormalities, including 11q23
in 30% (these cases should be classified as a recurrent genetic abnormality);
FLT3 mutations in 7% DD: ALL-L2, AML-M0, M1, M7 Acute
monocytic leukemia (M5b) 3-6%
of AML; affects all ages Mature
monocytes or promonocytes predominate in peripheral blood (<80% of monocyte
lineage cells are monoblasts, usually <20%) Treatment
may cause tumor lysis syndrome, DIC and falsely elevated platelet counts (Archives 1999;123:1111) Case
reports: cutaneous disease (Archives 2005;129:425), with coexisting myeloma (Archives 2003;127:1506), 60
year old woman with fatigue, with mycoses fungoides,
spontaneous remission after infection (Int
J Lab Hematol 2007;29:386), with mononucleosis syndrome due to Varicella
zoster virus (Eur J
Haematol 2002;68:236) Micro: leukemic cells are often promonocytes with less
basophilic cytoplasm and more azurophilic granules than monoblasts; have folded
or cerebriform nuclei with fine chromatin; erythrophagocytosis is common Micro
images: blood
smears (Wright-Giemsa): promonocytes have
abundant cytoplasm with azurophilic granules that are myeloperoxidase negative,
nuclei have delicate folds, nucleoli are inconspicuous bone
marrow smears (Wright-Giemsa): monocytic cells
have range of differentiation, promonocytes have nuclei with delicate folds;
two
myeloblasts (round/oval nuclei, high N/C ratio) and three promonocytes
(abundant cytoplasm with delicate azurophilic granules, lobulated nuclei with
delicate folds); erythrophagocytosis;
various
images #1; #2;
#3 bone
marrow biopsy: cells have
moderate granular cytoplasm, nuclei are lobulated and indented with indistinct
nucleoli treatment:
before
and after treatment, alpha naphthyl butyrate esterase stains: monocytes and one
neutrophil are intensely positive for nonspecific esterase; skin
lesions: H&E and nonspecific (alpha naphthyl butyrate) esterase Positive
stains: CD13, CD14 (most),
CD68, CD61 (some) Negative
stains: CD41, glycophorin A Molecular: 30% have cytogenetics abnormalities; including 11q23
in 12% (these cases should be classified as a recurrent genetic abnormality);
FLT3 mutations in 30%; t(8;16)(p11;p13) fuses MOZ gene at 8p11 with CBP gene at
16p13 and is associated with erythrophagocytosis DD: AML M4, microgranular acute promyelocytic leukemia,
myelodysplastic syndrome (to distinguish, count promonoblasts in M5 with
monoblasts), malignant histiocytic disorders Either
erythroleukemia (more common) or pure erythroid leukemia (rare) One
study suggests that most cases may now be defined as AML with multilineage
dysplasia (Haematologica
2004;89:ELT11, free full text) References:
eMedicine Erythroleukemia
(M6a) 5% of
AML cases; usually adults 20% of
therapy related AML but only 1% of de novo AML Much
more common than pure erythroid leukemia (Haematologica
2002;87:148, free full text) Peripheral
smear may have prominent erythroblasts Criteria
for diagnosis: 50% of nucleated marrow
cells are erythroid lineage, including erythroblasts, 20%+ of nonerythroid
cells are myeloblasts (Leuk
Lymphoma 2006;47:683);
dyserythropoiesis is prominent Case
reports: 43
year old woman with leukocytosis, congenital disease presenting as
liver failure (Archives 2003;127:1362), associated with low dose
methotrexate for rheumatoid arthritis (Rheumatol Int 2005;25:311) Micro: hypercellular marrow; predominance of erythroid
precursors which have PAS+ cytoplasmic vacuoles, abnormal nuclear development
including megaloblastoid cells, karyorrhexis and gigantoblasts with multiple
nuclei; often dysplastic platelets and megakaryocytes with megaloblastoid
nuclei; 20%+ of nonerythroid cells are myeloblasts; myeloblasts may have Auer
rods; ringed sideroblasts may be present Micro
images: bone
marrow smear (Wright-Giemsa): numerous
myeloblasts and erythroid precursors at all stages of maturation; megaloblastoid
erythroblast and three myeloblasts; multinucleated
erythroblast has megaloblastoid chromatin; acute
erythroleukemia; >20%
each of pronormoblasts and myeloblasts (formerly M6c); dysplastic
erythroid precursor with basophilic stippling; various
images #1; #2 bone
marrow biopsy: early to late
stage erythroblasts, small megakaryocytes at upper and lower margins, marked
reduction in granulocytes; marrow is
replaced by blasts with variable size and few mature erythroid forms, immature
erythroid cells have dispersed chromatin and prominent nucleoli stains: immature
erythroid cells are hemoglobin A+ Positive
stains: erythroid cells
- glycophorin A (mature forms), hemoglobin A, CD36, CD71, PAS (vacuoles),
variable mdr-1 ((Mod Path 2000;13:407) myeloid
cells - myeloperoxidase, CD13, CD33, CD36, CD71, CD117,
HLA-DR Negative
stains: erythroid cells - myeloperoxidase,
CD13, CD33, CD34 (or weak), HLA-DR (or weak), CD41 and CD61; immature
erythroblasts may be negative for hemoglobin A or glycophorin A DD: AML with multilineage dysplasia, megaloblastic
anemia, secondary dyserythropoiesis, myelodysplastic syndrome, AML-M2 Pure
erythroid leukemia (M6b) Very
rare (3% of acute erythroid leukemia cases) Also
called erythemic myelosis, acute Di Guglielmo syndrome Aggressive Case
reports: 51 year old man with
pancytopenia (Archives 2004;128:241), after essential thrombocythemia (Am
J Hematol 2004;77:140), post-myeloma, therapy related (Archives
2006;130:1075) Micro: usually proerythroblasts or early basophilic
erythroblasts that are medium to large with deeply basophilic cytoplasm
containing poorly demarcated vacuoles, often agranular; nuclei are round with
fine chromatin and 1+ prominent nucleoli; no apparent myeloid component Micro
images: bone
marrow smear (Wright-Giemsa):
pure
erythroid leukemia; abnormal
erythroid precursors at all stages of maturation, granulocyte lineage appears
normal; very large
erythroid precursors; proerythroblasts
and basophilic erythroblasts predominate, many have numerous cytoplasmic
vacuoles; three immature
erythroblasts with large, clear cytoplasmic vacuoles; erythroblasts
are intermediate to large with round nuclei, fine chromatin and 1+ prominent
nucleoli (fig A), cytoplasmic vacuoles are PAS+ (inset), bone marrow biopsy
shows sheets of blasts and occasional multinucleated giant cells (fig B), inset
shows no staining for myeloperoxidase; fig
1: large cells with deeply basophilic cytoplasm with vacuoles, round nuclei
