Neoplastic Myeloid Disorders Flashcards
Myeloid neoplasms
arise from hematopoietic stem cells that give rise to cells of myeloid (i.e., erythroid, granulocytic, and/or thrombocytic) lineage
Three Categories Myeloid Neoplasia
Acute Myelogenous Leukemias
Myelodysplastic Syndromes
Chronic MyeloproliferativeDisorders
Acute Myelogenous Leukemias
> 20% immature progenitor cells accumulate in the bone marrow
•Myeloid (Granulocytic) sarcoma –soft tissue mass of these cells
Myelodysplastic Syndromes
Associated with ineffective hematopoiesis and resultant peripheral blood cytopenias
Chronic MyeloproliferativeDisorders,
in which increased production of one or more terminally differentiated myeloid elements (e.g., granulocytes) usually leads to elevated peripheral blood counts
Acute myeloid neoplasms
immature/blasts
live months
kids and adults
Chronic myeloid neoplasms
maturation present
live years
adults
Molecular Pathogenesis of Acute Myeloid Leukemias
Class I mutations
FLT3-ITD FLT3-TKD KIT RAS PTPN11 JAK2
proliferation and/or survival advantage; not affecting differentiation
Molecular Pathogenesis of Acute Myeloid Leukemias
class II mutations
PML-RARA RUNX1-RUNX1T1 CBFB-MYH11 MLL FUSIONS CEBPA NMP1?
impaired haemotopoietic differentiation and subsequent apoptosis
AML with t(8;21)(q22;q22);
RUNX1/ETOfusion gene*
Prognosis
FABSubtype
Morphology/Comments
Favorable
M2
Full range of myelocyticmaturation; Auer rods easily found; abnormal cytoplasmic granules
AML with inv(16) (p13;q22);
CBFβ/MYH11 fusion gene*
Prognosis
FABSubtype
Morphology/Comments
Favorable
M4eo
Myelocyticand monocyticdifferentiation; abnormal eosinophilic precursors in marrow with abnormal basophilic granules
AML with t(15;17)(q22;11-12);
RARα/PMLfusion gene
Prognosis
FABSubtype
Morphology/Comments
Intermediate
M3, M3v
Numerous Auer rods, often in bundles within individual progranulocytes; primary granules usually very prominent (M3), but inconspicuous in microgranularvariant (M3v);
high incidence of DIC
AML with t(11q23;v); diverseMLLfusion genes
Prognosis
FABSubtype
Morphology/Comments
Poor
M4, M5
Usually some degree of monocytic differentiation
AML with normal cytogenetics and mutatedNPM
Prognosis
FABSubtype
Morphology/Comments
Favorable
Variable
Detected by immunohistochemicalstaining for NPM
With prior MDS
Prognosis
FAB Subtype
Morphology/Comments
Poor
Variable
Diagnosis based on clinical history
AML with multilineage dysplasia
Prognosis
FAB Subtype
Morphology/Comments
Poor
Variable
Maturing cells with dysplastic features typical of MDS
AML with MDS-like cytogenetic aberrations
Prognosis
FAB Subtype
Morphology/Comments
Poor
Variable
Associated with 5q-, 7q-, 20q-aberrations
AML,THERAPY-RELATED
Prognosis
FAB Subtype
Morphology/Comments
Very poor
Variable
If following alkylatortherapy or radiation therapy, 2-to 8-year latency period, MDS-like cytogenetic aberrations (e.g., 5q-, 7q-); if following topoisomeraseII inhibitor (e.g., etoposide) therapy, 1-to 3-yea
AML, minimally differentiated
Prognosis
FAB Subtype
Morphology/Comments
Intermediate
M0
Negative for myeloperoxidase; myeloid antigens detected on blasts by flow cytometry
AML without maturation
Prognosis
FAB Subtype
Morphology/Comments
Intermediate
M1
>3% of blasts positive for myeloperoxidase
AML with myelocyticmaturation
Prognosis
FAB Subtype
Morphology/Comments
ve for myeloperoxidase
AML with myelocyticmaturation
AML with myelomonocyticmaturation
Prognosis
FAB Subtype
Morphology/Comments
Intermediate
M4
Myelocyticand monocytic differentiation
AML with monocyticmaturation
Prognosis
FAB Subtype
Morphology/Comments
Intermediate
M5a, M5b
