Overview
Primary myelofibrosis is a clonal disorder of hematopoietic stem cells [ 1, 2, 3, 4 ]. Along with chronic granulocytic leukemia (CML), true erythrocytosis, and primary thrombocytosis, it is a myeloproliferative neoplasm [ 5 ].
The disease is characterized by anemia, bone marrow fibrous tissue hyperplasia, and extramedullary hematopoiesis. Teardrop-like red blood cells are seen in peripheral blood and hepatosplenomegaly is present.
Portal hypertension can occur in about 7% of patients. The etiology may be due to increased portal blood flow due to significant enlargement of the spleen and intrahepatic infarction due to thrombotic occlusion of fine portal veins. Variceal bleeding or ascites may occur accordingly. There can be thrombosis in the hepatic portal vein. Symptomatic portal hypertension can be managed by splenectomy with or without a portal shunt.
Splenic infarction may present with acute or subacute left upper abdominal pain that may radiate to the left shoulder and may be associated with nausea and fever. The symptoms are self-limiting and can last for several days. Treatment is mainly analgesic and symptomatic.
Extramedullary hematopoiesis can involve any organ. Symptoms depend on the organ or site of involvement. Gastrointestinal tract bleeding, spinal cord compression, seizures, hemoptysis and/or effusion may occur.
Patients with primary myelofibrosis can also develop infectious complications.
Patients may also develop osteophytes and hypertrophic osteoarthropathy. Periostitis may also develop, producing significant pain and discomfort. Non-steroidal anti-inflammatory drugs (NSAIDs) or opioid analgesics may be required for symptomatic treatment. Patients with high uric acid can produce gout or uric acid stones. Allopurinol needs to be given to effectively control uric acid levels.
Symptoms
One quarter of patients with primary myelofibrosis can be asymptomatic and are seen on physical examination for a large spleen or abnormal blood counts. Patient symptoms are generally associated with anemia, splenomegaly, hypermetabolic state, extramedullary hematopoiesis, bleeding, skeletal changes, portal hypertension, and associated immune abnormalities.
Anemia can be the result of ineffective hematopoiesis, red blood cell dysplasia, and hypersplenism. Anemia can lead to easy fatigue, weakness, dyspnea and palpitations.
Splenomegaly can lead to early satiety and left upper abdominal discomfort. Severe left upper abdominal or left shoulder pain can result from splenic infarction, perisplenitis, or subpericardial hematoma. Occasionally, patients may present with colonic pressure-related diarrhea.
A hypermetabolic state can cause weight loss, night sweats, and hypothermia. Gout and uric acid kidney stones can develop.
One quarter of all patients with primary myelofibrosis can present with bleeding symptoms. Severity varies, ranging from skin petechiae to life-threatening gastrointestinal bleeding. Platelet dysfunction, acquired factor V deficiency, thrombocytopenia, disseminated intravascular coagulation (DIC), esophageal varices, and peptic ulcers are all possible causes of bleeding.
Symptoms that may be caused by extramedullary hematopoiesis vary depending on the organ involved and include: gastrointestinal bleeding, spinal cord compression, seizures, hematuria, ascites, pericardial effusion, pleural effusion, hemoptysis, and respiratory failure.
Portal hypertension may significantly increase splenic portal venous blood flow and decrease hepatic vascular compliance. Ascites, esophagogastric fundic varices, gastrointestinal bleeding, and hepatic encephalopathy may occur. Hepatic portal vein thrombosis is also a complication that can occur.
Patients with primary myelofibrosis can also develop osteosclerosis, which can potentially cause severe joint and bone pain.
Half of the patients with primary myelofibrosis have humoral immune abnormalities. Many autoantibodies and circulating immune complexes can be detected, and amyloidosis has been reported. Due to immunodeficiency, the most common site of infection is the lung.
Physical signs
Splenomegaly is present in 90% of patients with primary myelofibrosis. The degree of spleen size varies. 35% of patients have a giant spleen.
Liver enlargement is present in 60-70% of patients with primary myelofibrosis, and pallor is seen in 60% of patients. Other positive findings may include petechiae and petechiae (20%), enlarged lymph nodes (10-20%), and manifestations of portal hypertension (10%).
Laboratory Tests
Complete blood count (CBC) and peripheral blood smear: teardrop-like red blood cells are seen in the peripheral blood. Sometimes large platelets and megakaryocyte fragments can be seen.
Patients with primary myelofibrosis may present with anemia, and >60% of patients may have a hemoglobin concentration less than 10 g/dl. Causes of anemia include hemodilution, ineffective red blood cell production, and hypersplenism with splenomegaly. Folic acid deficiency leading to anemia can occur due to increased consumption.
Leukopenia can be seen in one quarter of patients; leukocytosis can be seen in one third of patients. Primitive cells and Pelger-Huet cells can be seen in peripheral blood.
DIC is more common than thrombocytopenia and can occur in 15% of patients, often asymptomatic, but platelets and clotting factors may be reduced; fibrin degradation products may be increased. Therefore, preoperative DIC testing is necessary.
Imaging
Bone radiographs show heterogeneous increased bone density. unequal densities on x-ray.
Ultrasound or CT scan shows enlarged liver and spleen.
Bone marrow aspiration and biopsy
Performing a bone marrow aspiration and biopsy can help in the diagnosis of primary myelofibrosis.
Histological examination
Dry aspiration by bone marrow aspiration can be seen in 50% of patients. A bone marrow biopsy is necessary to confirm the diagnosis. Biopsy specimens show active bone marrow proliferation with an increase in megakaryocytes.
Also of diagnostic significance is reticulofibrillar hyperplasia. Reticulonodular protein is unevenly distributed. Megakaryocytes may be clumped or may be dysplastic. The bone marrow sinuses are dilated and there is often intravascular hematopoiesis.
Liver biopsy specimens usually show normal histology or minimal portal fibrosis. Portal vein thrombotic lesions can occur. Hepatic vein thrombosis can also occur.
Genetic and molecular tests
Chromosomal abnormalities may be present in 50-60% of patients. Chromosomal karyotype abnormalities suggest a poor prognosis. Bone marrow cytogenetics, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR) tests can help to exclude chronic granulocytic leukemia, myelodysplastic syndrome, or other chronic myeloid disorders. However, in patients with primary myelofibrosis, the bone marrow is often “dry” and it is difficult to obtain sufficient specimens for these tests.