have fine chromatin and single distinct nucleoli, fig 2: PAS shows cytoplasmic
block-like staining; various
images #1; #2 bone
marrow biopsy: extensive
replacement by immature erythroid precursors, with occasional very large
abnormal cells stains: large abnormal
cells and others are hemoglobin A+ Enzyme
cytochemistry: alpha naphthyl
acetate esterase (nonspecific esterase); also acid phosphatase Positive
stains: glycophorin A (mature
forms), hemoglobin A, CD36, CD71, mdr1 (Mod Path 2000;13:407); vacuoles are PAS+ Negative
stains: myeloperoxidase, CD13, CD33,
CD34 (or weak), HLA-DR (or weak), CD41 and CD61; immature erythroblasts may be
negative for hemoglobin A or glycophorin A Molecular:
often complex cytogenetics
abnormalities involving #5 and #7 DD:
reactive erythroid hyperplasia
associated with folate or vitamin B12 deficiency Acute megakaryoblastic leukemia (AMKL, M7) Up to
10% of AML in children (common with Down’s syndrome, see below), 5% of adult
AML Associated
with marrow fibrosis due to megakaryoblast secretion of fibrogenic cytokines,
which makes marrow aspirate difficult to obtain In
adults, median age is 57 years, 59% had prior hematologic disorder or
myelodysplastic syndrome, 19% had prior chemotherapy (Blood 2006;107:880) Criteria
for diagnosis: 50%+ blasts of
megakaryocyte lineage are present in bone marrow; megakaryocytic lineage based
on CD41+ or CD61+ or positive platelet peroxidase reaction on EM Survival: poor, median overall survival is 6 months Case
reports: 3
year old boy with multiple bruises, 1 year old child, with mediastinal germ cell tumor (Clin
Transl Oncol 2007;9:329) Peripheral
blood: often contains
micromegakaryocytes and atypical platelets Micro: megakaryoblasts (often better morphology on biopsy
than smear) are medium/large cells with blue vacuolated eosinophilic cytoplasm
containing fine granules, cytoplasmic projections resembling platelets,
irregular cytoplasmic borders, cytoplasmic zoning; nuclei are round or indented
with dense chromatin and 1+ nucleoli; myelofibrosis or increased marrow
reticulin is common; may also have small lymphoid-like blasts; Micro
images: bone
marrow smears (Wright-Giemsa): blasts have
abundant cytoplasm; promegakaryocytes
(larger than blasts, cytoplasmic budding, irregular nuclei, coarse chromatin)
and large blasts; touch prep shows
3 blasts with basophilic cytoplasm, coarse chromatin and distinct nucleoli;
various
images #1; #2;
#3 bone
marrow biopsy: extensive
infiltration by blasts with sparse cytoplasm, frequent convoluted nuclei with
fine chromatin and distinct nucleoli; marked
proliferation of megakaryocytes with variation in size and nuclear morphology;
stains: reticulin stain
shows marked increase in reticulin fibers #1; #2; PAS+ large
megakaryocytes and micromegakaryocytes, also immature cells and erythrocyte
precursors; CD61 #1; #2; #3; #4; #5
(figures C, D); CD34-red,
podocalyxin-brown; CD42b
(figure c) Positive
stains: CD41 and CD61 (megakaryocyte
specific), CD42b (Mod Path 2005;18:603), CD34, CD36, factor VIII, von Willebrand factor;
variable CD13, CD33, CD71, alpha naphthyl acetate esterase, PAS and HLA-DR;
rarely positive for alpha-1-antitrypsin, alpha-1-antichymotrypsin or lysozyme (AJSP
1987;11:883) Negative
stains: myeloperoxidase, Sudan Black
B, CD14, CD64, glycophorin A EM: megakaryoblasts have demarcation membranes and
“bulls-eye” alpha granules with peroxidase activity in nuclear envelope and
endoplasmic reticulum, but not in granules and Golgi complex DD: ALL, AML-M0, M1, M5a, metastatic small blue cell
tumors in children, blastic transformation of CML References: Orphanet
(children) Variant
- transient myeloproliferative disorder (TMD) / AMKL in Down’s syndrome Down’s
syndrome patients (trisomy 21) have increased risk for AML, usually AMKL (AML
M7) Transient
myeloproliferative disorder (TMD) affects 10% of newborns with Down’s syndrome TMD
usually resolves in 2-14 weeks in neonates, but 20-30% progress to AMKL within
3 years TMD:
early death in 17%, associated with high WBC at diagnosis, increased bilirubin
and liver enzymes, failure to normalized WBC (Blood
2006;107:4606) TMD rarely occurs without Down’s syndrome (Arch Dis Child Fetal
Neonatal Ed 1998;79:F215) Case
reports: stillborn fetus with severe
disease (Nat
Clin Pract Oncol 2007;4:433) Treatment: less intensive chemotherapy may be effective (J Clin Oncol 2007;25:5442) Micro: blasts have moderate basophilic cytoplasm with
coarse azurophilic granules resembling those in basophils, round to slightly
irregular nuclei; also promegakaryocytes, micromegakaryocytes,
dyserythropoiesis Micro
images: blasts
in transient myeloproliferative disorder of Down’s syndrome Peripheral
blood: WBC up to 100K with 30-50%
blasts, nucleated red blood cells, micromegakaryocytes Positive
stains: CD41, CD61, HLA-DR Negative
stains: CD11b, CD13,
myeloperoxidase, Sudan Black B Molecular: mutations in GATA1 gene in almost all cases (versus
4% of all Down’s syndrome infants, Blood
2007;110:2128), specific
mutations may differ in TMD and subsequent AMKL (Int
J Hematol 2007;86:250); loss
of GATA1 impairs maturation of megakaryocyte erythroid progenitors (Blood
2006;107:87), JAK3 mutations found in 50% (Br
J Haematol 2007;137:337) References: AJCP
2001;116:204, Hum
Path 2000;31:396 Acute
megakaryoblastic leukemia - t(1;22)(p13;q13) variant Young
children with marked organomegaly (Blood
1991;78:748), prominent myelofibrosis Tissue
involvement resembles metastatic tumor Poor
outcome (Leukemia 2000;14:216) Case
reports: 4 week old infant with
hepatic involvement and no initial marrow involvement (Pediatr
Dev Pathol 2007 May 16:1 [Epub ahead of print]), with proliferation of erythroid and megakaryocytic
lineages (Rinsho
Ketsueki 1999;40:230) Micro: prominent fibrosis, blasts may have spindle shape or
form intertwining bundles resembling metastatic disease References: Atlas of
Genetics and Cytogenetics, AJCP
1992;98:214 CD13, CD33 negative acute myeloid
leukemia Not
part of WHO classification Usually
AML M1 or M2 Typical
myeloid morphology and cytochemistry, but negative for CD13, CD14, CD33, CD61,
glycophorin (AJCP
2000;114:29) Elderly
patients negative for CD33 and CD34 have poor prognosis (Cancer 2007 Dec 17 [Epub
ahead of print]) May express CD13 or CD33 at relapse (Rinsho Ketsueki 2001;42:314,
