What Is Extramedullary Hematopoiesis?

Extramedullary hematopoiesis is the production of blood cells in organs outside the bone marrow. In healthy adults, nearly all blood cell manufacturing happens inside bone marrow, but when the marrow fails, becomes overcrowded, or cannot keep up with demand, the body can reactivate blood-cell production in the spleen, liver, and other organs as a backup system. The process is entirely normal during fetal development, yet when it reappears later in life it usually signals a serious underlying blood disorder, and the growing masses of blood-forming tissue can themselves cause problems.

Why Blood Is Normally Made in Bone Marrow

Bone marrow provides a specialized environment that supports the self-renewal and differentiation of hematopoietic stem cells, the precursors from which every type of blood cell originates. The marrow’s spongy interior is rich in the molecular signals, blood vessel networks, and support cells that stem cells need to divide, mature into red blood cells, white blood cells, and platelets, and then enter the bloodstream. Under normal conditions in adults, this system is efficient enough to produce hundreds of billions of new blood cells every day without assistance from any other organ.

How It Works During Fetal Development

Before a fetus has functional bone marrow, it still needs blood cells. The earliest blood formation starts in the yolk sac during the first weeks of embryonic life, then shifts to the fetal liver and spleen as those organs develop.¹ The fetal liver is the dominant blood-making organ during mid-pregnancy: in animal models, stem cell numbers in the fetal liver expand roughly 38-fold during a window that corresponds to the second trimester in humans.² As the skeleton matures and marrow cavities form, blood production gradually migrates into the bones. By the time a baby is born, bone marrow has taken over as the primary factory, and the liver and spleen largely retire from that role.

This developmental sequence matters because it helps explain why certain organs are the first to “switch back on” when adult bone marrow fails. The spleen and liver still retain traces of the microenvironment that once supported blood-cell production during fetal life, which may be why pathological extramedullary hematopoiesis tends to show up in those organs first.³

What Causes It to Reappear in Adults

When extramedullary hematopoiesis occurs after birth, it is almost always a compensatory response. The bone marrow is either not producing enough blood cells, producing defective ones, or has been physically replaced by abnormal tissue. The body detects the shortfall and activates stem cells in alternative locations to fill the gap. The triggers fall into a few broad categories.

Myeloproliferative Neoplasms and Myelofibrosis

Myeloproliferative neoplasms, a group of blood cancers in which the marrow overproduces certain cell types, are among the most common conditions associated with extramedullary hematopoiesis.⁴ Primary myelofibrosis is the classic example. In this disease, the marrow is progressively replaced by scar-like connective tissue fibers, essentially evicting stem cells from their normal home.¹ Those displaced stem cells migrate to the spleen, liver, and elsewhere, setting up shop and producing blood cells in organs that were never designed to handle that volume of cell production long-term. The spleen often bears the brunt. Spleens from patients with primary myelofibrosis contain increased numbers of stem cells and megakaryocytes, the giant cells responsible for producing platelets.⁵

Chronic Anemias and Hemoglobin Disorders

Thalassemia and sickle cell disease are inherited conditions in which the body produces abnormal hemoglobin, the oxygen-carrying protein in red blood cells. The result is chronic anemia: red cells break down prematurely or are produced defectively. In response, the body ramps up blood production wherever it can.⁶ In thalassemia patients, extramedullary hematopoiesis can expand aggressively enough to form tumor-like masses in the chest, along the spine, or in other locations.⁷ Various other chronic blood conditions, including other hemolytic anemias, lymphoma, and leukemia, can also drive the process.⁸

Infections, Tumors, and Other Stress

The marrow does not have to be permanently damaged for extramedullary hematopoiesis to kick in. During active immune responses to infections, the spleen and liver can ramp up production of immune cells like phagocytes and antigen-presenting cells, which is actually a normal and helpful version of the process.¹ Advanced cancers and severe metabolic stress can also trigger it.³ In these situations, the body perceives a need for more blood cells than the marrow alone can supply, even if the marrow itself is structurally intact.

Where It Shows Up in the Body

The spleen and liver are by far the most common sites, which makes sense given their history as fetal blood factories. Lymph nodes are another frequent location. But extramedullary hematopoiesis has been reported in a remarkably wide range of organs, including the lungs, kidneys, adrenal glands, skin, gastrointestinal tract, breast, brain, and epidural space around the spinal cord.⁹ The paravertebral region, the area alongside the spine, is a particularly well-recognized site. On imaging, paravertebral extramedullary hematopoiesis often appears as lobulated masses that can be mistaken for tumors.

