Myeloproliferative Neoplasms and Myelodysplastic Syndrome

Question 1

classically, myeloproliferative neoplasms contain which mutation? what are the classic MPNs?

Answer 1

GOF mutation in JAK2 (non-receptor tyrosine kinase) —> increased growth and survival of myeloid precursors, constitutively active

“classic” MPNs:
1. polycythemia vera (RBC)
2. essential thrombocythemia (platelets)
3. primary myelofibrosis (stroma)

*”non-classic” is chronic myeloid leukemia (CML), caused by BCR-ABL fusion protein

Question 2

describe the JAK2 mutation that is seen in all “classic” myeloproliferative neoplasms

Answer 2

“classic” MPNs: polycythemia vera, essential thrombocythemia, myelofibrosis

GOF (constitutively active) JAK2 tyrosine kinase —> increased growth and survival of myeloid precursors

usually activated by erythropoietin, thrombopoietin, GM-CSF receptors

Question 3

polycythemia

Answer 3

abnormal elevation of RBC mass (hemoglobin or hematocrit)

*can be relative due to decrease in plasma volume (dehydration)

Question 4

primary vs secondary absolute (not relative) polycythemia

Answer 4

primary: increased RBC mass due to intrinsic RBC problem - erythropoietin is normal or low

secondary: increased RBC mass due to increased EPO production

Question 5

chronic hypoxemia, hemoglobinopathy, and paraneoplastic syndrome are all secondary causes of _____ due to increased EPO synthesis

Answer 5

secondary causes of polycythemia, due to increased EPO

chronic hypoxemia - EPO regulated by O2 levels

hemoglobinopathy - increased affinity of hemoglobin for O2

paraneoplastic syndrome - produces EPO (renal cell carcinoma, hepatocellular carcinoma)

*also high altitude, pulmonary disease, sleep apnea, CO, renal tumors

Question 6

polycythemia vera

Answer 6

most common myeloproliferative disorder

mutation in hematopoietic stem cells —> unregulated growth and survival of mostly RBC

mutation: JAK V617F —> constitutively active tyrosine kinase

Question 7

how do patients with polycythemia vera present?

Answer 7

asymptomatic with high Hgb/Hct
or
symptoms due to hyperviscosity of blood: neurological, HTN/flushing, unusual venous/arterial thrombosis (Budd-Chiari syndrome), bleeding (platelet dysfunction)

unusual signs: pruritis (itch) following warm shower, erythromelalgia (increased platelets - warmth/pain in extremities), plethora (red skin because of excess blood)

*Budd-Chiari = hepatic vein thrombosis

Question 8

what do these signs collectively indicate?
- HTN
- Budd-Chiari syndrome
- acquired vWF deficiency (bleeding)
- pruritis following warm shower
- erythromelalgia (warm/pain in extremities)
- plethora

Answer 8

polycythemia vera: increased RBC, increases blood viscosity

Budd-Chiari: hepatic vein thrombosis (unusual location)

erythromelalgia: increased platelets

acquired vWF deficiency and bleeding: basically thick blood pushes clotting factors away

plethora: conjunctival or facial, “excess blood” (look red)

Question 9

how is polycythemia vera diagnosed? (4)

Answer 9

primary increase in RBC

1. elevated hgb/hct
2. EPO normal or low
3. hypercellular bone marrow
4. JAK V617F mutation

Question 10

how is polycythemia vera managed? (3)

Answer 10

1. phlebotomy to keep hct low
2. aspirin to prevent thrombosis
3. hydroxurea (blocks DNA synthesis) to lower RBC mass

Question 11

essential thrombocythemia

Answer 11

primary cause of thrombocytosis

overproduction of platelets (unregulated megakaryocytes) without definable cause

associated with JAK V617F mutation (common mutation of myeloproliferative neoplasms)

mostly in elderly, F>M

Question 12

how does essential thrombocythemia present?

Answer 12

asymptomatic with increased platelets, or…

microvascular disturbances (erythromelalgia), arterial and venous thrombosis

bleeding if count very high (too many platelets interfere with vWF function)

Question 13

how can you diagnose essential thrombocythemia, a primary cause of thrombocytosis? (3)

Answer 13

1. unexplained or persistent thrombocytosis (>450K)
2. bone marrow biopsy essential - megakaryocyte proliferation (largest cells in bone marrow)
3. JAK V617F mutation

*exclude polycythemia vera and primary myelofibrosis

Question 14

how is essential thrombocythemia treated?

Answer 14

patients can be stable for decades

goal - prevent complications (thrombosis), alleviate symptoms

—> low dose aspirin
—> hydroxyurea - reduces cell proliferation (disrupts DNA synthesis)

Question 15

primary myelofibrosis

Answer 15

neoplastic transformation of hematopoietic stem cells
—> bone marrow fibrosis, lower cell counts
—> extramedullary hematopoiesis (hepatosplenomegaly)

Question 16

what are 3 signs/symptoms of primary myelofibrosis?

Answer 16

1. hepatosplenomegaly (extramedullary hematopoiesis)
2. hypermetabolism (increased cytokines - low grade fever, weight loss, night sweats)
3. anemia (bone marrow fibrosis)

Question 17

what 2 key things will you see in a peripheral smear of a patient with primary myelofibrosis?

Answer 17

1. dacrocytes (tear drop cells, due to squeezing through bone marrow)
2. leukoerythroblastic peripehral smear: WBC/RBC precursors

Question 18

how can you diagnose primary myelofibrosis?

Answer 18

1. bone marrow aspirate - “dry tap” due to fibrosis
2. silver stain of bone marrow demonstrates fibrosis

Question 19

a patient with marrow fibrosis, extramedullary hematopoiesis, and splenomegaly likely has what going on?

Answer 19

myelofibrosis: neoplastic transformation of hematopoietic stem cells in bone marrow

Question 20

how can you treat myelofibrosis?

Answer 20

goal is to control symptoms

low risk: hydroxurea

high risk: allogeneic stem cell transplant (curative)

Question 21

myelodysplastic syndromes

Answer 21

clonal disorder resulting in abnormal (dysplastic) maturation of myeloid progenitor cells —> cytopenia

cells have alerted appearance and function (nucleated RBC, hypolobation of PMNs)

Question 22

what are 2 major risk factors for myelodysplastic syndrome?

Answer 22

1. ionizing radiation
2. chemotherapeutic agents (alkylating agents, DNA top inhibitors)

Question 23

what are the clinical features of myelodysplastic syndrome?

Answer 23

most patients asymptomatic but found to have abnormal cell counts and morphology

symptoms related to peripheral cytopenia or functional deficit: anemia (macrocytic), neutropenia (hypolobation), thrombocytopenia

Question 24

what kind of anemia can myelodysplastic syndrome cause?

Answer 24

RBC maturation is impaired —> macryoctic (non-megaloblastic) anemia with sideroblasts

Question 25

what is a Psuedo-Pelger-Huet abnormality?

Answer 25

bilobed nucleus of PMN

can be seen in peripheral smear of myelodysplastic syndrome

can be genetic (AD) mutation in lamin B gene (non-pseudo and benign), but if seen needs to be investigated

Question 26

myelodysplastic syndrome can present with increased number of blast cells, putting patients at risk for progression to…

Answer 26

acute myeloid leukemia (AML)