Intern Med 1993;32:733) Caution - may be easy to induce CD13 expression with in vitro
culture (Southeast
Asian J Trop Med Public Health 2002;33 Suppl 2:155) Molecular: often t(8;21)(q22;q22) (AJCP 1997;107:68, Ann Hematol 1999;78:237) Rare
(<1% of AML); tumor cells have basophilic differentiation Associated
with marrow failure, circulating blasts, skin involvement, organomegaly,
hyperhistaminemia symptoms Diagnosis: may require EM (AJCP
1991;96:160) Case
reports: 18 year old man with 11q23
gene rearrangement (Indian
J Pathol Microbiol 2007;50:443), 72 year old man with monosomy 7 (Cancer
Genet Cytogenet 2007;172:168), anaphylactoid reaction after chemotherapy (Cancer
1995;75:110) Treatment: imatinib if bcr-abl present (Ann
Biol Clin (Paris) 2006;64:361) Micro: hypercellular marrow composed of medium sized blasts
with high N/C ratio, moderate basophilic cytoplasm with variable number of
coarse basophilic granules; nucleus is round, oval or bilobed with 1+ nucleoli;
few mature basophils; dysplastic erythroid features Micro
images: peripheral
blood: immature
basophilic precursors bone
marrow smears: most blasts lack
differentiation, but one blast has coarse azurophilic granules bone
marrow biopsy: blasts and
immature basophils with variable nuclear size and nucleoli, also plasma cells,
endothelial cells and hemosiderophages stains: maturing
basophils have metachromatic granules with toluidine blue stain Enzyme
cytochemistry: myeloperoxidase
positive by EM but negative by light microscopy; acid phosphatase positive;
negative for Sudan Black B and nonspecific esterase Positive
stains: CD13 and CD33, CD34, HLA-DR;
toluidine blue (metachromatic granules), CD203c (Eur
J Clin Invest 2001;31:894) Negative
stains: myeloperoxidase by light
microscopy EM: basophilic granules and immature mast cell granules EM
images: granules contain
amorphous speckled substance, one granule has a myelin figure Molecular: often t(9;22) - Philadelphia chromosome DD: AML-M0 (EM shows no basophilic granules), CML in
blast crisis, AML-M2 subtypes with basophilia (Am
J Hematol 2004;76:134),
acute eosinophilic leukemia, ALL with coarse granules Myeloid sarcoma - acute leukemia
chapter Also
called extramedullary myeloid tumor, granulocytic sarcoma, chloroma if it forms
a mass See
also descriptions at various sites in respective chapters Extramedullary
tumor mass of neoplastic immature myeloid (granulocytic or monocytic) cells Often
misdiagnosed, particularly without immunostains Present
in 2-8% of AML patients; prognosis is that of underlying leukemia Equivalent
to blast transformation in setting of myelodysplastic syndrome or
myeloproliferative disease (Korean
J Lab Med 2006;26:143) Usually
associated with AML M4 or M5 (M4e or M5a in children), CML, chronic idiopathic
myelofibrosis, hypereosinophilic syndrome or polycythemia vera Rarely
no leukemia/myelodysplasia is identified in blood or bone marrow (J Neurosurg 2006;105:916) Common
sites: lymph nodes, subperiosteal
bone, skin, orbit, spinal canal, mediastinum Case
reports: Case of the Week
#130 (bone) Treatment: aggressive treatment recommended (Leukemia 2007;21:340, Cancer
2002;94:1739), usually evolves to AML
or has additional tumor masses at other sites Gross
images: kidney
tumor; bone tumor Micro:
myeloid tumors - blastic type
has myeloblasts with mild/moderate rim of basophilic cytoplasm, fine nuclear
chromatin, 2-4 nucleoli; immature type has myeloblasts,
promyelocytes and eosinophilic myelocytes; differentiated type
has promyelocytes, eosinophilic myelocytes and more mature forms; rarely
crystalline inclusions similar to Charcot-Leyden crystals (Archives 2002;126:85) Cytology: usually background lymphoglandular bodies; Auer rods
and eosinophilic myelocytes are rare; resembles large cell lymphoma (Cancer 2000;90:364) Micro
images: differentiated
(left) versus blastic types (center and right)-site unknown; various
images #1; #2 Myeloid sarcoma - acute leukemia chapter - continued lymph
node - cells have fine
chromatin resembling lymphoblastic lymphoma; large blast cells
resemble large cell lymphoma, also some eosinophilic myelocytes; tumor cells
have irregularly folded and convoluted nuclei; resembles
lymphoblastic lymphoma, but has cytoplasmic granules and distinct nuclei;
many tumor
cells have azurophilic granules; tumor cells mix
with residual normal lymphocytes; immature cells
with moderate to abundant cytoplasm, round/oval nuclei, distinct and prominent
nucleoli, also immature eosinophils case
of the week (bone) - #1;
#2;
#3;
#4;
CD45/LCA;
CD45RO;
CD3;
CD34;
CD20 other - appendix
#1; #2;
#3;
bladder;
breast
#1; #2;
#3 has blasts
with numerous azurophilic granules and promyelocytes, classified as AML with
maturation; same tumor with
fine needle aspiration; orbital mass
with t(8;21) has blasts with immature eosinophils; skin-eosinophilic
myelocytes and blasts; small
intestine #1; #2;
soft
tissue of paracervical spine (H&E and CD99); spinal dura-some
tumor cells have cytoplasmic granules; testes
#1; #2-prominent
eosinophilic myelocytes and blasts; intracytoplasmic
crystals stains:
chloroacetate
esterase-lymph node #1; #2; lysozyme-orbit;
myeloperoxidase
#1-lymph node; #2-lymph node;
#3-mediastinum;
#4-breast
(left), CD43 (right); CD68
#1-spine; #2-uterus Myeloid sarcoma - acute leukemia chapter - continued Positive
stains: almost all tumors -
lysozyme and CD43; myeloid tumors - myeloperoxidase and CD117;
myeloblasts - CD13, CD33 (Archives 2001;125:1448); monocytic tumors - CD68 and variable
CD163 (AJCP 2004;122:794); monoblasts - CD14, CD11c (Diagn
Pathol 2007;2:42), CD56 (AJCP 2000;114:807)
HLA-DR, CD99 (55%, Mod Path 2000;13:452),
chloroacetate esterase (Ann
Saudi Med 2001;21:287) Negative
stains: CD3, CD20, CD79a, CD34 Cytogenetics: most common are monosomy 7 (11%), trisomy 8 (10%)
and MLL rearrangements (9%) DD:
poorly differentiated lymphoma,
Burkitt’s lymphoma, small round cell tumors Myeloid
sarcoma of female genital tract - acute leukemia chapter Rare,
but may be initial clinical presentation Usually
ovary, also vagina, cervix Mean
age 40 years, range 13-76 years Micro: usually diffuse growth pattern, also cords,
pseudoacinar spaces; sclerosis common Micro
images: pelvic mass (various
images); uterus
Enzyme
cytochemistry: chloroacetate
esterase, lysozyme, myeloperoxidase, CD68, CD43, CD117 DD: lymphoma, carcinoma, granulosa cell tumor References: AJSP