Splenic Problems

In myeloproliferative neoplasms, sustained blood-cell production in the spleen causes it to enlarge progressively, a condition called splenomegaly. This is one of the hallmarks of advanced disease.¹⁰ A massively enlarged spleen is not just an incidental finding. It can cause abdominal pain, early satiety from pressure on the stomach, and further worsening of blood counts because the swollen spleen traps and destroys blood cells faster than the body can replace them.

Liver Complications

When blood-cell production takes root in the liver, it can obstruct blood flow through the organ’s tiny vessels. In patients with myelofibrosis, this has been linked to portal hypertension, a dangerous rise in pressure in the veins that carry blood from the gut to the liver. Portal hypertension can lead to variceal bleeding, where swollen veins in the esophagus or stomach rupture.¹¹ This is one of the more life-threatening complications and a reason clinicians monitor liver involvement closely.

Spinal Cord Compression

Perhaps the most dramatic complication occurs when masses of blood-forming tissue grow in the epidural space along the spine. As these masses expand, they can compress the spinal cord, potentially causing weakness, numbness, difficulty walking, or even paralysis depending on which part of the spine is affected.¹² This occurs in various blood disorders, including myeloproliferative diseases, thalassemia, and other chronic anemias.¹³ While rare, spinal cord compression from extramedullary hematopoiesis is a medical emergency that requires prompt treatment to preserve neurological function.

How It Is Diagnosed

Detecting extramedullary hematopoiesis depends heavily on imaging and, in many cases, tissue biopsy. The process is not always straightforward, because blood-forming tissue growing in an unexpected location can look a lot like cancer on a scan.

In the chest, extramedullary hematopoiesis typically presents as paravertebral masses that often contain fat, which gives radiologists a useful clue. The presence of fat within a mass next to the spine, in a patient with a known blood disorder, strongly suggests the diagnosis. But in the abdomen, the picture is murkier. The most common finding is simply an enlarged liver or spleen, which is nonspecific and could indicate many other conditions. When distinct soft-tissue masses form in the liver, spleen, kidneys, or peritoneum, they frequently lack the fat content that makes thoracic cases recognizable, and their imaging features can overlap with lymphoma, metastatic cancer, or sarcoma.¹⁴ In those cases, biopsy is often necessary to tell the difference.

On MRI, extramedullary hematopoiesis tends to show higher signal intensity than surrounding normal tissue, with variable contrast enhancement and sometimes lipid components. These features are atypical enough that the masses can easily be misdiagnosed as tumors.¹⁵ Sclerosing variants, where the blood-forming tissue becomes fibrotic, are particularly tricky and can be mistaken for sarcoma, carcinoma, or Hodgkin lymphoma if the pathologist does not have the patient’s clinical history in hand.¹⁶

What Pathologists See Under the Microscope

When tissue is biopsied, the hallmark of extramedullary hematopoiesis is the presence of all three blood cell lineages developing outside the marrow. Pathologists look for clusters of developing red blood cells, identifiable by their dense round nuclei surrounded by a ring of clear or pink cytoplasm; megakaryocytes, large cells with multilobed nuclei and abundant granular cytoplasm; and myeloid cells, which often include eosinophils and their precursors.¹⁷ Seeing all three lineages together in tissue outside the bone marrow is essentially diagnostic. In some cases, fine-needle aspiration can confirm the diagnosis without major surgery, and specialized testing can even determine whether the blood-forming cells are part of a malignant clone.¹⁸

Treatment Approaches

Because extramedullary hematopoiesis is a consequence of an underlying condition rather than a standalone disease, treatment focuses first on managing the root cause. But when the blood-forming masses themselves create problems, they need direct intervention. The approach depends on the location, size, and severity of symptoms.

