Myeloid Malignancies

Question 1

Myeloid neoplasms arise from

Answer 1

hematopoietic stem cells that give rise to cells of myeloid (i.e., erythroid, granulocytic, and/or thrombocytic) lineage.

Question 2

Three categories myeloid neoplasia

Answer 2

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.

Question 3

Why so much emphasis on mutations? 2 Classes.

Answer 3

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

Question 4

AML Subtypes and prognosis/ comments

Answer 4

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

Question 5

most common AML in Down syndrome

Answer 5

Acute megakaryoblastic leukemia

Question 6

AML FAB subtypes

Answer 6

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)

Question 7

auer rod means what?

Answer 7

acute myeloblastic leukemia (as a whole, the M1-M4)

Question 8

Acute Myelogenous Leukemia Chromosomal Abnormalities

Answer 8

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

Question 9

Acute Myelogenous LeukemiaClinical Course & Prognosis

Answer 9

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

Question 10

Acute Myelogenous LeukemiaPhysical Findings

Answer 10

Splenomegaly
Hepatomegaly
Gum swelling or skin nodules
Sternal tenderness
Petechiae

Question 11

Myelodysplastic syndromes (MDS)

Answer 11

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)

Question 12

Myelodysplastic Syndromes (MDS)Clinical Course

Answer 12

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

Question 13

Myelodysplastic Syndromes (MDS)Prognosis

Answer 13

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

Question 14

Chronic Myeloproliferative Disorders

Answer 14

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

Question 15

Chronic myeloid leukemia

mutation

Answer 15

BCR-ABL

–> constitutive ABL kinase activation

Question 16

polycythemia vera mutation

Answer 16

JAK2

–> constitutive JAK2 kinase activation

Question 17

essential thrombocythemia mutation

Answer 17

JAK2 and MPL point mutations

Constitutive JAK2 kinase and MPL kinase activation

Question 18

Primary myelofibrosis mutation

Answer 18

JAK2 point mutations, MPL point mutations

–> Constitutive JAK2 kinase and MPL kinase activation

Question 19

Chronic Myeloid Leukemia

Answer 19

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

Question 20

Chronic Myeloid Leukemia prognosis

Answer 20

***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

Question 21

Likely cell of origin in CML

Answer 21

multipotent progenitor

Question 22

Polycythemia Vera (PV)

Answer 22

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)

Question 23

The JAK2V617F mutation causes

Answer 23

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

Question 24

Polycythemia Vera (PV) Clinical presentations

Answer 24

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)

Question 25

polycythemia vera treatment

Answer 25

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)

Question 26

Essential Thrombocythemia

Answer 26

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

Question 27

Primary Myelofibrosis

Answer 27

**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

Question 28

Primary Myelofibrosis Clinical presentation

Answer 28

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

Question 29

Primary myelofibrosis (peripheral blood).

Answer 29

Nucleated erythroid precursors and dacryocytes (leukoerythoblastic)

Question 30

Chronic Myelomonocytic Leukemia (CMML)

Answer 30

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

Question 31

Langerhans Cell Histiocytosis

Answer 31

A.K.A. eosinophilic granuloma

Immature dendritic cell
- **On EM has “Birbeck” granules (HX bodies)

S-100+ ; CD1+; CD207+ (langerin), CD1a+,

Question 32

worst kind of langerhans cell histiocytosis

Answer 32

**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

Question 33

Unifocal and multifocal unisystem Langerhans cell histiocytoses (eosinophilic granuloma)

Answer 33

**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

Question 34

Hand-Schuller-Christian triad

Answer 34

calvarial bone defects, diabetes insipidus, and exophthalmos

Question 35

Pulmonary Langerhans Cell Histiocytosis presents as

Answer 35

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

Question 36

another name for langerhans cell histiocytosis

Answer 36

Eosinophilic Granuloma