1997;21:1156, AJCP
2006;125:783 Acute panmyelosis with myelofibrosis Also
called acute myelofibrosis, acute myelosclerosis, acute myelodysplasia with
myelofibrosis Some
question if it is a distinct entity (Ann
Hematol 2004;83:513, Leuk
Lymphoma 2004;45:681) Rare,
rapid onset, aggressive, usually adults
Weakness,
fatigue, bone pain, pancytopenia; usually no marked splenomegaly Aspirate
smear is often hypocellular due to marked fibrosis Median
survival is 2-9 months Case
reports: successful treatment with
biphosphonates (Eur
J Haematol 2004;73:215) Micro: hypercellular marrow with erythroblasts, immature
granulocytes and megakaryocytes; prominent megakaryocytic abnormalities with
variation in size and dysplastic changes, immature granulocytes with dysplasia,
immature erythrocytes; usually marked fibrosis (reticulin > collagen) Micro
images: bone
marrow smear (Wright-Giemsa): numerous blasts,
some CD61+, also abnormal erythroid and granulocyte cells; blasts and more
mature granulocytes, also a large megakaryocyte with a poorly lobulated nucleus
and dispersed chromatin, occasional neutrophils and late stage erythroblasts;
various
images bone
marrow biopsy: partial
replacement of marrow by blasts and increased fibrous tissue; numerous blasts
with some clustering lymph
node biopsy: total effacement
by blasts, also scattered megakaryocytes at various stages of maturation;
blasts have
fine chromatin and small but distinct nucleoli, mitotic figures are present stains: increase in
coarse reticulin fibers; reticulin stain
shows markedly hypercellular marrow with proliferation of blasts and maturing
cells, and increase in coarse reticulin fibers Positive
stains: CD34 and HLA-DR (Leuk
Lymphoma 2004;45:1873); erythroblasts
- glycophorin A and hemoglobin
A; granulocytes - myeloperoxidase, CD13, CD33, CD117; monocytes
- lysozyme and CD68; megakaryocytes - CD41, CD61, CD31, PAS,
factor VIII Negative
stains: usually CD42b (Mod Path 2005;18:603), von Willebrand factor DD: chronic idiopathic myelofibrosis with myeloid
metaplasia (marked splenomegaly and prominent dysplasia), acute
megakaryoblastic leukemia (no prominent changes in granulocytes or erythroid
cells), myelodysplastic syndrome with myelofibrosis (lacks high % blasts),
metastatic carcinoma with desmoplasia AML with Philadelphia chromosome Not
part of WHO classification 1% of
AML (Leuk
Res 2004;28:579, Zhongguo
Shi Yan Xue Ye Xue Za Zhi 2005;13:358), more common in bilineal, biphenotypic and acute
basophilic leukemias Rarely
is a secondary cytogenetic abnormality (Cancer
Genet Cytogenet 2006;165:70) Compared
to CML in blast crisis, has less frequent splenomegaly and peripheral
basophilia, lower marrow cellularity and lower M/E ratios in marrow (AJCP
2007;127:642) Median survival 9 months Associated with poor prognosis in biphenotypic leukemia (Haematologica 1999;84:699,
free full text) Case reports: dual presence of t(9;22) and inv(16) (AJCP 2006;125:260), AML-M7 (Ann
Hematol 2004;83:381) Treatment: possibly imatinib, then allogeneic stem cell transplant (Eur
J Haematol 2007;79:170) Micro: may occur in various AML subtypes Micro images: fig A:
hypercellular marrow (80%), fig B: mild increase in reticulin, fig C: erythroid
cells are dysplastic, fig D: CML References: Wikipedia
(Philadelphia chromosome) AML with pseudo-Chèdiak-Higashi
anomaly Not
part of WHO classification Frequent
in acute promyelocytic leukemia; up to 25% of AML-M2 (Acta Paediatr Jpn 1990;32:651) Giant
granules may be due to fusion of primary granules or small dense vesicles See
also Chediak-Higashi syndrome in Bone
Marrow-Nonneoplastic chapter Case
reports: 16 year old Chinese girl
with AML M5a and t(10;11) (Clin
Lab Haematol 2000;22:303) Micro: giant cytoplasmic granules Micro
images: specific
granules resemble Chediak-Higashi anomaly #1; #2;
in
blast cells in AML-M2 patients; acute
promyelocytic leukemia #1; #2 Chediak-Higashi
syndrome (for comparison): #1;
#2 Positive
stains: CD2 (AJCP
2006;125:791) Cytogenetics: may be associated with double minutes (Leukemia
2002;16:152) EM: peroxidase positive granules with a dense matrix but
no obvious crystalline structure, may contain membranous lamellae or tubular
structures (Cancer Res 1980;40:4473, Sangre
(Barc) 1994;39:135) Not
part of WHO classification Up to
10% of AML cases Median
age 67 years (Leuk Res 1996;20:563) Defined
by WHO as <20% bone marrow cellularity, 20% or more are blasts, other
definitions range up to 40% cellularity Rare
blasts in peripheral blood Often
has smoldering course, although intensive chemotherapy may cause complete
remission Case
reports: elderly patients (Nippon Ronen Igakkai Zasshi 1997;34:70) Micro
images: markedly
hypocellular marrow in 57 year old man with severe pancytopenia and rare blasts
in blood #1; #2-cells in
interstitium are predominantly blasts; various
images Positive
stains: myeloperoxidase DD: substance abuse (Archives 2005;129:e35), refractory anemia with excess
blasts, aplastic anemia (no excess blasts, interstitial bone marrow cells are
plasma cells, lymphocytes and mast cells, not blasts) ALL Acute lymphoblastic leukemia (ALL) -
general 5200
cases/year in US (National Cancer
Institute), peaks at age 4,
usually age 15 years or less 80% of
childhood leukemia is ALL Higher
incidence in whites, males, advanced (not developing) countries 85%
are B cell, 15% are T cell, but both often express aberrant myeloid or lymphoid
associated antigens Note
that only 10-20% of lymphoblastic lymphoma is B cell lineage Risk
factors: in utero radiation, Down’s
syndrome, ataxia telangiectasia, but most cases have no known cause Symptoms: abrupt stormy onset, symptoms related to bone marrow
depression (fatigue, fever, bleeding), bone pain and tenderness (due to marrow
expansion), joint pain, generalized lymphadenopathy, hepatosplenomegaly,
testicular involvement, CNS manifestations Atypical
presentation: hypercalcemia, bone
lesions, no circulating blasts Laboratory: anemia common, platelet count < 100K in 75% and
<10K in 15%; leukopenia (25%), WBC > 100K (10%) Cytogenetics
/ FISH is single most important prognostic factor for adults (Blood
2007 Dec 21 [Epub ahead of print]) Favorable
prognosis: age 2-10 years,
female, white; preB phenotype, hyperdiploidy >50, t(12,21), normal WBC count