In M5a nonspecific esterase-positive monoblastsand pro-monocytes predominate in marrow and blood; in M5b mature monocytes predominate in the blood
AML with erythroidmaturation
Prognosis
FAB Subtype
Morphology/Comments
Intermediate
M6a, M6b
Erythroid/myeloid subtype (M6a) defined by >50% dysplastic maturing erythroid precursors and >20% myeloblasts; pure erythroid subtype (M6b) defined by >80% erythroid precursors without myeloblasts
AML with megakaryocytic maturation
Prognosis
FAB Subtype
Morphology/Comments
Intermediate
M7
Blasts of megakaryocytic lineage predominate; detected with antibodies against megakaryocyte-specific markers (GPIIb/IIIaor vWF); often associated with marrow fibrosis; most common AML in Down syndrome
Age of Initial Diagnosis
Acute Myelogenous Leukemia
67
Age of Initial Diagnosis
Acute Lymphoblastic Leukemia
14
AML in marrow
slide
Almost exclusively leukemic cells
Hematopoiesis reduced via replacement (myelophthisic) or stem cell supression
Acute myeloid leukemia without maturation (FAB M1 subtype
slide
Myeloblastshave delicate nuclear chromatin, prominent nucleoli, and fine azurophilic granules in the cytoplasm.
In the flow cytometric analysis shownthe myeloid blasts
express CD34, a marker of multipotent stem cells, but do not express CD64, a marker of mature myeloid cells
The same myeloid blasts express CD33, a marker of immature myeloid cells, and a subset express CD15, a marker of more mature myeloid cells. Thus, these blasts are myeloid cells showing limited maturation
Acute promyelocyticleukemia with the t(15;17) (FAB M3 subtype
slide
Bone marrow aspirate shows neoplastic promyelocyteswith abnormally coarse and numerous azurophilicgranules. Other characteristic findings include the presence of several cells with bilobednuclei and a cell in the center of the field that contains multiple needle-like Auer rods.
Acute myeloid leukemia with monocytic differentiation (FAB M5b subtype).
slide
Peripheral smear shows one monoblastand five promonocyteswith folded nuclear membranes
Acute Myelogenous Leukemia Clinical Course
- Presents with same acute onset and symptoms as ALL (anemia, infection, fever, bone pain, and bleeding)
- DIC occurs in AML with t(15;17)(q22;11-12);RARα/PMLfusion gene
- Neoplastic cells with monocytic differentiation infiltrate skin
- Variable blast count 100,000/mm3
Acute Myelogenous Leukemia Clinical prognosis
- Much poorer overall prognosis than ALL
- 60% can achieve one complete remission, but only 15-30% remain disease free after 5 years.
- Survival dependent specific subtype and cytogenetic findings
- Pre-existing MyelodysplasticSyndrome (MDS) confers “Dismal Prognosis”
- Increased incidence in Down Syndrome
- Myeloid Leukemia is usually Acute MegakaryoblasticLeukemia
- Not as common as Acute Lymphoblastic Leukemia in Down Syndrome
Acute Myelogenous Leukemia Physical Findings
- Splenomegaly
- Hepatomegaly
- Gum swelling or skin nodules
- Sternal tenderness
- Petechiae
AML Incidence
median age at diagnosis 67
AML Mortality
MEDIAN AGE AT DEATH 72
2008 WHO Classification Myelodysplastic syndrome (MDS)
- Refractory cytopeniawith unilineagedysplasia
- Refractory anemia
- Refractory neutropenia
- Refractory thrombocytopenia
- Refractory anemia with ring sideroblasts
- Refractory cytopeniawith multilineagedysplasia
- Refractory anemia with excess blasts
- Myelodysplastic syndrome with isolated del(5q)
- Myelodysplastic syndrome, unclassifiable
- Childhood myelodysplastic syndrome
- Provisional entity: refractory cytopeniaof childhood
Myelodysplasia slides
A, Nucleated red cell progenitors with multilobatedor multiple nuclei.
