Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers where the bone marrow makes too many blood cells. This overproduction can affect different types of cells and lead to various health issues. MPNs are diagnosed based on the results of a physical examination, blood tests, cytogenetic testing (a test that looks at chromosomes), and in some cases, a bone marrow biopsy. These test results help doctors pinpoint the specific type of MPN and identify risk factors. This information helps them choose the safest and most effective MPN treatment options.

Medical History and Physical Examination

A doctor will typically start the diagnostic process with a medical history and physical exam. During the medical history, they will ask about any symptoms, such as fatigue, fevers, or shortness of breath. The doctor may ask whether you have had cancer before and whether you’ve been exposed to radiation or chemicals such as benzene, which are known risk factors for MPNs.

During the physical exam, the doctor may check for signs such as an enlarged spleen or liver. MPNs can also cause the skin to look discolored, appearing reddish or purple. Your doctor may also check for hypertension (high blood pressure), blood clots, or signs of abnormal bleeding, such as bruising easily or frequent nosebleeds.

MPNs are sometimes discovered based on physical symptoms. However, people often do not have obvious symptoms in the early stages of MPNs. Instead, MPNs are often discovered by chance when routine blood tests return unusual or unexpected results.

When a primary care provider or internal medicine physician discovers abnormal blood test results, they often refer the person to a hematologist-oncologist, a specialist in blood disorders and cancer.

Diagnostic Testing

Diagnosing MPNs may require several tests and procedures to get a complete picture. Each test provides unique information that helps the doctor identify the condition and assess risk factors to recommend the best treatment.

Blood Tests

There are a few different types of blood tests a doctor might order when an MPN is suspected. The most common blood test a doctor will order is called a complete blood count (CBC) with differential. A CBC with differential assesses:

• The number of red blood cells (RBCs)
• The number of platelets
• The number and types of white blood cells (WBCs)
• The amount of hemoglobin (the protein that carries oxygen)
• The percentage of hematocrit (the proportion of RBCs in your blood)
• The sizes and distribution pattern of red cells and platelets.

The doctor may also order a peripheral blood smear, a lab test to examine a smear of your blood under a microscope. A peripheral smear can check for immature blood cells called blasts as well as abnormally shaped RBCs and platelet clumps.

Depending on the blood test results, doctors may order a follow-up bone marrow aspiration and biopsy to help diagnose an MPN.

Bone Marrow Aspiration and Biopsy

Bone marrow is the spongy tissue in the center of most bones where blood cells are formed. A bone marrow aspiration and a biopsy are needed for a definitive diagnosis for most MPNs. A definitive diagnosis means confirming the diagnosis with a final, accurate identification after all necessary tests. A bone marrow aspiration and biopsy are often performed at the same time. A bone marrow aspiration collects the liquid part of the bone marrow, which contains cells, while a bone marrow biopsy takes a small solid sample of the bone itself. Both samples are taken with needles.

These tests are usually taken from the back part of the pelvic bone, near the hip. The doctor will numb the area to reduce discomfort before performing the aspiration and biopsy. The samples will be analyzed in a laboratory. A hematopathologist, a specialist in diagnosing blood and bone marrow diseases, will perform genetic testing on cells found in the samples.

Cytogenetic Testing

Most MPNs are associated with specific genetic mutations (variants or changes) in cancer cells. A pathologist may also use samples of the blood and bone marrow to test for gene mutations. Cytogenetic testing is the study of chromosomes and chromosomal abnormalities. Two tests that may be used to identify genetic abnormalities to indicate if an MPN is present are called fluorescent in situ hybridization (FISH) and quantitative polymerase chain reaction (qPCR). In FISH, pathologists will use fluorescent molecules to highlight chromosomes and find abnormalities. The qPCR test is a very sensitive test that can identify small, hard-to-find genetic changes.

Diagnostic Criteria for MPNs

Diagnostic criteria — the signs, symptoms, and test results that lead doctors to diagnose MPNs — are based on World Health Organization (WHO) revisions to classifications of MPNs. These guidelines help doctors make the right diagnosis and choose the best treatment for each type of MPN.

Polycythemia Vera

In polycythemia vera (PV), blood work results will show high values for the red cell count, hemoglobin level, and hematocrit levels. In addition, PV leads to a high WBC count or platelet count. In fact, about 50 percent of people with PV have a high platelet count. Examining the blood content may show a decreased level of erythropoietin, which is a hormone that stimulates the production of RBCs. Mutations in the JAK2 gene are also found in almost all people with PV.

Essential Thrombocythemia

A raised platelet count is common in essential thrombocythemia (ET). One-third of people with ET have slightly elevated RBC or WBC counts. When examining the bone marrow biopsy, the pathologist will see an unusually high number of cells, especially large megakaryocytes, which are the cells that produce platelets. In addition, the peripheral blood smear may show enlarged platelets or platelets clumped together.