at presentation, rapid response to chemotherapy, CD10+ Intermediate
prognosis: hyperdiploidy 47-50,
diploid, 6q-, rearrangements of 8q24 Unfavorable
prognosis: under age 2 (usually have
11q23 translocations) or over age 10; t(9;22) (but not if age 59+ years, AJCP 2002;117:716); hypodiploidy, near tetraploidy, 17p-, t(11q23); CD10 negative preB
ALL; also increased microvessel staining using CD105 in children (Leuk
Res 2007;31:1741), MDR1
expression in children (Oncol
Rep 2004;12:1201) and adults (Blood 2002;100:974) Diagnosis: immunostains required for diagnosis Case
reports: mature phenotype but non-L3
morphology (Mod Path 2004;17:832) Treatment: children - multiagent
chemotherapy plus CNS chemotherapy; 90% go into remission, 2/3 are cured;
thrombopoietin may induce CML like changes (AJCP 2002;117:844); adults - choice of
chemotherapy or stem cell transplantation is not clear (Hematology Am Soc Hematol Educ Program 2007;444) Relapse: blasts usually unchanged; may progress from L1 to
L2, TdT positive to negative (25%), gain or lose an antigen (CD10, HLA-DR),
evolve clonally (75%), evolve to AML; CNS relapse common Acute lymphoblastic leukemia (ALL) - general - continued Micro: blasts have scant agranular cytoplasm, no Auer rods,
coarse to fine chromatin, often indistinct nucleoli, no dysplastic myeloid
cells Peripheral
smear: leukoerythroblastosis
common with granulocyte precursors and nucleated RBCs, lymphoblasts,
occasionally reactive lymphocytes, rarely marked eosinophilia Bone
marrow: hypercellular, high
percentage of lymphoblasts Micro
images: Peripheral
smear images: blasts
with scant cytoplasm and prominent nucleoli L1
type (blood smears): blasts have
minimal cytoplasm, variable nuclear size and chromatin density, irregular
nuclear contour, some small nucleoli; blasts have
moderate cytoplasm, round nuclei of variable size, coarse chromatin, some
resemble mature lymphocytes L1
type (bone marrow smears): blasts contain
large cytoplasmic azurophilic granules (uncommon), but were B cells by IHC and
cytochemistry L1
type (bone marrow biopsy): markedly
hypercellular marrow with lymphoblasts replacing normal marrow elements;
lymphoblasts
occupy marrow, have minimal cytoplasm and indistinct cell borders, convoluted
nuclei, angulated borders; lymphoblasts are
small with more condensed chromatin; marrow contains
lymphoblasts, one megakaryocyte, normoblasts in upper half and occasional eosinophils
and eosinophil precursors L1
type (stains): lymphoblasts have
block and coarse granular PAS staining L2
type (blood smears): three large
lymphoblasts have moderate cytoplasm, large nuclei with coarsely reticular
chromatin, 1-3 prominent nucleoli; lymphoblasts have
variable size, moderate cytoplasm, markedly irregular nuclei with coarse
chromatin and distinct nucleoli; most lymphoblasts
have variable size, reticular chromatin with prominent nucleoli, some have L1
features; blasts have
cytoplasmic azurophilic granules (uncommon) L2
type (bone marrow smears): large
lymphoblasts with cytoplasm that has numerous, sharply defined clear vacuoles
similar to L3, non-L3 features are reticular chromatin, prominent nucleoli,
TdT+ and CD10+ L2
type (bone marrow biopsy): relatively large
lymphoblasts with variable nuclear shape, dispersed chromatin, prominent
nucleoli Acute lymphoblastic leukemia (ALL) - general - continued L3
type (bone marrow smears): no prominent
vacuoles, dispersed chromatin and more obvious nucleoli than usually observed
in L3, diagnosed as ALL-L3, non-Burkitt’s type L3
type (stains): strong
cytoplasmic staining by methyl green pyronine (left), vacuoles are Oil Red O
positive (right) Lymph node (aspirate smear): lymphoblasts and some
lymphocytes Other:
various
images; relapsed
ALL; CNS
relapse of ALL; refractory
ALL Children: 80% are L1, 10-20% L2, <5% L3 Adults: 35% are L1, 60% L2, <5% L3 Enzyme
cytochemistry: negative for
myeloperoxidase, chloroacetate esterase, nonspecific esterase (usually), only
rarely positive for Sudan Black B (Mod Path 1992;5:68); positive for PAS
(75%, coarse clumping corresponds to glycogen), acid phosphatase (T-ALL has
focal paranuclear staining) Only
L3 stains for glycogen with Sudan Black B and PAS Positive
stains: CD99 (MIC2), TdT, bcl2,
CD34 Negative
stains: myeloperoxidase
(usually, but positive in 23% of adults using a polyclonal antibody, AJCP 2001; 116:25) Note:
TdT negative cases may demonstrate early T-cell lineage by flow cytometry (Archives 2000;124:92) Cytogenetics: 90% have cytogenetic abnormalities, usually
hyperdiploidy (>50 chromosomes), also pseudodiploidy (46 chromosomes but
structural anomalies), t(12,21); t(9,22) [Philadelphia chromosome], t(4,11) EM
images: DD: AML, hematogones (normal B lymphoid precursors, AJCP 2000;114:66), reactive lymphocytosis, hypoplastic anemia, CLL,
adult T cell leukemia, AML-M3, non-Hodgkin’s lymphoma, Merkel cell carcinoma
(may be TdT+, Mod
Path 2007;20:1113) WHO
classification system includes former FAB classifications ALL-L1 and L2 FAB L3
is now considered Burkitt’s lymphoma WHO classification of Acute Lymphoblastic Leukemia Precursor
B lymphoblastic leukemia / lymphoblastic lymphoma - ALL
with t(9;22)(q34;q11) (BCR-ABL-Philadelphia chromosome) - ALL
with t(v;11q23) (MLL rearranged) - ALL
with t(1;19)(q23;p13) (PBX-E2A) - ALL
with t(12;21)(p13;q22) (TEL-AML1) -
Hyperdiploid > 50 -
Hypodiploid Precursor
T lymphoblastic leukemia / lymphoma References:
Mod Path 2000;13:193 FAB classification of Acute Lymphoblastic Leukemia Terminology
now considered to not be relevant because L1 and L2 morphology do not predict
immunophenotype, genetic abnormalities or clinical behavior: L1: small cells, scant basophilic cytoplasm with
variable vacuoles, small nucleoli, regular nuclear shape, homogenous chromatin L2: large heterogeneous cells with moderate cytoplasm,
often intensely basophilic, variable vacuoles; large nucleoli, irregular
nuclear shape with clefting and indentation, large nucleoli, variable nuclear
chromatin L3: medium to large homogenous cells with moderate
cytoplasm that is intensely basophilic with prominent cytoplasmic vacuoles; at
least one prominent nucleoli (may be 2-4), round to oval nucleus, finely
stippled homogenous chromatin, cytologically identical to Burkitt’s and
Burkitt’s like lymphoma (small noncleaved); has mature phenotype (i.e.