B, Ringed sideroblasts, with iron-laden mitochondria (blue granules)
C, Pseudo-Pelger-Hüetcells, neutrophils with two nuclear lobes instead of three to four
D, Megakaryocytes with multiple separate nuclei
Refractory cytopenia with unilineage dysplasia
Refractory anemia
Refractory neutropenia
Refractory thrombocytopenia
Blood (/μL(1 ×109/L)
BoneMarrow
Cytopenia
Blasts (
Refractory anemia with ring sideroblasts
Blood (/μL(1 ×109/L)
BoneMarrow
Anemia
No blasts
Monocytes≤1,000/μL
Erythroid dysplasia only
Refractory cytopenia with multilineage dysplasia
Blood (/μL(1 ×109/L)
BoneMarrow
Cytopenia(s)
Blasts (10% of the cells of ≥2 myeloid lineages
Refractory anemia with excess blasts
RAEB 1
Blood (/μL(1 ×109/L)
BoneMarrow
Refractory anemia with excess blasts
RAEB 2
Blood (/μL(1 ×109/L)
BoneMarrow
5-19% blasts
+/-Auer rods
10%-19% blasts
+/-Auer rods
Myelodysplastic syndrome with isolated del(5q)
del (5q) is sole cytogenetic abnormality
Blood (/μL(1 ×109/L)
BoneMarrow
Anemia
↔or ↑platelets
Refractory anemia with excess blasts
Blood (/μL(1 ×109/L)
BoneMarrow
Cytopenia(s)
Monocytes≤1,000
Unilineage or multilineage dysplasia
Myelodysplastic Syndromes (MDS)Clinical Course
Affects individuals older than 50 years (mean age of onset 70 years)
Presents with weakness, infection and hemorrhage caused by bone marrow failure and peripheral pancytopenia
~ 50% discovered incidentally during routine blood testing for another reason
Anemia that may be accompanied by monocytosis
Myelodysplastic Syndromes (MDS)Clinical note
- If it looks like myelodysplasia and has >1000 monocytes/uLin the blood than the patient has chronic myelomonocyticleukemia
- If it looks like myelodysplasia or a myeloproliferative syndrome and there is more than 20% blasts in the bone marrow or blood than it is acute myeloid leukemia
Myelodysplastic Syndromes (MDS) Prognosis
Some good prognostic groups may live 5 years or more
Median survival in primary MDS varies from 9-29 months
t-MDS prognosis is 4-8 months
MDS is serious disease in its own right without progression to AML
Overall progression to AML occurs in 10-40% and in these patients the prognosis is “dismal”…..6 months or less
Chronic Myeloproliferative Disorders
- Multipotent progenitor cell capable of giving rise to mature erythrocytes, platelets, granulocytes (except CML)
- In chronic myelogenousleukemia (CML) pluripotent stem cell gives rise to myeloid cells and lymphocytes
- The neoplastic cells displace normal bone marrow and suppress normal hematopoiesis
- The terminal differentiation of the neoplastic clone is unaffectedand mature end-stage cells are increased in the peripheral blood in markedly increased numbers
- Associated with an abnormal increase in the activity of mutated tyrosine kinases with growth factor independent proliferation and survival
Chronic myelogenous leukemia
Mutation
Frequency1
Consequences2
BCR-ABLfusion gene
100%
Constitutive ABL kinase activation
Polycythemia vera
Mutation
Frequency1
Consequences2
JAK2point mutations
>95%
Constitutive JAK2kinase activation
Essential thrombocythemia
Mutation
Frequency1
Consequences2
JAK2point muations
50% to 60%
Constitutive JAK2kinase activation
Primary myelofibrosis
Mutation
Frequency1
Consequences2
MPLpoint mutations
5% to 10%
Constitutive MPLkinase activation
Systemic mastocytosis
Mutation
Frequency1
Consequences2
c-KITpoint mutations
>90%
Constitutive KIT kinase activation
Chronic eosinophilic leukemia
Mutation
Frequency1
Consequences2
FIP1L1-PDGFRαfusion gene
Common
Constitutive PDGFRα kinase activationConstitutive
PDE4DIP-PDGFRβfusion gene
Rare
Constitutive PDGFRβ kinase activation
Stem cell leukemia
Mutation
Frequency1
Consequences2
VariousFGFR1fusion genes
100%
Constitutive FGFR1 kinase activation
Tyrosine Kinase Mutations in Myeloproliferative Disorders
Chronic myelogenousleukemia
Polycythemia vera
Essential thrombocythemia
Primary myelofibrosis
Systemic mastocytosis
Chronic eosinophilic leukemia4
Stem cell leukemia5
2008 WHO Classification Myeloproliferative neoplasms (MPN)
