Myeloproliferative neoplasms

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 increased levels of blood cells circulating in the bloodstream.

“Myelo” refers to bone marrow, which is the body’s blood-cell factory.

“Proliferative” refers to the rapid growth and production of cells.

“Myeloproliferative” means increased growth and production of bone marrow and blood cells.

“Neoplasm” means an abnormal growth of cells. A neoplasm can be either benign (noncancerous) or malignant (cancerous). In MPN, the neoplasm starts out benign; over time it may turn into malignant disease.

To understand more about MPN, it’s important to understand some basics about how blood cells normally form.

Healthy blood-cell formation

In a healthy person, the stem cells in the bone marrow make daughter cells. The daughter cells go through several stages of development within the marrow. Eventually they mature into red blood cells (RBCs), white blood cells (WBCs), or platelets. These get released from the marrow to circulate in the bloodstream.

The circulating cells perform important functions.

  • RBCs carry oxygen throughout the body.
  • WBCs fight infection.
  • Platelets protect against easy bleeding by helping your blood to clot.
Blood-cell formation in MPN

In a person with MPN, stem cells in the bone marrow develop genetic defects (called acquired defects) that cause them to grow and survive abnormally. This results in unusually high numbers of blood cells in the bone marrow (hypercellular marrow) and in the bloodstream.

  • A high level of RBCs is called polycythemia.
  • A high level of WBCs is called leukocytosis.
  • A high level of platelets is called thrombocytosis.

High levels of blood cells cause some of the symptoms of MPN.

Sometimes in MPN, the abnormal stem cells cause scarring in the marrow, called myelofibrosis. Myelofibrosis may lead to low levels of blood cells, especially low levels of red blood cells (anemia).

In MPN, the abnormal stem cells can also grow in the spleen, causing the spleen to enlarge (splenomegaly), and in other sites outside the marrow, causing enlargement of other organs.

Types of MPN

There are several types of chronic MPN, based on the cells affected. The information about diagnosis and treatment in this section is mainly about the three classic types of MPN.

  1. Polycythemia vera (PV), in which there are too many RBCs
  2. Essential thrombocythemia (ET), in which there are too many platelets
  3. Primary myelofibrosis (PMF), in which fibers and blasts (abnormal stem cells) build up in the bone marrow
Other types of MPN
  • Chronic myeloid leukemia, in which there are too many WBCs
  • Chronic neutrophilic leukemia, in which there are too many white blood cells called neutrophils
  • Chronic eosinophilic leukemia, not otherwise specified, in which there are too many white blood cells called eosinophils (hypereosinophilia)
  • Mastocytosis, also called mast cell disease, in which there are too many mast cells, which are a type of immune system cell found in tissues, like skin and digestive organs, rather than in the bloodstream
  • Myeloproliferative neoplasms, unclassifiable—meaning your MPN does not fit into one of the other types
  • Myeloid and lymphoid neoplasms with eosinophilia and abnormalities of the PDGFRA, PDGFRB, and FGFR1 genes

Some problems with blood-cell formation are not only myeloproliferative (having to do with overproduction of cells in the marrow) or only myelodysplastic (having to do with abnormal production of cells in the marrow). Instead, these problems have features of both MPN and myelodysplastic syndrome (MDS). They are described in the section about MDS subtypes.

Prognosis

The prognosis for people with myeloproliferative neoplasms (MPN) is relatively good, in general, with the appropriate treatment.

People with essential thrombocythemia typically have a normal lifespan. People with polycythemia vera (PV) or primary myelofibrosis (PMF) may have a shorter-than-normal life, living maybe more than 10 years from diagnosis with PV and possibly less time with PMF.

Many factors can affect the outlook for an individual, including their degree of myelofibrosis, the percentage of blasts (abnormal blood stem cells) in their blood and bone marrow, and any chromosome abnormalities they may have.

MPN can change over time, progressing from early chronic phases to accelerated phases. This can be followed either by burn-out phases (when the bone marrow is “burned out” and doesn’t make enough healthy blood cells) or by a blast crisis (when the disease resembles acute leukemia and there is an increase in the number of abnormal stem cells in your bone marrow or blood; this is a reason your doctor might recommend chemotherapy).