expresses surface immunoglobulin); fat vacuoles are Sudan black+, Oil red O+,
PAS -; cytoplasm is methyl green-pyronine positive Not
part of WHO classification ALL
with marked eosinophilia is rare (<50 cases reported thru 2005), but may
obscure ALL diagnosis Symptoms
are related to hypereosinophilia, including respiratory failure, myocardial
infarction, cerebrovascular accident (Leuk
Lymphoma 2005;46:1045) Eosinophilia
resolves with remission, returns with relapse Eosinophilia
is usually reactive, not part of leukemic cells Treatment: steroids suppress eosinophlia Case
reports: t(5;9) with detection of
residual disease in CSF by PCR (Archives 2003;127:601); prior idiopathic hypereosinophilic
syndrome (Leuk
Res 2005;29:975), prior eosinophilic myelodysplasia (J Clin Pathol 1999;52:388), T-ALL with eosinophilia and AML (Cytometry B Clin Cytom 2005;65:37), 10 year old with urticaria (J
Am Acad Dermatol 2004;51:S151), 5q- deletion (Pediatr
Dev Pathol 2003;6:558) Molecular: may have t(5;14)(q31;q32) - IL3 and IgH (Atlas of
Genetics and Cytogenetics) Micro
images: bone
marrow smear shows blasts, eosinophilic myelocytes, granulocytes and
normoblasts; CSF
shows prominent eosinophilia, basophilia and rare blasts (center) PreB ALL Precursor-B cell acute lymphoblastic
leukemia (ALL) / lymphoblastic lymphoma (LBL) - acute leukemia chapter See
also Lymphomas:
B cell chapter Also
called B cell acute lymphoblastic leukemia / lymphoblastic lymphoma Usually
children Pre B
acute lymphoblastic leukemia presents with pancytopenia due to extensive
marrow involvement, stormy onset of symptoms, bone pain due to marrow
expansion, hepatosplenomegaly due to neoplastic infiltration, CNS symptoms due
to meningeal spread, testicular involvement Pre B
acute lymphoblastic lymphoma often presents with cutaneous nodules, bone
or nodal involvement, but NO marrow involvement Tumors
are derived from pre-germinal center naive B cells with unmutated VH region
genes Have
multiple immunophenotyping aberrancies relative to normal B cell precursors
(hematogones); at relapse, 73% show loss of 1+ aberrance and 60% show new
aberrancies (AJCP
2007;127:39) Best
prognosis: age 2-10 years, early
preB phenotype, hyperdiploidy, t(12,21) Worse
prognosis: less than 2 years, older
than 10 years, t(9;22), CD10 negative or expression of myeloid antigens Case
reports: arising from follicular
lymphoma (Archives 2002;126:997), with basal cell carcinoma (Diagn Pathol 2007;2:32), mature phenotype but no
translocations (Archives 2003;127:1340), with hemophagocytic
lymphohistiocytosis (Pediatr
Blood Cancer 2008;50:381) Treatment: chemotherapy cures more children than adults;
adolescents benefit from intensive regimens (Hematology Am Soc Hematol Educ Program 2005;123) Micro: bone marrow smears - intermediate
sized blast-like cells with scant, variably basophilic cytoplasm, round/oval or
convoluted nuclei, fine chromatin, indistinct nucleoli; frequent mitotic
figures; may have “starry sky” appearance similar to Burkitt’s lymphoma; may
have large lymphoblasts with 1-4 prominent nucleoli resembling myeloblasts;
usually no sclerosis marrow
biopsy: usually markedly
hypercellular with reduction of trilinear maturation; cells have minimal
cytoplasm, medium sized nuclei that are often convoluted, moderately dense
chromatin and indistinct nucleoli, brisk mitotic activity Precursor-B cell acute lymphoblastic leukemia (ALL) /
lymphoblastic lymphoma (LBL) - continued Micro
images: peripheral
blood: blasts
with scant cytoplasm but prominent nucleoli; L1 type has
smaller blasts with minimal cytoplasm, coarse chromatin, some cleaved nuclei or
irregular contours, no distinct nucleoli; blasts
have L1 morphology, but mature phenotype bone
marrow smears: various
images #1; #2;
#3;
#4;
#5 lymphoblastic
lymphoma: skin
and marrow; TdT
negative cases; figure
a: H&E; b: CD179b; c/d: CD179a (FF is frozen tissue, PF is paraffin fixed) lymphoblastic
lymphoma with basal cell carcinoma: #1;
#2;
#3:
TdT+; #4:
CD79a+; #5:
CD34+ Positive
stains: TdT (negative in 3%, AJCP 2004;121:810), CD19, CD22, CD79a; CD34 (75%), usually cytoplasmic (not surface)
immunoglobulin but rarely surface immunoglobulin (AJCP 2004;121:512), also CD9, CD24, CD38, CD45, HLA-DR; variable CD10 and CD20 (Blood 2006;108:3302); myeloid antigens CD13 or CD33 in 27% (Exp
Mol Pathol 2007;83:471), particularly pediatric cases with Philadelphia chromosome or 11q23
rearrangements (AJCP
1999;111:467) Negative
stains: cytoplasmic IgM, CD15, CD30 Flow
cytometry images: various
images Molecular: usually chromosomal abnormalities DD
(based on morphology): Burkitt’s
lymphoma, granulocytic sarcoma, blastic variant of mantle cell lymphoma, Ewing’s
sarcoma (negative for CD79a, CD43, TdT and immunoglobulin or T cell receptor
rearrangement, vimentin++), Hodgkin’s lymphoma, AML (prominent nucleoli,
delicate chromatin, fine azurophilic cytoplasmic granules) PreB ALL with t(9;22)(q34;q11) ALL
with bcr-abl fusion transcript (Philadelphia chromosome) 30% of
adults with ALL, 4% of children but 80% of infants Older
age and higher WBC at presentation than other preB ALL (excluding infants) May
have more organomegaly or CNS involvement than other preB ALL Poor
prognosis Treatment: tyrosine kinase inhibitors cause some complete
responses (Cancer
2007;110:1178), but change in overall survival is minimal (Cancer
2007;109:2068, Hematology
Am Soc Hematol Educ Program 2007;435) Micro: no defining morphology, but large blasts with
prominent nucleoli and cytoplasmic granules are more common than other preB-ALL Micro
images: leukemic cells
resemble early erythroblasts; various
images Cytology
images - contributed by Dr. Julia Braza, Beth Israel Deaconess Medical
Center, Boston, Massachusetts (USA) - CSF #1; #2; #3 Positive
stains: myeloid antigens in 71% (AJCP
1999;111:467) Molecular: translocation involves abl on #9q34 (tyrosine
kinase) and bcr on #22q11 (breakpoint cluster region) FISH
images - contributed by Dr.