- Chronic myelogenousleukemia, BCR-ABL1–positive
- Chronic neutrophilic leukemia
- Polycythemia vera
- Primary myelofibrosis
- Essential thrombocythemia
- Chronic eosinophilic leukemia, not otherwise specified
- Mastocytosis
- Myeloproliferativeneoplasms, unclassifiable
2008 WHO Classification
Myeloid and lymphoid neoplasms associated with eosinophilia and abnormalities of PDGFRA, PDGFRB, or FGFR1
- Myeloid and lymphoid neoplasms associated with PDGFRArearrangement
- Myeloid neoplasms associated with PDGFRBrearrangement
- Myeloid and lymphoid neoplasms associated with FGFR1abnormalities
2008 WHO Classification
Myelodysplastic/myeloproliferative neoplasms (MDS/MPN)
- Chronic myelomonocyticleukemia
- Atypical chronic myeloid leukemia, BCR-ABL1–negative
- Juvenile myelomonocyticleukemia
- Myelodysplastic/myeloproliferativeneoplasm, unclassifiable
- Provisional entity: refractory anemia with ring sideroblastsand thrombocytosis
Chronic Myeloproliferative Disorders
Chronic Myelogenous Leukemia
genes
CML is distinguished from other chronic MPDs by the presence of a chimeric BCR-ABL gene derived from portions of the BCR gene on chromosome 22 and the ABLgene on chromosome 9 ….in more than 90% of cases … (9;22)(q34;q11) .. Philadelphia Chromosome(Ph)
t(9;22) is also seen in some ALL and AML patients
Chronic Myeloproliferative Disorders
Chronic Myelogenous Leukemia
overview
•100% cellular marrow (no fat)
•Increased precursors of all cell lines, including megakaryocytes
•Peripheral marked leukocytosis 50,000 or even 100,000 total granulocyte count with PMNs, bands, metamyelocytes, myelocytes, +/-basophilia,
but
Chronic myeloid leukemia.
Peripheral blood smear shows
many mature neutrophils, some metamyelocytes, and a myelocyte
Molecular pathogenesis of chronic myeloid leukemia.
Breakage and joining of BCR and ABL creates a chimeric BCR-ABL fusion gene that encodes a constitutively active BCR-ABL tyrosine kinase. BCR-ABL activates multiple downstream pathways, which drive growth factor-independent proliferation and survival of bone marrow progenitors. Because BCR-ABL does not interfere with differentiation, the net result is an increase in mature elements in the peripheral blood, particularly granulocytes and platelets.
CML characteristically ( 90% of time) has Philadelphia chromosome (Ph1).
This translocation involves transfer of portion of q arm, C22, to q arm, C9, and is designated t(9:22). This translocation brings c-ablproto-oncogene on chromosome 9 in proximity with bcr(breakpoint cluster) gene on chromosome 22.
Fish
Useful adjunct to routine cytogenetics
heat to relax dna,seperate strands
add fluorescently tagged dna probe
cool to allow annealing of probe and target
Detection of a BCR-ABLfusion gene by fluorescence in situ hybridization
Because of the pairing of sister chromatids during mitosis, signals on metaphase chromosomes may be seen as a single dot or a pair of closely spaced dots. Two pairs of red signals and two green signals are seen on metaphase, while 2 red and 2green signals are present in interphase nucleus, indicating the presence of normal, spatially distant copies of ABLand BCR, respectively.With CML show one normal ABLsignal, one normal BCRsignal, and an abnormal yellow signal created by superimposition of one BCRand one ABLsign
Chronic Myeloproliferative Disorders Chronic MyelogenousLeukemia
•Natural history is one of slow progression with moderate anemia and hypermetabolism(high cell turnover)
•Major symptoms are weakness, easy fatigability and weight loss……..markedly enlarged spleen is a constant finding
•Massive splenomegaly may lead to splenic infarcts
•3 years median survival without treatment
•50% of patients enter an “accelerated” phase (worse anemia and thrombocytopenia) then enter after 6 to 12 months a “blast crisis”—-development of acute leukemia
•Other 50% eventually develop “blast crisis” without accelerated phase
•70% develop myeloid leukemia and 30% pre-B leukemia
Rx-Gleevac/imatinib(BCR-ABL kinase inhibitor)
Chronic myeloid leukemia (spleen).
