Myelofibrosis (MF) is a rare chronic blood cancer belonging to a group of conditions called myeloproliferative neoplasms (MPNs). The disease is characterized by the accumulation of scar tissue (fibrosis) within the bone marrow, the soft tissue responsible for creating blood cells. This scarring disrupts the normal production of red blood cells, white blood cells, and platelets, leading to complications. Because its symptoms are often non-specific, diagnosing myelofibrosis requires integrating clinical findings with specialized laboratory, tissue, and genetic tests.
Initial Signs and Clinical History
Diagnosis often begins when patients report vague, non-specific symptoms to a healthcare provider. Common complaints include severe fatigue, unexplained weight loss, profuse night sweats, and shortness of breath due to anemia. These constitutional symptoms are caused by the disease’s hypermetabolic state and the disruption of healthy blood cell production.
The physical examination plays a role in establishing suspicion for myelofibrosis. A healthcare provider checks for organ enlargement, a common finding. Splenomegaly (enlarged spleen) is present in approximately 90% of patients and can cause a feeling of fullness or pain beneath the left ribs. Hepatomegaly (enlarged liver) is also observed in over half of the cases. This enlargement occurs because the body attempts to compensate for the failing bone marrow by producing blood cells in other organs, a process called extramedullary hematopoiesis.
Peripheral Blood Examination
If myelofibrosis is suspected, the next step is a complete blood count (CBC) and a careful examination of the peripheral blood smear. The CBC typically reveals anemia, a low red blood cell count, which is the primary cause of fatigue and pallor. White blood cell and platelet counts can be highly variable, sometimes being high in the early stages, but often becoming low as the bone marrow scarring progresses.
The peripheral blood smear provides unique visual clues characteristic of myelofibrosis. A hallmark finding is the presence of teardrop-shaped red blood cells, known as dacrocytes, which are thought to be squeezed into this shape as they exit the scarred bone marrow. The smear also frequently shows leukoerythroblastosis—the premature release of immature white blood cells and nucleated red blood cells into the circulating blood. These features indicate that normal blood cell production has been significantly compromised.
Definitive Diagnosis: Bone Marrow and Genetic Testing
The definitive diagnosis of myelofibrosis relies on a bone marrow biopsy (BMB) and specialized molecular genetic testing. The BMB is an essential procedure where a small core of bone and marrow is extracted, usually from the hip bone. This tissue sample allows a pathologist to visually assess the degree of fibrosis and the abnormal proliferation of megakaryocytes, the large cells that produce platelets.
The degree of scarring is formally assessed using a standardized scoring system, such as the one recommended by the World Health Organization (WHO), which grades reticulin and collagen fibrosis from 0 to 3. A BMB is crucial for distinguishing overt myelofibrosis, which has significant scarring, from prefibrotic myelofibrosis or other similar blood disorders. The clustering and atypical appearance of megakaryocytes are also a major diagnostic criterion for the disease.
Molecular testing for specific genetic mutations is performed on blood or bone marrow samples to confirm the diagnosis. About 90% of myelofibrosis cases are associated with an acquired mutation in one of three primary driver genes: JAK2, CALR (calreticulin), or MPL. The JAK2 V617F mutation is the most common, found in approximately 50% to 60% of patients with primary myelofibrosis.
If the JAK2 mutation is absent, testing proceeds to look for mutations in the CALR gene (found in about 20% to 40% of cases) or the MPL gene. These driver mutations lead to uncontrolled cell growth and proliferation, which ultimately causes the bone marrow scarring. Cases lacking all three mutations are termed “triple-negative,” and their diagnosis relies heavily on the integration of clinical symptoms and the bone marrow biopsy findings.