Julia Braza, Beth Israel Deaconess Medical Center, Boston, Massachusetts (USA)
- bcr-abl FISH
probe Molecular
images: drawing
of translocation; karyotype Rearrangements
of MLL gene 20% of
ALL overall (Anticancer
Res 2005;25:1931), including 80% of
infants (Leukemia
2007;21:633), 10% of older children and adults May be
bilineal with monoblasts and promonocytes Usually
infants < 1 year with markedly increased WBC, CNS involvement Poor
prognosis (30% event free survival) Treatment: intensive chemotherapy followed by hematopoietic
stem cell transplantation Micro: no defining morphology Positive
stains: TdT, CD19, CD34, HLA-DR;
also CD15, often myeloid antigens CD13 and CD33 (AJCP
1999;111:467) Negative
stains: CD10 Molecular: most translocations at 11q23 involve MLL (mixed
lineage leukemia) gene; over 75 genetic arrangements; t(4;11)(q21;q23) -
MLL-AF4 occurs in 60% of infants, 2% of other children, 3-6% of adults; also
t(11;19)(q23;p13.3) - MLL-ENL and others Molecular
images: diagram of ALL1/MLL
duplication References: Atlas
of Genetics and Cytogenetics PreB ALL with t(1;19)(q23;p13) Commonly
detected by conventional cytogenetics in children 5-6%
of ALL High
WBC counts, frequent CNS involvement In
children, is no longer a poor prognostic factor (Blood
1984;63:721), due to intensive
therapy and bone marrow transplantation; in adults, is associated with short
survival (Leuk Lymphoma
2006;47:469) Case
reports: t(1;19) without fusion
transcript by PCR or Southern blot (Rinsho Ketsueki 2005;46:7), 5
year old boy with splenomegaly and neurologic symptoms Micro: no distinct morphologic findings Positive
stains: CD9, CD10, CD19 Molecular: produces fusion transcript of PBX and E2A; occurs in
balanced and unbalanced forms; unbalanced form is der(19)t(1;19); the
reciprocal product of der(1)t(1;19) is lost and the normal chromosome 1 is
duplicated (Leukemia
2001;15:95) Notes:
“unbalanced translocations”
means the exchange of chromosomal material is unequal resulting in extra or
missing genes “der”
means derivative chromosome; term is used when only one chromosome from a
translocation is present, or when one chromosome has two or more structural
abnormalities Molecular
images: karyotype
(unbalanced) #1 with loss of der(1)t(1;19); #2 References: Mol Cell Biol 1994;14:3938, Atlas of Genetics
and Cytogenetics PreB ALL with t(12;21)(p13;q22) 20-30%
of childhood preB ALL (most common translocation, Chin
Med J (Engl) 2003;116:1298) and 3% of adults 5
different patterns of gene expression involving 14 genes, detected with gene
chip (BMC Genomics 2007;8:385) Excellent prognosis due to good response to chemotherapy; almost 100%
remissions Persistence
of TEL-AML1 transcripts is not necessarily related to relapse (Pediatr Int 2003;45:275) Micro: no distinct morphology Positive stains: CD10 (bright), HLA-DR; also CD13 and CD33 (Diagn Mol Pathol 2000;9:184) Negative stains: CD9, CD20 Molecular: fusion of TEL/ETV6 and AML1/RUNX1/CBFA2 genes; not
found by conventional cytogenetics (cryptic) because rearranged segments are
too small; detect with FISH or PCR; may have no other molecular abnormalities,
almost never > 50 chromosomes References: Atlas of
Genetics and Cytogenetics PreB ALL with hyperdiploidy with
> 50 chromosomes “High
hyperdiploidy” means >50 chromosomes Generally
arises by simultaneous gain of all additional chromosomes in a single abnormal
mitosis (Genes
Chromosomes Cancer 2005;44:113) Hyperdiploidy
appears to be an early event occurring prenatally (Genes Chromosomes Cancer
2004;40:38, Leukemia
2003;17:2202, Blood
2002;100:347) Affects
25-33% of children (usually age 3-5 years) and 5% of adults with preB ALL Favorable
overall survival (Am
J Hematol 2007;83:34), although outcome in children varies by specific trisomy present (Blood 2003;102:2756) Micro: no distinct morphology Molecular: mutations in NRas (10%), FLT3 (9%), PTPN11 (9%) and
KRas (6%) (Genes
Chromosomes Cancer 2008;47:26) 5% of
preB ALL Most
have 45 chromosomes, fewer chromosomes is rare Poorer
prognosis: near haploid and low
hypodiploid groups compared to those with 42-45 chromosomes (Br J Haematol 2004;125:552), <44 versus 44 chromosomes (Blood
2007;110:1112), <45 versus 45 chromosomes (Cancer
2003;98:2715) Overall
50% survival at 8 years Micro: no distinct morphology Molecular: defined as fewer than 45 or 46 chromosomes Cytogenetic
images: karyotype
of severe hypodiploidy Mature B cell ALL - acute leukemia
chapter Also
called Burkitt’s leukemia, FAB L3 See
also Lymphoma-B cell chapter for Burkitt’s lymphoma WHO
classifies Burkitt’s lymphoma with secondary marrow or peripheral blood
involvement and ALL-L3 as same disease Variants
are endemic, sporadic and immunodeficiency associated, which have different
clinical and geographic presentations Extramedullary
masses are prominent, often the presenting feature Pure
leukemic involvement is rare Cases
with mature B phenotype but no c-myc translocations are best classified and
managed as pre-B ALL (Archives 2003;127:1340) Case
reports: 53 year old woman with
hepatosplenomegaly (Archives 2004;128:1459) Treatment: more intensive chemotherapy than standard ALL plus
CNS prophylaxis; overall survival up to 50-70% in adults (Blood
2004;104:3009) Micro:
intermediate to large blasts with
intensely basophilic cytoplasm containing prominent vacuoles, nuclei are round
with coarse / mildly clumped chromatin and indistinct nucleoli; low power has
starry sky appearance in biopsies Micro
images: peripheral
blood (fig 1A), bone marrow aspirate (fig 1B), bone marrow biopsy (fig 2),
inset-CD20; Burkitt’s
lymphoma peripheral
blood smears: large
cells with prominent vacuoles #1; #2
bone
marrow smears: large
cells with basophilic cytoplasm and vacuoles #1; #2;
#3 stains: Oil
Red O+ Positive
stains: CD10, CD19, CD20, CD22,
CD79a; bright surface immunoglobulin with light chain restriction (overall is
mature B cell phenotype); Oil Red O Negative
stains: CD5, CD23, CD34, TdT Molecular: c-myc gene amplification with t(8;14), t(2;8) or
t(8;22) Other ALL Precursor T cell acute lymphoblastic
leukemia (T-ALL) / lymphoma (T-LBL) - acute leukemia chapter Also
called T cell acute
lymphocytic leukemia See
also Lymphoma
non B cell chapter Teens
and young men (older than preB ALL) Most
cases begin after birth (Blood
2007;110:3036) T-ALL
versus T-LBL: T-ALL has a more
immature phenotype, CD47 expression, no 11q23 rearrangement (Pediatr Blood Cancer
2006;47:130), a different gene expression profile, and may derive
from T cell progenitor of bone marrow; T-LBL is derived from thymocytes (Leuk
Lymphoma 2007;48:1745) PreT
ALL constitutes 15% of childhood and 20-25% of adult ALL cases PreT