gross
Enlarged spleen (2630 gm; normal: 150 to 200 gm) with greatly expanded red pulp stemming from neoplastic hematopoiesis
Chronic Myelogenous Leukemia
incidence
median age at diagnosis
Chronic Myelogenous Leukemia
mortality
median age at death 76
Chronic Myeloproliferative Disorders Polycythemia Vera (PV)
overview of disease
- True polycythemia with panmyelosis(erythrocytosis, granulocytosis and thrombocytosis) +/-basophilia
- Peripheral blood hematocrit around 60%
- increases in red cell mass produces symptoms related to hyperviscositysyndromes with thromboses and infarcts
- Peripheral blood hematocrit around 60%
- Bone marrow-all precursors increased
- Progenitor erythroblasts in PV are hypersensitive to erythropoietin (usually due to JAK2 V617F mutation) and serum erythropoietin levels are suppressed
- JAK2 mutation occurs in >95% of patients
Chronic Myeloproliferative Disorders Polycythemia Vera (PV)
clinical
Median age onset 60 years
Plethoric and cyanotic
Abnormal viscosity and perhaps increased, but abnormal platelets leads to increased major bleeding and thrombosis
Patients develop massive splenomegaly
Pruritis and peptic ulcers due to released histamine from increased basophils
5-10% develop gout (hyperuricemia from nuclei breakdown)
Chronic Myeloproliferative Disorders Polycythemia Vera (PV)
treatment and prognosis
Hemoglobin usually 14-28 gm/dLand Hct> 60%
WBC 12,000 -50 ,000 /mm3
Platelets >500,000/mm3common
Treat with phlebotomy to control symptoms and avoid bleeding/thrombosis complications
Untreated survival is months
With extended survival by treatment, 15-20% tend to evolve to a “spent phase” during which clinical and anatomic features of primary myelofibrosis develop
Occasionally (1-2%) can develop blast crisis (AML)
Polycythemia vera, spent phase
Massive splenomegaly (3020 gm; normal: 150 to 200 gm) largely due to extramedullary hematopoiesis occurring in the setting of advanced marrow myelofibrosis.
Chronic Myeloproliferative Disorders Essential Thrombocytosis
overview
•Least common of chronic myeloproliferativedisorders
•JAK2 (50%) and MPL (5-10%)tyrosine kinase mutations or calreticulinmutations
•Increased proliferation confined to megakaryocytes with platelet counts of
> 450,000 with megathrombocytes
•Since all chronic myeloproliferative disorders may be associated with thrombocytosis, essential thrombocythemiais a diagnosis of exclusion-
No polycythemia or progressive marrow fibrosis
Chronic Myeloproliferative Disorders Essential Thrombocytosis
symptoms
- Bone marrow cellularity only mildly to moderately increased but megakaryocytes are substantially increased in number
- Thromboses (erythromelalgia) and bleeding occur
- Indolent clinical course with onset after age 60 and median survival of 12 to 15 years
Essential Thrombocytosis: Bone marrow
-numerous megakaryocytes, some much larger than normal. Peripheral platelet counts can exceed 1,000,000/microliter.