Doctors must first rule out other conditions before diagnosing ET. They may consider reactive thrombocythemia, which can also cause an increase in platelets. Other conditions that can lead to reactive thrombocythemia include active arthritis, gastrointestinal inflammatory disease, iron-deficiency anemia, other types of cancer, or having undergone splenectomy (removal of the spleen).

Before diagnosis, hematologists will want to rule out chronic myeloid leukemia (CML), PV, primary myelofibrosis (MF or PMF), or myelodysplastic syndromes (MDS).

Genetic testing of cancer cells helps with diagnosing ET. Roughly 60 percent of ET cases involve a JAK2 gene mutation, and about 33 percent involve an MPL mutation. The CALR mutation may also be present.

Primary Myelofibrosis

In MF, RBCs are shaped differently than normal. Rather than having a round, concave shape, RBCs in people with MF are shaped like teardrops. In the early stages of MF, people may have higher-than-normal counts of WBCs and platelets. In later stages, however, both WBCs and platelets tend to be lower. A bone marrow biopsy will show too many or abnormal megakaryocyte cells.

MF may be diagnosed if a person has unexplained anemia, an enlarged spleen, or a high white blood cell count, along with other signs and symptoms.

Before an MF diagnosis, a doctor will exclude MF caused by an infection, an autoimmune or other chronic inflammatory condition, or another cancer such as CML, which is also associated with fibrosis. Hematologists will want to rule out CML, PV, ET, or MDS.

In 50 percent to 60 percent of people with MF, cancer cells test positive for a JAK2 gene mutation. The CALR mutation is found in about 3 percent to 24 percent of people with certain blood conditions, while the MPL gene variant appears in 5 percent to 33 percent. Other genetic mutations can also play a role in developing MF.

PV or ET can sometimes progress to MF. In those cases, called post-polycythemia vera myelofibrosis (post-PV MF) or post-essential thrombocythemia myelofibrosis (post-ET MF), the diagnosis criteria are different.

Chronic Myeloid Leukemia

People with CML (also known as chronic myelogenous leukemia) will often have a very high WBC count and a low RBC count. In addition, the blood may show abnormal levels of immature blood cells (blasts), early-stage WBCs (called myeloid precursors), and increased eosinophils and basophils, which are types of WBCs.

In 95 percent of CML, cancer cells have a genetic abnormality called the Philadelphia chromosome (Ph+). Named for the city in which doctors discovered it, this genetic abnormality affects chromosome 22, which swaps sections with part of chromosome 9. This translocated gene (gene change) is known as BCR-ABL1. Pathologists use FISH and qPCR to help diagnose CML. These tests can identify the BCR-ABL1 gene even when cytogenetic testing doesn’t pick up the Philadelphia chromosome.

Chronic Neutrophilic Leukemia

Chronic neutrophilic leukemia (CNL) happens when there are too many neutrophils, a type of white blood cell, in the body. The excess of neutrophils in the blood is known as neutrophilia. To have a definitive diagnosis of CNL, doctors need to first eliminate other potential causes of neutrophilia. Other possible causes of neutrophilia include severe bacterial infections, inflammatory diseases such as rheumatoid arthritis, or metastatic cancers (cancer that spreads).

In most people with CNL, cancer cells will have a genetic mutation known as colony-stimulating factor 3 receptor (CSF3R). This gene controls the growth and function of certain WBCs. Typically, doctors will diagnose CNL if a person has neutrophilia and a CSF3R mutation.

Chronic Eosinophilic Leukemia

In chronic eosinophilic leukemia (CEL), the bone marrow produces too many eosinophils, a type of WBC that reacts to allergens and fights some types of parasites. In people with CEL, there are often too many immature WBCs, called myeloblasts, found in the blood.

Before a CEL diagnosis, a hematologist will want to rule out other causes of excess eosinophils, such as parasitic infections, autoimmune or connective tissue diseases, allergic reactions to medications, or immune deficiencies.

Additionally, CEL will only be diagnosed after other MPNs have been ruled out. No specific genetic mutations have been identified with CEL. In CEL, certain genetic changes are expected, but doctors need to rule out the BCR-ABL1 mutation, which is linked to CML, to make an accurate diagnosis.

Triple-Negative MPNs

In more than 95 percent of MPN cases, one of three genetic mutations is present: JAK2, CALR, or MPL. However, a small number of cases are triple-negative, meaning they are negative for mutations in these three genes — although other genetic mutations may be found. About 12 percent of ET cases and 5 percent of MF cases are triple-negative. Research indicates that people with triple-negative MPNs may have less severe symptoms and their disease will progress slowly.

Talk With Others Who Understand

Find others to connect with on myMPNteam, the online social network for people and their loved ones living with myeloproliferative neoplasms. On myMPNteam, more than 4,700 members come together to ask questions, give advice, and share their stories with others who understand life with MPNs.

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