An internal medicine physician evaluates a 71-year-old man who is referred due to progress… — USMLE Step 3

An internal medicine physician evaluates a 71-year-old man who is referred due to progressively worsening fatigue and dyspnea on exertion over the past 4 months. Complete blood count reveals a hemoglobin of $8.2 \text{ g/dL}$ , mean corpuscular volume of $106 \text{ fL}$ , leukocyte count of $3,100/\text{mm}^3$ , and platelet count of $92,000/\text{mm}^3$ . Vitamin B12 and folate levels are within normal limits. A bone marrow aspiration and trephine biopsy are performed. The synoptic histopathology report describes a hypercellular marrow for age ( $85\%$ cellularity) with marked erythroid predominance. Silver staining is negative for reticulin fibrosis. Iron staining reveals that $25\%$ of the nucleated red blood cell precursors have iron granules encircling the nucleus. Dysplastic features are prominent in the megakaryocytic lineage, including several small, mononuclear megakaryocytes. The blast count is estimated at $3\%$ . Based on the integrated clinical and biopsy findings, which of the following is the most definitive diagnosis?

Myelodysplastic syndromeAnswer
B
Megaloblastic anemia
C
Aplastic anemia
D
Acute myeloid leukemia
E
Primary myelofibrosis

Answer

Myelodysplastic syndrome

The correct diagnosis is myelodysplastic syndrome (MDS). The clinical presentation of pancytopenia and macrocytic anemia, in the setting of normal vitamin B12 and folate, strongly points toward a primary bone marrow disorder. The definitive diagnosis relies on the bone marrow biopsy interpretation. The biopsy reveals a hypercellular marrow, which rules out aplastic anemia. The presence of ring sideroblasts (erythroid precursors with iron-engorged mitochondria surrounding the nucleus) and dysplastic, mononuclear megakaryocytes are pathognomonic morphologic features of ineffective hematopoiesis in MDS. Furthermore, the blast count is 3%, which distinguishes it from acute myeloid leukemia (requires

\geq 20\%

blasts).

Step-by-Step Solution

Analyze the patient's peripheral blood findings.

The patient has pancytopenia (anemia, leukopenia, thrombocytopenia) with a macrocytic anemia (MCV 106 fL), despite normal vitamin B12 and folate levels.

Identifying the baseline hematologic derangements is the first step in formulating a differential diagnosis for bone marrow failure syndromes.

Evaluate the bone marrow cellularity and fibrosis.

The marrow is hypercellular for age (85%) and silver staining is negative for reticulin fibrosis.

This rules out causes of pancytopenia associated with hypocellular marrow (such as aplastic anemia) or fibrotic marrow (such as primary myelofibrosis).

Interpret the specific histopathologic features and special stains.

Iron staining shows 25% ring sideroblasts, dysplastic mononuclear megakaryocytes are present, and blasts are low (3%).

The presence of ring sideroblasts and specific morphological dysplasia, without meeting the threshold for acute leukemia, confirms a myelodysplastic syndrome.

Key Concept

Diagnosis of myelodysplastic syndrome relies on correlating peripheral cytopenias with a bone marrow biopsy showing hypercellularity, distinct morphologic dysplasia (e.g., ring sideroblasts, mononuclear megakaryocytes), and a blast count below the threshold for acute leukemia.

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