Macrocytic Pancytopenia: Marrow Blast Discordance and Clonal Mutations
A 72-year-old man has Hb 9.1 g/dL, MCV 104 fL, WBC 2.8 ×10^9/L, ANC 0.9 ×10^9/L, and platelets 88 ×10^9/L. B12, folate, TSH, and creatinine are normal; LDH is 210 U/L. A 1.1 cm trephine biopsy is 25% cellular with erythroid hyperplasia and megaloblastoid change; the aspirate is hemodilute. Morphologic blasts are 2%; flow cytometry reports 4.2% CD34+ cells with CD117, CD13, and CD33 co-expression. Karyotype is 46,XY; FISH for -5/5q-, -7/7q-, +8, and 20q- is normal. NGS shows DNMT3A R882H at 34% variant allele frequency, SRSF2 P95H at 38%, and ASXL1 G646Wfs*12 at 27%. No ring sideroblasts are seen. The hematologist asks whether this is MDS or CHIP and whether to repeat the marrow.
1. Does this marrow meet criteria for a myelodysplastic neoplasm? Address the 2% versus 4.2% blast discordance and the NGS findings.
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The case is suspicious for MDS but cannot be settled by the blast count alone. The patient has sustained cytopenias, macrocytosis, erythroid hyperplasia with megaloblastoid change, and a clonal myeloid panel. The morphologic blast count of 2% is below the 5% threshold, while flow reports 4.2% CD34+ cells; flow can be falsely elevated by hemodilution, regenerating progenitors, or gating differences, but aberrant CD117/CD13/CD33 co-expression supports a neoplastic population. I would perform CD34 immunohistochemistry on the trephine and a careful 500-cell differential, because the diagnosis hinges on the integrated blast count and dysplasia, not on one assay.
The mutations support clonality but are not specific: DNMT3A, SRSF2, and ASXL1 occur in CHIP and in MDS. However, CHIP is defined by clonal hematopoiesis without cytopenia or dysplasia; this patient has both cytopenias and dysplastic erythroid change, so CHIP is not the best label. If the integrated blast count remains below 5%, the diagnosis is MDS with <5% blasts, provided the dysplasia is unequivocal and not explained by B12/folate deficiency, medication, or another marrow disorder.
2. How would you report this case and what additional testing or follow-up would you recommend?
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I would issue an integrated report stating 'myelodysplastic neoplasm with <5% blasts' if CD34 immunohistochemistry and morphology support the flow findings, with a comment that the aspirate was hemodilute and that the blast estimate is based on the trephine and flow. If the CD34 count is clearly below 5% and dysplasia is definite, the diagnosis can still be made; a repeat marrow is not mandatory solely because of the aspirate quality. If the trephine is also inadequate or the dysplasia is equivocal, I would recommend a repeat aspirate and biopsy rather than diagnose CHIP in a cytopenic patient.
Additional testing should include iron stain if not already done, though ring sideroblasts are absent, and correlation with medications, alcohol, and thyroid disease. I would recommend hematology follow-up with CBC monitoring and discussion of prognosis. The report should avoid the term 'CHIP' because CHIP lacks cytopenia and dysplasia; 'CCUS' is also inappropriate when dysplasia is present.
3. A second marrow six months later shows 6% blasts by 500-cell differential and persistent multilineage dysplasia. How does the classification and management discussion change?
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A blast count of 6% moves the case into the category of MDS with increased blasts, 5-9% (MDS-IB1 in WHO 2022; the ICC uses a similar blast-defined category). The key is that the count must be reproducible on a good-quality aspirate and supported by CD34 immunohistochemistry, because a single hemodilute sample can misclassify. Persistent multilineage dysplasia and the same clonal mutations support progression of the same neoplasm rather than a new process.
Management discussion should shift toward disease-modifying therapy and transplant eligibility. The patient's age, comorbidity, cytogenetic risk, transfusion needs, and blast trajectory matter. I would recommend repeat cytogenetics/FISH at progression and a hematology-oncology consultation. The report should explicitly compare the two marrow examinations and state the new blast category, because the clinical team will use it to decide whether to start hypomethylating therapy or pursue transplantation.