A 64-year-old woman comes to the physician for her routine health maintenance examination. She feels well. She had cervical cancer and received radiotherapy 8 years ago. Her vital signs are within normal limits. On percussion, the spleen size is 15 cm. Otherwise, the physical examination shows no abnormalities. The laboratory test results are as follows: Hemoglobin 10 g/dL Mean corpuscular volume 88 μm3 Leukocyte count 65,000/mm3 Platelet count 500,000/mm3 Two images of the peripheral blood smear are shown on the image. Which of the following is the most appropriate next step in management?

Allogeneic stem cell transplantation

A 70-year-old man presents to his physician for evaluation of fullness and swelling of the left side of the abdomen over the last month. During this time, he has had night sweats and lost 2 kg (4.4 lb) unintentionally. He has no history of severe illness and takes no medications. The vital signs include: blood pressure 115/75 mm Hg, pulse 75/min, and temperature 36.8℃ (98.2℉). The abdomen has asymmetric distention. Percussion and palpation of the left upper quadrant reveal splenomegaly. No lymphadenopathy is detected. Heart and lung examination shows no abnormalities. The laboratory studies show the following: Hemoglobin 9.5 g/dL Mean corpuscular volume 95 μm3 Leukocyte count 8,000/mm3 Platelet count 240,000/mm3 Ultrasound shows a spleen size of 15 cm, mild hepatomegaly, and mild ascites. The peripheral blood smear shows teardrop-shaped and nucleated red blood cells (RBCs) and immature myeloid cells. Marrow is very difficult to aspirate but reveals hyperplasia of all 3 lineages. The tartrate-resistant acid phosphatase (TRAP) test is negative. The cytogenetic analysis is negative for translocation between chromosomes 9 and 22. Which of the following laboratory findings is most likely to be present in this patient?

Hair-like cell-membrane projections

A 6-year-old boy is brought to the emergency department due to a severe infection. Laboratory work shows leukocytosis of 60 × 109/L with marked left shift, but no blast cells. The patient is febrile and dehydrated. The physician believes that this is a severe reaction to the infection and orders a leukocyte alkaline phosphatase (LAP) stain on a peripheral smear. The LAP score is elevated. Which of the following statements best describes an additional characteristic of the condition this child is suffering from?

A blood count will contain band forms, metamyelocytes, and myelocytes.

Chemotherapy is the treatment of choice.

Myeloblasts and promyelocytes are expected to be found.

This condition can lead to chronic myelocytic leukemia.

The patient may develop anemia secondary to infection.

A 64-year-old woman comes to the physician because of a 7-month history of abdominal discomfort, fatigue, and a 6.8-kg (15-lb) weight loss. Physical examination shows generalized pallor and splenomegaly. Laboratory studies show anemia with pronounced leukocytosis and thrombocytosis. Cytogenetic analysis shows a BCR-ABL fusion gene. A drug with which of the following mechanisms of action is most appropriate for this patient?

Ribonucleotide reductase inhibitor

A 55-year-old male presents with complaints of intermittent facial flushing. He also reports feeling itchy after showering. On review of systems, the patient says he has been having new onset headaches recently. On physical exam, his vital signs, including O2 saturation, are normal. He has an abnormal abdominal mass palpable in the left upper quadrant. A complete blood count reveals: WBCs 6500/microliter; Hgb 18.2 g/dL; Platelets 385,000/microliter. Which of the following is most likely responsible for his presentation?

Elevated serum erythropoietin levels

Chronic leukemias for USMLE Step 3: High-Yield Pathology Lessons

Chronic Leukemias - The Slow Creep

General: Insidious onset, mature circulating cells, older adults.

Leukemia	Cell Type	Key Feature / Genetics	Buzzwords
CML	Neutrophils	t(9;22), BCR-ABL	Philadelphia Chromosome, low LAP
CLL	B-cells	CD5+, CD20+	Smudge cells, Richter transformation
Hairy Cell	B-cells	BRAF mutation	TRAP positive, "dry tap"
ATLL	T-cells	HTLV-1	Flower cells, lytic bone lesions

CLL / SLL - Smudge & Grudge

CLL (Chronic Lymphocytic Leukemia) & SLL (Small Lymphocytic Lymphoma) are the same B-cell neoplasm, differing in primary location (blood vs. lymph nodes). Most common adult leukemia in the West; typically affects elderly (>60 yrs).
Pathognomonic Finding: Peripheral smear shows significant lymphocytosis with fragile lymphocytes, creating characteristic smudge cells.
- 📌 Crushed Little Lymphocytes.
Diagnosis: Flow cytometry confirms clonality with co-expression of B-cell markers (CD19, CD20, CD23) and the T-cell marker CD5.
Complications:
- Hypogammaglobulinemia → recurrent infections (common cause of death).
- Richter transformation to aggressive large B-cell lymphoma.

⭐ A classic complication is the development of autoimmune hemolytic anemia (AIHA), often due to warm agglutinins.

CML - A Philly Story

CML peripheral blood smear with myeloid cells and basophilia

Pathogenesis: Driven by t(9;22), creating the BCR-ABL fusion gene with ↑ tyrosine kinase activity.
Presentation: Often asymptomatic. Can have fatigue, weight loss, and massive splenomegaly.
Labs: Marked leukocytosis (>100,000/mm³). See all stages of myeloid maturation. Basophilia is a key finding.
Phases:
- Chronic: <10% blasts.
- Accelerated: 10-19% blasts.
- Blast Crisis: ≥20% blasts; transforms to AML/ALL.
Treatment: Tyrosine Kinase Inhibitors (TKIs) like Imatinib.

⭐ CML is distinguished from a leukemoid reaction by a low Leukocyte Alkaline Phosphatase (LAP) score. A leukemoid reaction shows a high LAP score.

Hairy Cell Leukemia - TRAPped in Spleen

Chronic B-cell neoplasm, typically affecting older males (>50 years).
Clinical Picture: Insidious onset of pancytopenia (leading to infections, fatigue, bleeding) and massive splenomegaly from red pulp infiltration. Bone marrow aspiration often results in a "dry tap" due to extensive reticulin fibrosis.
Diagnosis:
- Peripheral Smear: Shows lymphocytes with fine, hair-like cytoplasmic projections.
- 📌 Stain: Cells are positive for Tartrate-Resistant Acid Phosphatase ($TRAP^+$).
- Immunophenotype: Expresses pan B-cell markers (CD19, CD20) plus characteristic CD11c, CD25, and CD103.

⭐ The BRAF V600E mutation is present in over 90% of cases, serving as a highly specific diagnostic marker.

Hairy cell leukemia dissemination and homing mechanisms

High‑Yield Points - ⚡ Biggest Takeaways

CLL, the most common adult leukemia, shows CD5+ B-cells and smudge cells; beware of Richter transformation.

CML is driven by the Philadelphia chromosome (t(9;22)), creating the BCR-ABL fusion gene targeted by tyrosine kinase inhibitors.

CML presents with marked leukocytosis and can progress to a blast crisis.

Hairy cell leukemia features TRAP-positive cells with cytoplasmic projections and BRAF mutations.

Chronic leukemias involve mature cells and have an insidious onset.

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