Myeloid Neoplasms I

Question 1

What are the basis of dividing some of the hematologic neoplasms?

Answer 1

They can be divided into myeloid and lymphoid neoplasms, they can be further divided by the types of genetic mutations and chromosomal abnormalities and their respective concequences.

Question 2

What is the difference between leukemia and lymphoma?

Question 3

What are myeloproliferative disorders?

Answer 3

Neoplasms of hematopoietic stem cells with proliferation of one or two myeloid lineages.
* CML
* Polycythemia vera
* Primary myelofibrosis
* Essential thrombocytopenia
* Mastocytosis
Hallmark of these diseases is constitutively activated tyrosine kinase.

Question 4

Epidemiology, key findings and treatment of CML

Answer 4

• Occurs across the age spectrum with peak incidence 45–85 years, median age at diagnosis 64 years. (disease of older individuals)
  Philadelphia chromosome (t[9;22], BCR-ABL)
  ​ABL on chromosome 9 goes next to BCR on chromosome 22
• Chromosome 22 looks extra short Marked granulocytosis including all stages of maturation
• May accelerate and transform to AML or ALL (“blast crisis”). Responds to bcr-abl tyrosine kinase inhibitors (eg, imatinib).

Question 5

What are the symptoms of CML?

Answer 5

Initially assymptomatic for many years as its a slowly progressing disease, may present with non specific symptoms such as fatigue, fever, malaise, weight loss.Patients often develop massive splenomegaly (early satiety and LUQ discomfort). There can also be thrombosis and bleeding disorders.

Question 6

What are the pathological findings of CML?

Answer 6

On blood smear we can see granulocytes of all stages of maturity Leukocytosis, defined to be above 20,000/microL.
Basophilia
* Bone marrow is markedly hypercellular Massive splenomegaly due to expanded red pulp that carries out extramedullary hematopoiesis.

Question 7

How do we make a definitive diagnosis of CML?

Answer 7

Looking for the Philedelphia chromosome.

Question 8

What are the different stages of CML?What is the treatment for CML?

Answer 8

• Chronic phase, lasts from 2 to 8 years Accelerated phase:
• Blasts 10-19%
• Increased basophils
• Persistent thrombocytopenia or thrombocytosis
• Increasing splenomegaly and WBC Karyotypic evolution Blast crisis –survival <1 y
• Blasts ≥20%
• Can progress to ALL of AML kind of illness
  Only bone marrow transplantis curative, Imatinib is not a long termsolution since tumor cellsdevelop resistance by changing the ATP binding site of TK receptors.

Question 9

Explain Polycythemia Vera.

Answer 9

• Disorder of multipotent stem cell with predominant effects inerythroid lineage, leads to 1° polycythemia. Disorder of hematocrit.
• May present as intense itching after hot shower. Rare but classic symptom is erythromelalgia (severe, burning pain and red-blue coloration) due to episodic blood clots in vessels of the extremities
• Responds to aspirin.
• EPO levels are low (vs 2° polycythemia, which presents with endogenous or artifcially high EPO).

Question 10

Explain the genetics of polycythemia vera.What drug can be used to cure this?

Answer 10

Point mutation in pseudokinase domain of JAK2, as a result it is constitutively active as there is a loss of autoinhibition.
* This leads to increases phosphorylation of downstream targets including STAT5.
* NOT seen in CML or lymphoproliferative disorders.
Ruxolitinib can be used to inhibit JAK2, but it is not as widely used to due to higher incidence of toxic effects

Question 11

What are the clinical features of PV?

Answer 11

Increased RBC mass, it can cause	
* Plethora	
* Dizziness	
* Angina	
* Headache	
* Visual disturbances	
* Intermittent claudification
Splenomegaly and thrombosis or bleeding can also occur.Important to know that RBCs are normochromic and normocytic.

Question 12

What are the findings in the spleen and bone marrow in PV?

Answer 12

Decreased or absent iron in the bone marrow together with hypercellularity and an increase in red pulp with extramedullary hematopoiesis in spleen.

Question 13

Explain the course of polycythemia vera.

Answer 13

There is a proliferative phase during which the RBC count can get very high, this is followed by Spent consisting of a stable or decrease in RBC count.Finally the last phase is post polycythemia myelofibrosis, consisting of progressive anemia, splenomegaly, myelofibrosis.In 2% of the cases patients with PV can develop AML like disease.

Question 14

Explain the disease process of Primary Myelofibrosis.

Answer 14

• Obliteration of bone marrow with fibrosisdue to increase in fibroblast activity. Often associated with massive splenomegaly and “teardrop” RBCs.
• Neoplasm of multipotential hematopoietic stem cell with reactive fibrosis
• Pro-fibrotic growth factors (PDGF, TGF-β) from megakaryocytes Leukoerythroblastosis and extramedullary hematopoiesis
• Epidemiology Middle aged and older adults
• Excludes CML and PCV that progress to fibrosis

Question 15

What genes are associated with primary myelofibrosis?

Answer 15

Genetics
JAK2 mutation in up to 50% of cases
Calreticulin mutations in 35% of cases
MPL mutation in 1-5% of cases - this is a thrombopoietin receptor, thrombopoietin is a factor for megakaryocyte growth and development

Question 16

What are the symptoms of Primary myelofibrosis?What are the pathological findings of the disease?

Answer 16

• Non specific flu-like symptoms
• Hemorrhage
• Recurrent infections
• Hallmark of this disease is massive splenomegaly
  Leukoerythroblastocytosis and tear-drop RBCs are 2 important pathological findings.

Question 17

Explain what is obsered in bone marrow in primary myelofibrosis.

Answer 17

Reticulin, collagenous fibrosis and osteosclerosis

Question 18

Explain the disease process, epidemiology and genetics of Primary Thrombocytosis.

Answer 18

• Characterized by massive proliferation of megakaryocytes and platelets.
• Symptoms include bleeding and thrombosis.
• Blood smear shows markedly increased number of platelets, which may be large or otherwise abnormally formed B . Erythromelalgia may occur.
• Epidemiology - middle aged and older adults
• Genetics - JAK2, Calreticulin mutations and MPL mutation.

Question 19

Explain mastocytosis.

Answer 19

Increased and morphologically abnormal mast cells, these are associated with c-KIT mutation.It can be localized mastocytosis which is called Urticaria pigmentosaor it can be systemic