Facts

Myeloproliferative neoplasms (MPN) are a group of diseases that affect blood cell formation. In all forms of MPN, a bone marrow problem leads to increase levels of blood cells circulating in the blood. “Myelo” refers to bone marrow, which is the body’s blood-cell factory and “proliferative” refers to the increase growth and production of cells.   Thus, “myeloproliferative” mean an increase growth and production of bone marrow and blood cells.   “Neoplasm” means an abnormal growth of cells that can be malignant or benign.    In MPN, the neoplasm may start as a benign process but has the potential to progress to a more malignant disease. 

Types of Myeloproliferative Neoplasms

There are several types of chronic myeloproliferative neoplasms based on whether too many red blood cells, white blood cells, or platelets are being made. Blood tests, bone marrow biopsies, and genetic tests are used to diagnose myeloproliferative neoplasms.  
 
Classic

• Chronic myelogenous leukemia (CML) 
• Polycythemia vera  (PV)
• Primary myelofibrosis   (PMF)
• Essential thrombocythemia  (ET)

Non-classic

• Chronic neutrophilic leukemia 
• Chronic eosinophilic leukemia
• Mastocytosis 
• Myeloproliferative neoplasms, unclassifiable

Blood Cell Formation in MPN

In MPN, blood stem cells have acquired genetic defects that cause them to grow and survive abnormally.   This results in increase numbers of cells in the bone marrow (so called hypercellular marrow) and in the blood.

• A high level of red blood cells  is called polycythemia. 
• A high level of WBCs is called leukocytosis.  
• A high level of platelets is called thrombocytocytosis.

Sometimes in MPNs, the abnormal blood stem cells cause scarring in the marrow that is called myelofibrosis.  The abnormal MPN stem cells can also grow in the spleen and other sites outside the marrow causing splenomegaly (a large spleen) or enlargement of other organs.

Symptoms and Complications of classic MPN

At diagnosis, people with myeloproliferative neoplasms may have no symptoms, only elevated blood counts.  Others may present with generalized symptoms of fever, night sweats, and weight loss.  Each specific MPN may be associated with symptoms specific to their elevated blood counts.  For instance, in polycythemia vera the red blood cells are elevated and this may result in headaches, fatigue,itching, gastritis and pains in the hands and feet called erythromelalgia.  

MPN cell growth in the spleen my cause abdominal pain and fullness when eating. High platelet counts may cause headaches, stroke symptoms, chest pains or in some cases bleeding. A major complication of MPNs is blood clots in the arteries (causing heart attacks and strokes) or in the veins (causing deep vein thrombosis and pulmonary emboli). A severe type of clot involves the blood vessels leading to the liver and is call Budd Chiari syndrome. Blood clots can occur both early, even preceding the diagnosis, or late.  Other complications include scarring of the bone marrow called myelofibrosis and transformation into acute leukemia. The myelofibrosis can occur early and be the prominent finding in the disease in primary myelofibrosis. It can occurs after many years of disease in polycythemia vera and essential thrombocythemia. The risk for development of myelofibrosis and leukemia depends on the disease type, duration, and likely the treatment. 

Diagnosis 

To find out whether you have MPN, your doctor will first do a thorough physical exam and ask about your health history. Next the doctor will perform a series of blood tests to tell whether any blood cells are abnormal and, if so, which ones. Common blood tests include the following:

• Complete blood cell count (CBC): determines how many cells of each type are circulating in the blood stream
• Peripheral blood smear: looks at the appearance of the blood cells 
• Blood chemistry: looks for abnormalities in the blood, including certain enzymes, iron level, and other factors

For a definitive diagnosis, doctors generally will need to perform a bone marrow aspiration and biopsy. For this purpose a small area of skin over the lower back (pelvis) is cleaned and numbed. Then a marrow needle is used to withdraw bone marrow. If a biopsy is performed, the doctor uses a different needle to punch out a small piece of marrow from the bone (a marrow core). In either case, the sample will be examined under a microscope, to determine the presence and number of abnormal cells in the marrow and myelofibrosis.
 
Flow cytometry (a computer analysis of cells) studies may be of assistance to look at disease progression.
 
In addition, doctors will perform cytogenic analysis. This means the marrow cells will be set up in a culture dish to make them divide. This will then allow us to see the chromosomes under a microscope and to identify the presence of abnormal chromosomes. Doctors use the number and type of chromosome abnormalities to help predict how the disease will progress and which types of treatment might be most effective. Chromosomes contain our genes and can provide the instructions for how our cells function.

Molecular studies are very sensitive and specific tests for mutations associated with different myeloproliferative processes.  These tests may include polymerase chain reaction (PCR) that amplifies small amounts of DNA or RNA for the tests and sequencing (reading the genetic material).  In some cases, the tests are called quantitative because they not only tell that the disease is present but how much is there.

In myeloproliferative neoplasms, your doctors will use the above techniques to look for one or more of the following specific gene mutations:

(1) BCR-ABL: a genetic joining of two genes found almost exclusively in chronic myeloid leukemia and rare cases of acute lymphoid leukemia
(2) JAK2 V617F: a small mutation found in over 90% of polycythemia vera cases and approximately 50% of cases of essential thombocythemia and primary myelofibrosis
(3) MPL mutations:  these are mutations in a different protein that is found in some cases of essestial thrombocythemia
(4) C-KIT D816V:  a small mutation found in most cases of mastocytosis
(5) FIP1L1-PDGFR: a genetic joining of two genes found in some cases of hypereosinophilia and associated with response to treatment 

Prognosis & Staging

Compared to people with cancer, the prognosis is relatively good for the MPNs. People with ET in general have a normal life expectancy. Shortened life expectancies are observed in people with PV and PMF but may be more than 10 years from diagnosis for PV and shorter for PMF.  The degree of myelofibrosis, the percentage of blasts (abnormal blood stem cells) in the blood and bone marrow, and the findings of addition chromosome abnormalities may indicate worse prognosis.  The MPN can progress from early chronic phases, to accelerated phases followed by either burn out phases or blast crisis (disease resembling acute leukemia).

Risk Factors

It is currently not known what causes the cellular changes that lead to MPNs. Exposure to toxins, such as benzene, certain solvents or pesticides, and heavy metals, such as mercury or lead may be involved in the development of genetic changes in stem cells. It is extremely difficult, if not impossible, to establish a clear cause-and-effect relationship between those exposures and the development of MPN. MPNs are seen in all age groups but more common in middle age and older adults. PV is more common in males and ET and PMF are more common in females.  Very rarely, there can be clustering of cases in families where there is an inheritied genetic defect.