LBL constitutes 85-95% of LBL, usually presents as mediastinal mass with
no/minimal marrow involvement CNS
involvement if untreated Comparison
of younger (age 16-60 years) vs. older involvement (61+ years): more hepatosplenomegaly, presents with mediastinal
mass and lymphadenopathy; myeloid antigens and lineage inappropriate gene
rearrangements are less common (AJCP 2002;117:252) Good
prognostic factors: HOX11
overexpression in adults (AJCP
2007;127:528) Poor
prognostic factors:
expression of CFLAR, NOTCH2 and
BTG3 genes (Br J Haematol
2007;137:319),
3+ methylated genes (J
Clin Oncol 2005;23:7043) Diagnosis: T-ALL if lymphoblasts are 25% or more of marrow
cells or no mass lesion; T-LBL otherwise Case
reports: 25
year old man with hemoptysis Treatment: chemotherapy cures 60%; earlier relapse and poorer
prognosis than preB ALL, often in CNS Micro: similar to B-cell disease; scant cytoplasm;
delicate chromatin, indistinct nucleoli, convoluted nuclear membrane and
grooves; frequent mitotic figures; starry sky pattern produced by interspersed
benign macrophages; usually features of FAB L1 or L2; pattern in marrow is
usually interstitial Micro
images: blood smear
shows markedly elevated leukocyte count with variable lymphoblast size and
chromatin density; various
images #1; #2;
#3;
#4 L1
type (blood smears) - moderate
cytoplasm with variable basophilia, coarse chromatin; various
images L2
type (blood smears) - large leukemic
blasts. also small cells with minimal cytoplasm, markedly hyperchromatic nuclei
and prominent nuclear convolution, suggestive of T cell ALL bone
marrow biopsy: sheets of
lymphoblasts with variable size and moderate nuclear irregularity, also mitotic
figures stains: focal paranuclear
acid phosphatase staining Precursor T cell acute lymphoblastic leukemia / lymphoma
(preT ALL/LBL) - continued Positive
stains: CD1, CD2 (78%), CD3
(cytoplasmic, not surface in 100%), CD5 (100%), CD7 (100%), TdT (73%); CD4 and
CD8 both positive in 22%; variable CD10 (47%), CD13 (6%), CD16, CD33 (12%),
CD57, CD79+ (40-60%, AJCP 2000;113:823), CD117 (12%, Exp
Mol Pathol 2006;81:162) Negative
stains: CD19, CD20 Note: ALL with aberrant myeloid antigen expression is
correct name, not biphenotypic leukemia Molecular:
different cytogenetic abnormalities
than B-ALL, often are cryptic and identified only by FISH or PCR t(1;14)(p32;q11)
involving SCL (TAL1) and T cell receptor delta/alpha in 15-30% t(10;14)(q24;q11)
involving HOX11 (TLX1) and T cell receptor delta/alpha in 7% Activating
mutations of NOTCH1 in 50% (Science
2004;306:269) CDKN2A (INK4A) deletions in up to 80% (Blood
1995;85:2321 DD: Burkitt’s leukemia (B cell phenotype), granulocytic
sarcoma (positive for myeloid markers), lymphoblastoid mantle cell lymphoma (B
cell phenotype), thymoma (AJCP 2004;121:268) References:
Atlas of
Genetics and Cytogenetics, Stanford
University Defined
as two separated blast populations, one myeloid and the other lymphoid, or
rarely one B cell and one T cell Acute
bilineal and biphenotypic leukemias are less than 4% of acute leukemias Often
poor prognosis Case
reports: t(9;17)(p11;q11) (Leuk
Lymphoma 1997;25:179) Cytogenetics: B cell plus myeloid cases may have
t(9;22)(q34;q11.2) or 11q23 translocations or del(9); T cell plus myeloid cases
may have 2p13 translocations or other unrelated anomalies (Leukemia
2007;21:2264) Cytogenetics
images: t(4;11)(q21;23)
in bilineal leukemia DD: ALL or AML with aberrant antigen expression <4%
of acute leukemias Also
called acute mixed lineage leukemia Single
population of blasts expresses myeloid, and usually either B or T cell
antigens; expression of B & T or B, T & myeloid antigens is rare May
derive from primitive stem cell with capacity to express markers of both
myeloid and lymphoid lineage Either
de novo or therapy related European
Group for the Immunological Characterization of Leukemias has developed a
scoring system based on degree of lineage specificity of each antigen (Haematologica 1997;82:64-scoring system, Leukemia 1995;9:1783) Scoring
system: diagnosis requires score
greater than 2 from 2 separate lineages: 2
points: B cell - CD79a, CD22, cytoplasmic IgM; T cell
- CD3; myeloid - myeloperoxidase by cytochemistry or IHC 1
points: B cell - CD19 or CD10, T cell - CD2 or CD5,
myeloid - CD13 or CD33 0.5
points: B cell - TdT, T cell - TdT or CD7, myeloid
- CD14, CD15, CD11b or CD11c Often
poor prognosis Case
reports: 80 year old man with blasts
coexpressing CD79a and myeloid markers (Archives 2003;127:356), with myeloid, B cell and NK
phenotype (Archives 2003; 127:E93), due to transformation of essential
thrombocythemia (Am J Hematol 2006;81:624), 58
year old woman with pancytopenia Treatment:
usually based on morphology of
blasts Micro:
no consistent morphology; myeloid
features usually resemble AML-M1 (without differentiation) or AML-M5
(monoblastic / monocytic) Micro
images: blood smears -
child with t(4;11)(q21;q23)
- small blasts are early B cell precursors that are CD10 negative / large cells
are monocyte precursors that are alpha naphthyl butyrate esterase+; blasts
have minimal cytoplasm, fine chromatin with 1+ prominent nucleoli bone
marrow smears - 2 week old girl
with t(4;11)(q21;q23) - lymphoblasts and monoblasts #1; #2-large cells
are monoblasts and promonocytes, small cells are lymphoblasts with minimal
cytoplasm and coarse chromatin; myeloid
features include Auer rod (fig 1A-asterisk) and myeloperoxidase staining (fig
1B); various
images Positive
stains: by definition, express
myeloid and lymphoid markers; most specific markers are - B cell:
CD79a, CD22 and cytoplasmic Ig; T cell - CD3 and anti-T cell
receptor; myeloid - myeloperoxidase (cytochemistry or flow
cytometry) Flow
cytometry images: biphenotypic
acute leukemia with CD19 and myeloperoxidase coexpression (figure B) EM
images: monocytoid blast
has folded nucleus and scattered small electron dense granules Molecular:
often complex abnormalities, most
common are t(9;22) and 11q23 changes; also 2p13 or other abnormalities (Leukemia
2007;21:2264) DD: ALL or AML with aberrant antigen expression References: Atlas
of Genetics and Cytogenetics
End of Leukemia-acute chapter
Primary references, acute leukemia-general, AML general, AML classification
American Journal of Clinical Pathology
American Journal of Surgical Pathology
Archives of Pathology and Laboratory Medicine
Human Pathology
Modern Pathology
Brunning: Tumors of the Bone Marrow (AFIP Atlas of Tumor Pathology, Series 3, Vol 9, 1994)
Please refer to these primary references for more detailed discussions and photographs
AML with recurrent
genetic abnormalities
