The Chronic Myeloproliferative Neoplasms pdf - د. علاء فاضل

Lecture 11 by Dr.Alaa Fadhil Alwan

The Chronic Myeloproliferative Neoplasms

Essential Thrombocythemia, Polycythemia Rubra Vera, and

Myelofibrosis

Nomenclature: we will include 1. Polycythemia Rubra Vera (PRV or PV); 2. Essential (Primary)
Thrombocythemia (ET); and 3. Myelofibrosis (MF - also known as Agnogenic Myeloid
Metaplasia [AMM], and Myelofibrosis with Myeloid Metaplasia [MMM]) within the category of the
Chronic Myeloproliferative Diseases.

Concepts: these conditions are all clonal disorders of the hemopoietic stem cell, which lead to
dysregulated production of blood cells, and fibrosis. The fibroblasts are not part of the clone. In
Polycythemia Rubra Vera, overproduction of red blood cells is the dominant feature, although
increased white cells and platelets are also often present. In Essential Thrombocythemia,
overproduction of platelets predominates. Myelofibrosis may be the end result of PV, or may
apparently occur de novo.

Genetics: virtually all cases of PV, and about half of ET and MF carry a gain-of-function
mutation in JAK-2 (V617F). This kinase is downstream of the cytokine receptors for
erythropoietin (EPO) and thrombopoietin (TPO). When constitutively activated by the mutation,
cytokine-independent signaling takes place leading to increases in red cell and platelet counts.
V617F-negative cases may have different mutations in the JAK-2 gene.

ESSENTIAL THROMBOCYTHEMIA (ET)

Regulation of platelet numbers in normal individuals: thrombopoietin (TPO) is produced
constitutively in the liver. It is bound by normal platelets, and the remainder stimulates
megakaryopoiesis. Thus, when the platelet count is low, there is more free TPO, and platelet
production is stimulated, and vice versa.

Pathology: In most cases, ET is a neoplastic (clonal) stem cell disorder, which leads to
excessive production of abnormal platelets. Some cases, especially in young women, may not
be clonal. The abnormal platelets can lead to microvascular occlusion, frank thrombosis, and
also to abnormal bleeding, especially after surgery.

Incidence: 'uncommon'. 1-2 per year . More in females than males. Peak incidence age 50-80.

Typical Blood Count:

WBC x 10

10.0

[4-11]

Hb g/L

156

[140-180]

MCV fl

[80-100]

Platelets x 10

1560

[150-450]

Neuts x 10

7.0

[2-7.5]

Lymphs x 10

2.0

[1.5-4]

Monos x 10

0.8

[0.2-0.8]

Eos x 10

0.1

[0-0.7]

Basos x 10

0.1

[0-0.1]

Film Comment:

many large and abnormal platelets present

Clinical Findings: often asymptomatic. Thrombotic manifestations are both arterial (transient
ischemic attacks (TIA), strokes, myocardial infarction, peripheral vascular occlusion), and
venous (deep vein thrombosis). Erythromelalgia is an unpleasant burning and tingling
sensation in the hands and feet, and the affected parts are usually red and swollen. It is caused
by microvascular occlusion. The spleen may be enlarged, but usually not. Bleeding is
uncommon, but surgery poses a particular hazard.

Diagnosis: can usually be made on the blood findings alone, and by excluding other causes of
thrombocytosis. A marrow may help in cases of doubt. In young patients especially, Chronic
Myeloid Leukemia must be excluded, as it can sometimes present as isolated thrombocythemia,
and the treatment is different. The JAK-2 mutation is present in about 50% of cases.

Differential Diagnosis: reactive thrombocytosis (infection, bleeding, inflammation, connective
tissue diseases, cancer), other myeloproliferative diseases, CML.

Treatment: asymptomatic young patients do not need any therapy. Occlusive symptoms
respond well to aspirin in low dose. Control of the platelet count with hydroxyurea helps to
prevent thrombosis, but leukemia is an important potential adverse effect of this drug, even
though the incidence is low.

Clinical Course: with appropriate treatment, life expectancy is almost normal. The incidence of
leukemia is probably greater than in normals, and may be increased by hydroxyurea.

POLYCYTHEMIA RUBRA VERA

Pathology: A neoplastic (clonal) stem cell disorder, which leads to excessive production of all
myeloid cell lines, but predominantly red cells. The increase in whole blood viscosity causes
vascular occlusion and ischemia, compounded by the increase in platelets. 90% of cases have
a mutation in the JAK-2 gene, which causes activation of the pathway downstream of the
erythropoietin receptor.

Incidence: peaks at 60-80 y: slightly commoner in males. 2/100,000 per year.

Typical Blood Count:

WBC x 10

18.0

[4-11]

Hb g/L

200

[140-180]

HCt

0.62

[.42-.51]

MCV fl

[80-100]

Platelets x 10

850

[150-450]

Neuts x 10

14.6

[2-7.5]

Lymphs x 10

2.0

[1.5-4]

Monos x 10

0.8

[0.2-0.8]

Eos x 10

0.1

[0-0.7]

Basos x 10

0.5

[0-0.1]

Film Comment:

microcytosis: large and abnormal platelets present

Clinical Findings: headaches, itch, vascular occlusion, thrombosis, TIA, strokes.
Splenomegaly is common.

Diagnosis:

a. exclude secondary causes of true polycythemia (smoking, COPD, left to right shunts,

hypoxia, tumours or cysts which secrete erythropoietin)

b. look for features which suggest primary polycythemia (splenomegaly, increased basophil

count, increased WBC and platelets)

c. measure erythropoietin level
d. look for the JAK-2 mutation

Differential Diagnosis:
a. secondary polycythemia (see above)
b. spurious polycythemia – this is a condition in which the plasma volume is spontaneously

reduced, (aka Gaisbock’s syndrome or stress polycythemia). A firm diagnosis requires a
measurement of the ‘red cell mass’

Treatment:
a. phlebotomy to control the hematocrit (less than 0.45)
b. low-dose aspirin – 81 mg/day
c. hydroxyurea if necessary
d. do not treat with iron

Clinical Course: with appropriate treatment, life expectancy is good (median 13 years). The
incidence of leukemia (1.5%) is greater than in normals, and may be exacerbated by
hydroxyurea. Some (25%) patients develop myelofibrosis.

MYELOFIBROSIS

Pathology: A neoplastic (clonal) hemopoietic stem cell disorder, which leads to marrow fibrosis
and bone marrow failure. Myeloid metaplasia (extra-medullary hemopoiesis) occurs, especially
in the liver and spleen.

Incidence: approximately 0.5/100,000 per year

Typical Blood Count:

WBC x 10

2.4

[4-11]

Hb g/L

[140-180]

MCV fl

[80-100]

Platelets x 10

[150-450]

Neuts x 10

1.0

[2-7.5]

Lymphs x 10

1.0

[1.5-4]

Monos x 10

0.2

[0.2-0.8]

Eos x 10

0.1

[0-0.7]

Basos x 10

0.1

[0-0.1]

Film Comment:

a few nucleated red cells and myelocytes (leukoerythroblastic). Tear
drop poikilocytes

Clinical Findings: symptoms of marrow failure. Discomfort from splenomegaly. Spleen is
usually enlarged and may be huge

Diagnosis: can often be suspected from the blood count, and the clinical findings. A marrow
aspirate is usually impossible ('dry tap') but a trephine biopsy will show the fibrosis.

Differential Diagnosis: secondary fibrosis e.g. in breast cancer, and other malignancies.

Treatment: supportive care, including blood transfusions. Splenectomy if necessary for pain, or
thrombocytopenia.

Clinical Course: median survival 5 years.