Symptoms

Some people with myeloproliferative neoplasms (MPN) have no symptoms when their disease is diagnosed. But a routine blood test may show high levels of red blood cells, white blood cells, or platelets. Other people with MPN may have general symptoms, such as fever, night sweats, and weight loss. Each type of MPN may cause specific symptoms related to high blood counts.

Polycythemia vera (PV) symptoms

Symptoms of PV, in which there are too many RBCs, may include the following:

  • A feeling of pressure or fullness below the ribs on the left side
  • Headaches
  • Double vision or seeing dark or blind spots that come and go
  • Itching all over the body, especially after being in warm or hot water
  • Reddened face that looks like a blush or sunburn
  • Weakness
  • Dizziness
  • Weight loss for no known reason
Essential thrombocythemia (ET) symptoms

Symptoms of ET, in which there are too many platelets, may include the following:

  • Headaches
  • Stroke symptoms
  • Chest pains
  • In some cases, bleeding
Primary myelofibrosis (PMF) symptoms

Symptoms of PMF, in which fibers and blasts (abnormal stem cells) build up in the bone marrow, may include the following:

  • Weakness and fatigue from severe anemia
  • Abdominal pain and fullness from enlarged spleen and liver
Complications

A major complication of MPN is blood clots in the arteries, causing heart attacks and strokes, or in the veins, causing deep vein thrombosis and pulmonary emboli (clots that block the arteries that go from the heart to the lungs). Budd Chiari syndrome is a severe type of clot that involves the blood vessels leading to the liver. Blood clots can occur early, even before the diagnosis, and late in the disease.

Other complications may include the following:

  • Scarring of the bone marrow, called myelofibrosis. In PMF, this scarring can occur early on and be the main finding in the disease. In PV and ET, scarring can occur after many years of disease.
  • The transformation of MPN into acute leukemia.

Diagnosis

To find out whether you have MPN, your doctor will first do a thorough physical exam and ask about your health history and any symptoms.

Next your 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 count (CBC): determines how many cells of each type are circulating in the bloodstream
  • Peripheral blood smear: looks at the appearance of the blood cells
  • Blood chemistry: looks for abnormalities in the blood, including certain enzymes or abnormal iron level
Bone marrow aspiration and biopsy

For a definitive diagnosis, doctors generally need to perform a bone marrow aspiration and biopsy. A small area of skin over your 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 remove a small piece of marrow from your 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 your marrow and whether you have myelofibrosis.

Cytogenetic analysis

In addition, doctors will perform cytogenetic analysis. This means your marrow cells will be set up in a culture dish to make them divide. This will allow us to see your chromosomes under a microscope and tell whether any are abnormal. Doctors use the number and type of chromosome abnormalities to help predict how your disease will progress and which types of treatment might be most effective. Your chromosomes contain your genes and can provide instructions for how your cells function.

Fluorescent in situ hybridization (FISH) is a specialized cytogenetic analysis. The fluorescent dyes used in this test attach to specific parts of certain chromosomes. More chromosomal abnormalities can be seen under a microscope using this technique than with the standard technique described above.

Molecular studies are very sensitive, specific tests for gene mutations associated with different myeloproliferative processes. Your doctors will use these tests to look for one or more of the following mutations:

  • BCR-ABL: a genetic joining of two genes found almost exclusively in chronic myeloid leukemia and rare cases of acute lymphoid leukemia
  • JAK2 V617F: a small mutation found in more than 90 percent of cases of PV and approximately 50 percent of cases of ET and PMF
  • MPL mutations: mutations in a protein that is found in some cases of ET
  • C-KIT D816V: a small mutation found in most cases of mastocytosis
  • FIP1L1-PDGFR: a genetic joining of two genes found in some cases of hypereosinophilia and associated with how the disease responds to treatment
Other tests

You may have flow cytometry (a computer analysis of cells) to tell how your disease is progressing.

Risk factors

Doctors don’t know what causes the cellular changes that lead to MPN. 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.

MPN is seen in all age groups but is more common in middle age and older adults. PV is more common in men, and ET and PMF are more common in females. Very rarely, there can be clustering of cases in families that have an inherited genetic defect.