Transfusion and Medication

For patients with chronic anemias like thalassemia, regular blood transfusions (sometimes called hypertransfusion) can suppress the body’s drive to produce blood cells outside the marrow. By providing enough healthy red cells from an external source, the feedback loop that pushes stem cells into the spleen and other organs is quieted. This has been recommended as a first-line approach, especially for spinal cord compression caused by paravertebral masses.¹⁹

Hydroxyurea, a medication that stimulates the production of fetal hemoglobin, is another option, particularly for thalassemia patients. By improving the effectiveness of the patient’s own red blood cell production, hydroxyurea reduces the stimulus for extramedullary expansion. Case reports have shown that hydroxyurea can shrink paravertebral masses without the need for radiation, surgery, or regular transfusions.²⁰ It works by boosting a form of hemoglobin that the body normally stops producing after infancy, effectively making existing red cells more functional and reducing the marrow’s need for backup production sites.²¹

Radiation and Surgery

Low-dose radiation therapy is effective at shrinking extramedullary masses, especially in the paraspinal area. Blood-forming tissue is radiosensitive, so relatively modest doses can reduce mass size and relieve compression. Surgery, including laminectomy to decompress the spinal cord, is reserved for emergencies or cases where other treatments have failed. A systematic review of spinal cord compression caused by extramedullary hematopoiesis found that the majority of patients received multimodal treatment combining some mix of surgery, radiation, transfusion, hydroxyurea, and steroids. Treatment started early, within a month of symptom onset, correlated with better outcomes, and surgery with or without additional therapy was linked to fewer poor results.²²

The Diagnostic Trap of Looking Like Cancer

One of the most practically important things to understand about extramedullary hematopoiesis is how often it gets confused with cancer. This is not just an academic concern. A patient with myelofibrosis who develops a mass in the kidney or liver may undergo an unnecessary invasive procedure because the mass is assumed to be a malignant tumor. The imaging characteristics overlap heavily with lymphoma, metastatic disease, and sarcoma, particularly in abdominal locations where the typical fat-containing clues seen in chest masses are often absent.¹⁴

The lesson here is context. When a radiologist or pathologist knows the patient has a chronic blood disorder, the threshold for suspecting extramedullary hematopoiesis drops considerably. Without that history, a biopsy showing unusual cells in the kidney or mediastinum might be read as a malignancy. This is why clear communication between hematologists, radiologists, and pathologists is critical in these patients. A mass that would demand aggressive cancer treatment in a healthy person may be a benign (if problematic) expansion of blood-forming tissue in someone with known myelofibrosis or thalassemia.

The Blueberry Muffin Baby

One of the more striking presentations of extramedullary hematopoiesis occurs in newborns. Some babies are born with scattered blue-purple skin nodules that give them an appearance doctors have long nicknamed “blueberry muffin baby.” These nodules are nests of blood-forming cells in the skin, representing dermal extramedullary hematopoiesis. The condition can result from congenital infections, such as cytomegalovirus, which stress the developing blood system to the point where the marrow cannot keep up and blood-cell production spills into the skin.²³ While the appearance can be alarming, the skin lesions themselves often resolve once the underlying infection is treated and the marrow recovers. The main concern is identifying and addressing whatever triggered the extramedullary response in the first place, since the list of possible causes includes not just infections but also blood-type incompatibilities, inherited blood disorders, and, more rarely, congenital cancers.

Pediatricians who recognize the pattern can avoid unnecessary skin biopsies or cancer workups by connecting the dots between the skin findings and the infant’s clinical picture. Like its adult counterpart, neonatal extramedullary hematopoiesis is not a disease in itself but a signal that something is pushing the blood system beyond the marrow’s capacity.

When the Body’s Backup System Becomes the Problem

There is an inherent tension in extramedullary hematopoiesis that makes it medically challenging. The process starts as a rescue mechanism. When the marrow fails, the body’s ability to start making blood cells elsewhere is what keeps oxygen delivery and immune function going. In that sense, it is adaptive and even life-saving in the short term. But the organs conscripted for this work were not built to handle sustained blood-cell production. The spleen balloons. The liver’s blood flow gets disrupted. Masses of hematopoietic tissue grow into spaces they do not belong, like the spinal canal, and start compressing vital structures.

In myeloproliferative neoplasms, the situation is further complicated by the fact that the cells produced outside the marrow can themselves be malignant. The same genetic mutations that drove the marrow disease are carried by the stem cells that migrate to the spleen and liver, meaning extramedullary production is not just compensatory but can actively perpetuate the disease.¹⁰ This is a fundamentally different situation from the benign extramedullary hematopoiesis seen in, say, a thalassemia patient whose displaced stem cells are genetically normal and just trying to compensate for defective hemoglobin. Distinguishing between these two scenarios matters for treatment decisions, because aggressive therapy aimed at eliminating malignant extramedullary tissue has a different risk-benefit profile than supportive measures designed to reduce benign compensatory expansion.