How to diagnose and treat a patient with suspected anisocytosis or anisokaryosis?

Anisocytosis: Diagnosis and Management

Critical First Step: Identify the Underlying Cause

Anisocytosis (variation in red blood cell size) is not a diagnosis itself but a morphologic finding that requires systematic evaluation to identify the underlying hematologic disorder, with myelodysplastic syndromes (MDS) being a critical consideration when accompanied by other dysplastic features. 1

Diagnostic Approach

Initial Peripheral Blood Smear Evaluation

When anisocytosis is identified, examine the blood smear for additional dysplastic features that suggest MDS versus other causes:

Red Cell Features to Assess:

• Poikilocytosis (abnormal cell shapes), dimorphic erythrocytes, polychromasia, hypochromasia, megalocytes, basophilic stippling, nucleated erythroid precursors, tear drop cells, ovalocytes, and fragmentocytes 1
• The presence of multiple dysplastic features strongly suggests MDS rather than nutritional deficiencies 1

White Cell and Platelet Features:

• Pseudo-Pelger-Huët cells, abnormal chromatin clumping, hypo/degranulation in granulocytes 1
• Giant platelets and platelet anisometry (anisocytosis of platelets) 1

Laboratory Workup

Complete Blood Count with Differential:

• Assess for cytopenias: hemoglobin <11.0 g/dL, neutrophils <1500/mL, platelets <100,000/mL 1
• Evaluate mean corpuscular volume (MCV) and red blood cell distribution width (RDW) as quantitative measures of anisocytosis 2
• Check reticulocyte count to distinguish hemolytic processes from marrow dysfunction 1, 3

When to Proceed to Bone Marrow Examination:

Bone marrow aspiration and biopsy are mandatory when: 1, 4

• Cytopenias persist for ≥4 months without clear etiology
• Multiple dysplastic features are present on peripheral smear
• Unexplained cytopenias exist alongside anisocytosis

Bone marrow evaluation must include: 1

• Morphologic assessment of dysplasia in erythroid, granulocytic, and megakaryocytic lineages (≥10% dysplasia in any lineage is significant)
• Blast enumeration (<5% for MDS diagnosis)
• Iron staining with Prussian blue (Perls stain) to evaluate ring sideroblasts 1
• Bone marrow trephine biopsy to assess cellularity and fibrosis 1

Cytogenetic and Molecular Testing:

• Conventional cytogenetics (G-banding) detects clonal chromosomal abnormalities in >80% of MDS patients 1
• Molecular testing for MDS-related mutations (DNMT3A, ASXL1, TET2, JAK2, TP53) with variant allele frequency 2%-30% 1

Differential Diagnosis Algorithm

If Anisocytosis with Cytopenias and Dysplasia:

Consider MDS when: 1, 4

• Persistent cytopenias ≥4 months
• ≥10% dysplasia in one or more myeloid lineages
• Marrow blasts <5%
• Clonal cytogenetic abnormalities present

Distinguish from:

• Nutritional deficiencies (vitamin B12, folate, vitamin B6): Check serum levels; megaloblastic changes without clonal markers 5
• Chronic myeloid leukemia: Requires BCR-ABL testing; shows basophilia and immature granulocytes 4
• Myeloproliferative neoplasms: Different megakaryocyte morphology with giant forms and pleomorphism 4

If Anisocytosis with Reticulocytosis:

Consider hemolytic processes: 1, 3

• Autoimmune hemolytic anemia
• Microangiopathic hemolytic anemia (look for schistocytes) 3
• Hereditary hemolytic anemias (pyruvate kinase deficiency, membrane disorders)

If Teardrop Cells Present:

Evaluate for: 3

• Myelofibrosis (requires bone marrow biopsy with reticulin stain)
• MDS/myeloproliferative neoplasm overlap syndromes
• Extramedullary hematopoiesis

Management Based on Diagnosis

For MDS with Anisocytosis:

Risk stratification determines treatment: 1

Lower-risk MDS (IPSS low/intermediate-1):

• Erythropoietin ± G-CSF for anemia 1
• Lenalidomide for del(5q) patients 1
• Luspatercept for MDS with ring sideroblasts or SF3B1 mutation 1
• Supportive care with transfusions as needed 6

Higher-risk MDS (IPSS intermediate-2/high):

• Azacitidine as first-line disease-modifying therapy 1
• Allogeneic stem cell transplantation when feasible 1
• Clinical trial enrollment when appropriate 1

For Nutritional Deficiencies:

Vitamin B6 deficiency with anisocytosis: 5

• Vitamin B6 supplementation resolves anisocytosis
• Alcohol abstention if alcohol-related

Common Pitfalls to Avoid

• Do not rely solely on visual assessment of anisocytosis—RDW provides quantitative precision that should be the gold standard 2
• Do not diagnose MDS based on peripheral blood alone—bone marrow examination with cytogenetics is essential for definitive diagnosis 1, 4
• Do not delay bone marrow examination in patients with persistent unexplained cytopenias—early diagnosis impacts treatment decisions and prognosis 4
• Do not overlook concomitant myeloid neoplasms—bone marrow biopsy should be considered especially with unexplained cytopenias or monocytosis 1