Myeloid Malignancies 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 - >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 myeloproliferative disorders, in which increased production of one or more terminally differentiated myeloid elements (e.g., granulocytes) usually leads to elevated peripheral blood counts.
Why so much emphasis on mutations? 2 Classes.
Can take advantage of specific mutations for therapy
Can better understand what is driving the neoplastic proliferation
Class I mutations: Affect survival or proliferation, but not differentiation
KIT, RAS, JAK2
Class II mutations: Impair differentiation and thereby subsequent apoptosis
PML-RARA
AML Subtypes and prognosis/ comments
AML with t(8;21)- favorable
AML with inv(16)- favorable
APL with t(15;17); fusion gene- FAB Subtype m3, M3v- progranulocytes,
– PML/RARA high incidence of DIC
most common AML in Down syndrome
Acute megakaryoblastic leukemia
AML FAB subtypes
M0- AML with minimal differentiation
M1- AML without maturation
M2- AML with (myelocytic) maturation
M4- Acute myelomonocytic leukemia
M5- Acute monoblastic/ monocytic leukemia (nonspecific esterase positive)
M6- Pure erythroid leukemia
M7- acute megakaryoblastic leukemia (most common AML in down syndrome)
auer rod means what?
acute myeloblastic leukemia (as a whole, the M1-M4)
Acute Myelogenous Leukemia Chromosomal Abnormalities
t(15;17) in acute promyelocytic leukemia (APL)
PML/RARA fusion proteins block differentiation at promyelocyte
pharmacologic doses of all trans-retinoic acid or arsenic trioxide overcome this block
Acute Myelogenous LeukemiaClinical Course & Prognosis
DIC occurs in APL with t(15;17)
Pre-existing Myelodysplastic Syndrome (MDS) confers “Dismal Prognosis”
Increased incidence in Down Syndrome
Myeloid Leukemia is usually Acute Megakaryoblastic Leukemia
Not as common as Acute Lymphoblastic Leukemia in Down Syndrome
Acute Myelogenous LeukemiaPhysical Findings
Splenomegaly Hepatomegaly Gum swelling or skin nodules Sternal tenderness Petechiae
Myelodysplastic syndromes (MDS)
with singe lineage dysplasia (MDS-SLD) with ring sideroblasts (MDS-RS) with multilineage dysplasia (MDS-MLD) with excess blasts (MDS-EB) with isolated del(q)
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
NOTE
If it looks like myelodysplasia and has >1000 monocytes/uL in the blood than the patient has chronic myelomonocytic leukemia
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 myelogenous leukemia (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 unaffected and 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 myeloid leukemia
mutation
BCR-ABL
–> constitutive ABL kinase activation
polycythemia vera mutation
JAK2
–> constitutive JAK2 kinase activation
essential thrombocythemia mutation
JAK2 and MPL point mutations
Constitutive JAK2 kinase and MPL kinase activation
Primary myelofibrosis mutation
JAK2 point mutations, MPL point mutations
–> Constitutive JAK2 kinase and MPL kinase activation
Chronic Myeloid Leukemia
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 ABL gene 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
, +/- basophilia
Chronic Myeloid Leukemia prognosis
***70% develop acute myeloid leukemia and 30% pre-B leukemia
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
Likely cell of origin in CML
multipotent progenitor
Polycythemia Vera (PV)
True polycythemia with panmyelosis (erythrocytosis, granulocytosis and thrombocytosis) +/- basophilia
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
(Increases in red cell mass produces symptoms related to hyperviscosity syndromes with thromboses and infarcts)
The JAK2V617F mutation causes
activation of STAT pathway in the absence of EPO!
Binding of erythropoietin (EPO) to receptor → receptor dimerization of JAK2 → phosphorylation of STAT3 and 5 → stable homodimers and heterodimers → gene transcription → cell proliferation and survival
Polycythemia Vera (PV) Clinical presentations
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)
polycythemia vera treatment
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)
Essential Thrombocythemia
lots of dysfunctional platelets
JAK2 (50%) and MPL (5-10%) tyrosine kinase mutations
Bone marrow cellularity only mildly to moderately increased but megakaryocytes** are substantially increased in number
Thromboses (erythromelalgia**) and bleeding occur
Primary Myelofibrosis
**JAK2 (50-60%) and MPL (1-5%) tyrosine kinase mutations
Hallmark: rapidly developing obliterative marrow fibrosis caused by extensive collagen deposition by non-neoplastic fibroblasts
Stimulated by platelet derived growth factor and TGF-β
Early in progression of fibrosis, marrow is hypercellular and 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 cytopenias develop
Primary Myelofibrosis Clinical presentation
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).
Nucleated erythroid precursors and dacryocytes (leukoerythoblastic)
Chronic Myelomonocytic Leukemia (CMML)
Has features of myelodysplastic and myeloproliferative disorders
Peripheral blood monocytosis (>1 x 109/L) and > 10% of WBCs in differential
Total white count may be increased or decreased depending on subtype
Usually occurs in older (~70) adults or post radiation or chemotherapy
Present with anaemias, thrombocytopenia, infections, hepatosplenomegaly
Prognosis – 19 months on average
Can develop acute myelogenous leukemias
Langerhans Cell Histiocytosis
A.K.A. eosinophilic granuloma
Immature dendritic cell
- **On EM has “Birbeck” granules (HX bodies)
S-100+ ; CD1+; CD207+ (langerin), CD1a+,
worst kind of langerhans cell histiocytosis
**Multifocal multisystem Langerhans cell histiocytosis (Letterer-Siwe disease)
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)
**Unifocal lesions
Skeletal system in older children or adults (occasionally skin, lung, or stomach)
**Multifocal unisystem
Multiple erosive bony masses young children
50% have diabetes insipidus (involve posterior pituitary stalk of hypothalamus)
**Hand-Schuller-Christian triad: calvarial bone defects, diabetes insipidus, and exophthalmos
Many patients experience spontaneous regression
Treatment:
Chemotherapy if multifocal
Local excision or irradiation if unifocal
Hand-Schuller-Christian triad
calvarial bone 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 BRAF mutations indicative of neoplastic proliferation
another name for langerhans cell histiocytosis
Eosinophilic Granuloma
