What are the differential diagnoses for pancytopenia in a 60-year-old man?

Differential Diagnoses for Pancytopenia in a 60-Year-Old Man

In a 60-year-old man with pancytopenia, the primary differentials to consider are myelodysplastic syndrome (MDS), aplastic anemia, megaloblastic anemia (vitamin B12/folate deficiency), medication/toxin-induced bone marrow suppression, autoimmune disorders, chronic infections (HIV, hepatitis B/C), paroxysmal nocturnal hemoglobinuria (PNH), acute leukemia, and other hematologic malignancies. 1, 2

Primary Hematologic Malignancies

Myelodysplastic syndrome is a critical consideration in this age group, as it commonly presents with cytopenias and typically shows hypercellular bone marrow with dysplasia. 1 The diagnosis requires blood and bone marrow examination showing cytopenias with dysplastic features in ≥10% of cells in one or more lineages. 1

• Acute leukemia represents the most common malignancy presenting with cytopenia, with 97% of cases showing this finding and over 90% of hematologic malignancies presenting with cytopenias overall. 2
• Lymphoproliferative disorders should be considered, particularly if lymphadenopathy, splenomegaly, or hepatomegaly are present, as these physical findings are significantly associated with malignancies (p<0.001). 2

Reversible Causes (Must Exclude First)

Megaloblastic anemia from vitamin B12 or folate deficiency is a critical reversible cause that can completely mimic serious hematologic conditions and must be excluded early. 3, 4

• Vitamin B12 deficiency can present with macrocytic anemia (MCV >100 fL), hypersegmented neutrophils, and elevated LDH with indirect hyperbilirubinemia due to ineffective erythropoiesis. 3
• Medication exposure is essential to assess, including antibiotics, anti-HCV drugs, chemotherapy agents, and alcohol consumption, as drug-induced bone marrow suppression is a common reversible cause. 2

Bone Marrow Failure Syndromes

Aplastic anemia is the second most common cause of pancytopenia (18.26% in clinical series) and presents with hypocellular bone marrow. 4

• Paroxysmal nocturnal hemoglobinuria (PNH) should be considered, especially in younger patients or those with hypoplastic bone marrow, as small PNH clones can accompany MDS or aplastic anemia. 1, 2
• Screen for HLA-DR15 in young patients with hypoplastic bone marrow, as they may respond to immunosuppressive therapy. 2

Infectious and Autoimmune Causes

Chronic infections must be excluded, including HIV, hepatitis B/C, and CMV (particularly if lymphopenia is present). 2

• Autoimmune disorders can cause pancytopenia through immune-mediated destruction or bone marrow suppression. 1
• H. pylori testing is necessary, particularly in new thrombocytopenia cases. 2

Critical Diagnostic Pitfalls to Avoid

Do not diagnose simple sideroblastic anemia if pancytopenia is present - this indicates MDS-unclassified (MDS-U) with worse prognosis and higher risk of progression to acute myeloid leukemia. 5

• The duration and tempo of cytopenias are crucial: stable cytopenias for at least 6 months suggest MDS, while rapid progression may indicate acute leukemia. 2
• Do not rely on flow cytometry blast percentage for prognostic assessment - morphologic evaluation by an experienced hematopathologist is essential. 2
• Over 58% of hematologic malignancy presentations involve bicytopenia and pancytopenia together, making bone marrow evaluation critical when peripheral smear shows dysplasia or cytopenias remain unexplained. 2

Algorithmic Approach to Diagnosis

Initial workup should include: CBC with differential, peripheral blood smear review by experienced hematopathologist, reticulocyte count and index (RI <1.0-2.0 suggests decreased production), vitamin B12 and folate levels, iron studies, LDH, and infectious screening (HIV, hepatitis B/C, CMV if lymphopenic). 2

Bone marrow aspiration AND biopsy should be performed simultaneously when abnormalities are detected on peripheral smear or when unexplained persistent pancytopenia remains after excluding reversible causes - they are complementary and both necessary for complete evaluation. 2

• Morphologic evaluation must assess dysplasia in all three lineages, with Prussian blue stain for ring sideroblasts (≥15% indicates sideroblastic features). 2
• Cytogenetics of bone marrow cells is essential, as specific abnormalities help confirm MDS diagnosis and provide prognostic information. 1
• In difficult cases with unspecific morphological changes and no cytogenetic changes, molecular analysis by next generation sequencing to demonstrate clonality is recommended. 1