What is Extramedullary Hematopoiesis?
Extramedullary hematopoiesis (EMH) is the production and differentiation of blood cells outside the bone marrow, occurring in organs such as the spleen, liver, and lymph nodes. 1, 2
Physiologic vs. Pathologic EMH
EMH occurs in two distinct contexts that must be differentiated:
Normal Physiologic EMH
- During fetal development, EMH is the primary mechanism of blood cell production before bone marrow maturation, occurring sequentially in the yolk sac, fetal liver, and spleen 2
- During active immune responses to pathogens, EMH occurs physiologically in the spleen and liver to produce antigen-presenting cells and phagocytes 2
Pathologic EMH
- Pathologic EMH represents a compensatory mechanism triggered when bone marrow hematopoiesis becomes ineffective or insufficient 1
- This occurs in response to hematopoietic disorders, chronic anemia, bone marrow dysfunction, infection, advanced tumors, and metabolic stress 1
Common Sites of Pathologic EMH
The anatomic distribution reflects reactivation of embryonic hematopoietic structures:
- Most common sites: Spleen and liver 1, 2
- Less common sites: Lymph nodes 3, paravertebral areas 3, kidneys 4, and rarely serous effusions (pleural fluid) 5
- In myeloid sarcoma: Skin (leukemia cutis), orbits (chloroma, particularly with t(8;21)), soft tissue, kidneys, and testes 6
Underlying Conditions Associated with Pathologic EMH
Pathologic EMH develops in specific clinical scenarios:
- Myeloproliferative disorders: Primary myelofibrosis (where marrow is replaced by collagenous fibers) 2, polycythemia vera 4
- Chronic hemolytic anemias: Thalassemia and other conditions causing ineffective erythropoiesis 1
- Bone marrow infiltration or failure: When marrow becomes inhabitable for stem and progenitor cells 2
- Advanced malignancies: Late-stage tumors can induce EMH, contributing to tumor immunosuppression 1
Diagnostic Features
Cytologic Characteristics
When EMH is sampled by fine-needle aspiration, the key diagnostic features include 3:
- Trilineage hematopoiesis: Presence of all three blood cell lineages (erythroid, myeloid, megakaryocytic)
- Megakaryocytes (0-6% of cells): Critical diagnostic element 5, 3
- Myeloid precursors (myelocytes, metamyelocytes): Typically 18-33% 3
- Erythroid precursors: 0-7% 3
- Mature elements: Polymorphs (10-36%), lymphocytes (21-60%) 3
Diagnostic Pitfalls
- EMH can be misdiagnosed as lymphoma, particularly non-Hodgkin lymphoma, especially when occurring in lymph nodes or as mass lesions 6, 4
- Recognition of megakaryocytes and hematopoietic precursors is essential to avoid unnecessary surgical interventions 4
- Fine-needle aspiration cytology provides rapid, accurate diagnosis when interpreted correctly 3
Clinical Significance: A Double-Edged Sword
EMH has both beneficial and detrimental effects 1:
Beneficial Effects
- Compensates for inadequate bone marrow function by supplementing blood and immune cell production 1
Detrimental Effects
- Clinical complications from mass effect: Organomegaly, organ dysfunction, pleural effusions, ascites 6
- Tumor-induced EMH contributes to immunosuppression in advanced malignancies 1
- In plasma cell disorders: Disruption of adhesion molecules (decreased CD56, altered VLA-4 expression) facilitates extramedullary spread and disease dissemination 6
Special Considerations in Specific Diseases
Myeloid Sarcoma (Extramedullary AML)
- Represents a distinct manifestation where myeloid tumor masses occur at extramedullary sites 6
- Requires systemic AML-directed chemotherapy, not just local treatment 6
- Distinguished from frank AML by <20% bone marrow blasts 6
Down Syndrome-Associated Leukemia
- Leukemic blasts in transient leukemia and myeloid leukemia of Down syndrome originate from fetal liver hematopoiesis 6