Essential thrombocytosis
slide
Peripheral blood smear shows marked thrombocytosis, including giant platelets approximating the size of surrounding red cells
Chronic Myeloproliferative Disorders Primary Myelofibrosis
Hallmark
rapidly developing obliterativemarrow fibrosis caused by extensive collagen deposition by non-neoplastic fibroblasts
•Stimulated by platelet derived growth factor and TGF-β
Chronic Myeloproliferative Disorders Primary Myelofibrosis
overview
Early in progression of fibrosis, marrow is hypercellularand there may be transient leukocytosis and thrombocythemia
Eventually the fibrosis obliterates much of the marrow space and abnormal dysplastic precursor forms are seen (large clustered megakaryocytes) and cytopeniasdevelop
JAK2 (50-60%) and MPL (1-5%)tyrosine kinase mutations or calreticulinmutations
Chronic Myeloproliferative Disorders Primary Myelofibrosis
clinical
Onset after age 60 with initial symptoms of progressive anemia or marked splenomegaly (+/-infarcts) caused by extramedullary hematopoiesis
May develop hyperuricemia and gout
Exhibit “leukoerythroblastosis” in peripheral smear
Anemia, megathrombocytes and basophilia
Aggressive disease: Median survival is 3-5 years
5-20% may develop AML-like blast crisis
Primary myelofibrosis(peripheral blood smear).
Two nucleated erythroid precursors and several teardrop-shaped red cells (dacryocytes) are evident. Immature myeloid cells were present in other fields. An identical picture can be seen in other diseases producing marrow distortion and fibrosis.
Langerhans Cell Histiocytosis
overview
A.K.A. eosinophilic granuloma, Langerhans cell granulomatosis, histiocytosisX (“H-X”), Hand-Schuller-Christian disease, Letterer-Siwedisease
Immature dendritic cell
Vesicular nuclei with linear grooves or folds
On EM has “Birbeck” granules (HX bodies) composed of pentalaminartubules with dilations
BRAF, TP53, RAS and MET mutations seen
S-100+ ; CD1+; CD207+ (langerin), CD1a+, HLA-DR+
Langerhans Cell Histiocytosis
expresses
Express CCR6 like in normal Langerhans cells (CCL20 ligand in skin and bone)
Express CCR7 abnormally (CCL19 & CCL20 in lymphoid tissues)
Langerhans Cell Histiocytosis
clinical
Age: most cases occur in childhood
Incidence: 5 per million population per year
Race: Caucasian»>African-American
Survival: Unifocaldisease (>99% 5-year survival)
Multisystem disease (66% mortality)
Multifocal multisystem Langerhans cell histiocytosis(Letterer-Siwedisease)
Most frequently before 2 years of age (occasionally affects adults)
Cutaneous lesions resembling a seborrheic eruption (Langerhans cells infiltrate)
Hepatosplenomegaly, lymphadenopathy, pulmonary lesions and bone lesions
With chemotherapy, 50% 5 year survival, untreated disease is rapidly fatal
Unifocal and multifocal unisystem Langerhans cell histiocytoses(eosinophilic granuloma)
•Langerhans cells with mixed eosinophils, lymphocytes, plasma cells, and neutrophils
Many patients experience spontaneous regression
Treatment:
Chemotherapy if multifocal
Local excision or irradiation if unifocal
Langerhans Cell Histiocytosis
•Unifocallesions
•Skeletal system in older children or adults (occasionally skin, lung, or stomach)
Langerhans Cell Histiocytosis
•Multifocal unisystem
- Multiple erosive bony masses young children
- 50% have diabetes insipidus (involve posterior pituitary stalk of hypothalamus)
- Hand-Schuller-Christian triad: calvarialbone defects, diabetes insipidus, and exophthalmos
Pulmonary Langerhans Cell Histiocytosis
Presents as
Bilateral interstitial disease (Multifocal unisystem)
Multiple fine nodules and cysts in the middle and upper lung zones
Represents an inflammatory immunologic disorder (usually polyclonal) strongly associated with cigarette smoking
40% are clonal with BRAFmutations indicative of neoplastic proliferation
ulmonary Langerhans Cell Histiocytosis
Synonyms
Pulmonary Langerhans’ cell Granulomatosis
Pulmonary histiocytosisX
Pulmonary eosinophilic granuloma
Eosinophilic granuloma of the lung
ulmonary Langerhans Cell Histiocytosis
Clinical Features
Age of onset between ages 15 and 40
Can regress spontaneously on cessation of smoking
Langerhans cell histiocytosis.=
Eosinophilic Granuloma
Langerhans cell histiocytosis microscopy
A,Langerhans cells with folded or grooved nuclei and moderately abundant pale cytoplasm are mixed with a few eosinophils.
B,An electron micrograph shows rodlike Birbeckgranules with characteristic periodicity and dilated terminal end.
