From the Guidelines
The bone marrow findings of 10-20% cellularity with moderate fibrosis and negative genetic testing help rule out several hematologic disorders but leave others as possibilities. This pattern rules out most acute leukemias, myeloproliferative neoplasms with characteristic genetic markers (like BCR-ABL in CML, JAK2 in polycythemia vera), and myelodysplastic syndromes with cytogenetic abnormalities, as noted in the European LeukemiaNet guidelines 1. However, it does not rule out:
- Aplastic anemia
- Hypocellular myelodysplastic syndrome without genetic markers
- Paroxysmal nocturnal hemoglobinuria
- Some lymphomas with bone marrow involvement
- Non-hematologic causes of marrow suppression like medication effects, toxin exposure, or viral infections, as suggested by the diagnostic approach to suspected MDSs 1. The hypocellular marrow with fibrosis suggests an ongoing process affecting hematopoiesis, and further workup would be needed including:
- Flow cytometry for PNH
- Viral studies
- Medication review
- Possibly repeat bone marrow examination in 3-6 months to monitor for disease evolution, as recommended by the NCCN clinical practice guidelines in oncology: myelodysplastic syndromes 1. The absence of genetic markers is helpful diagnostically but doesn't exclude all malignant processes, as some hematologic disorders can present without detectable genetic abnormalities on standard testing panels, as noted in the proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis 1. Key considerations in the diagnostic workup include:
- Morphologic studies of peripheral blood and bone marrow to evaluate abnormalities of peripheral blood cells and hematopoietic precursors
- Bone marrow biopsy to assess marrow cellularity, fibrosis, and topography
- Cytogenetics to identify nonrandom chromosomal abnormalities, as emphasized in the diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet 1. Given the complexity of the diagnosis, a comprehensive approach is necessary to determine the underlying cause of the hypocellular bone marrow with fibrosis, and to guide further management and treatment.
From the Research
Conditions Ruled Out or Not Ruled Out
In a 25-year-old with hypocellular (low cell count) bone marrow (10-20% cellularity) and moderate fibrosis, with negative genetic testing results, several conditions can be considered:
- Acquired aplastic anemia (aAA) may not be ruled out, as hypocellular marrow failure can be a characteristic of this condition 2
- Hypocellular myelodysplastic syndrome (MDS) may also not be ruled out, as it can present with similar bone marrow features 2
- Inherited bone marrow failure syndromes, such as Fanconi anemia, dyskeratosis congenita, Diamond Blackfan anemia, and Shwachman Diamond syndrome, may be less likely given the negative genetic testing results, but comprehensive genetic testing is recommended to rule out these conditions 3, 2
- Myelofibrosis may be considered, as bone marrow fibrosis is a central pathological feature of this condition, but the presence of moderate fibrosis alone is not sufficient for a diagnosis 4, 5
Diagnostic Approach
A diagnostic approach incorporating comprehensive genetic testing, marrow array, and telomere length testing may be necessary to distinguish between acquired and inherited causes of hypocellular marrow failure 2
- Comprehensive genetic testing can help identify inherited bone marrow failure syndromes 2
- Marrow array can detect acquired 6p copy number-neutral loss of heterozygosity to support a diagnosis of aAA 2
- Telomere length testing can help diagnose short telomere syndromes, but its clinical utility is limited in patients with aAA and other inherited bone marrow failure syndromes 2
Prognostic Significance
The presence of megakaryocytes in bone marrow specimens has favorable prognostic significance, while lymphocytosis, plasmocytosis, and damaged marrow stroma are markers of bad prognosis 6