A 40-year-old man comes to the physician because of fatigue, increased sweating, and itching in his legs for the past 2 years. He has chronic bronchitis. He has smoked two packs of cigarettes daily for 24 years and drinks one to two beers every night. His only medication is a tiotropium bromide inhaler. His vital signs are within normal limits. He is 175 cm (5 ft 9 in) tall and weighs 116 kg (256 lb); BMI is 38 kg/m2. Physical examination shows facial flushing and bluish discoloration of the lips. Scattered expiratory wheezing and rhonchi are heard throughout both lung fields. Abdominal examination shows no abnormalities. Laboratory studies show: Erythrocyte count 6.9 million/mm3 Hemoglobin 20 g/dL Mean corpuscular volume 91 μm3 Leukocyte count 13,000/mm3 Platelet count 540,000/mm3 Serum Ferritin 8 ng/mL Iron 48 μg/dL Iron binding capacity 402 μg/dL (N: 251 - 406 μg/dL) Which of the following is the most appropriate next step in treatment?

Allogeneic stem cell transplantation

A 47-year-old woman presents for a routine wellness checkup. She complains of general fatigue and lethargy for the past 6 months. She does not have a significant past medical history and is currently not taking any medications. The patient reports that she drinks “socially” approx. 6 nights a week. She says she also enjoys a “nightcap,” which is 1–2 glasses of wine before bed every night. She denies any history of drug use or smoking. The patient is afebrile, and her vital signs are within normal limits. A physical examination reveals pallor of the mucous membranes. Her laboratory findings are significant for a mean corpuscular volume of 72 fL, leukocyte count of 5,300/mL, hemoglobin of 11.0 g/dL, and platelet count of 420,000/mL. Which of the following is the most likely cause of this patient’s thrombocytosis?

Chronic myelogenous leukemia (CML)

A 55-year-old man comes to the physician for a routine health visit. He feels well except for occasional left-sided abdominal discomfort and left shoulder pain. He has smoked 1 pack of cigarettes daily for 20 years. He does not drink alcohol. His pulse is 85/min and his blood pressure is 130/70 mmHg. Examination shows a soft, nontender abdomen. The spleen is palpated 5 cm below the costal margin. There is no lymphadenopathy present. The remainder of the examination shows no abnormalities. Laboratory studies show: Hemoglobin 12.2 g/dL Hematocrit 36 % Leukocyte count 34,000/mm3 Platelet count 450,000/mm3 Cytogenetic testing of his blood cells is pending. Further evaluation of this patient is most likely to show which of the following findings?

Low leukocyte alkaline phosphatase score

Elevated serum β2 microglobulin

A 73-year-old man is brought to the emergency department because of fever and a productive cough for 2 days. He has had increasing fatigue and dyspnea for the past 2 weeks. During this time he has lost 3 kg (6.6 lb). He received chemotherapy for myelodysplastic syndrome (MDS) 1 year ago. He is currently on supportive treatment and regular blood transfusions. He does not smoke or drink alcohol. The vital signs include: temperature 38.5℃ (101.3℉), pulse 93/min, respiratory rate 18/min, and blood pressure 110/65 mm Hg. He has petechiae distally on the lower extremities and several purpura on the trunk and extremities. Several enlarged lymph nodes are detected in the axillary and cervical regions on both sides. On auscultation of the lungs, crackles are heard in the left lower lobe area. Physical examination of the heart and abdomen shows no abnormalities. The laboratory studies show the following: Hemoglobin 9 g/dL Mean corpuscular volume 95 μm3 Leukocyte count 18,000/mm3 Platelet count 40,000/mm3 Prothrombin time 11 sec (INR = 1) Based on these findings, this patient is most likely to have developed which of the following?

Non-cardiogenic pulmonary edema

Disseminated intravascular coagulation

A 56-year-old man presents to his general practitioner with frequent episodes of facial flushing for the past 2 weeks. He says the episodes are associated with mild headaches and a sensation of fullness in his head and neck. Additionally, he has developed recurrent, often severe, itching after taking a hot shower. The patient denies any smoking history but says he drinks alcohol socially. His blood pressure is 160/90 mm Hg, and his temperature is 37.0°C (98.6°F). On physical examination, his face and neck appear red. Cardiac examination reveals a regular rate and rhythm. Lungs are clear to auscultation bilaterally. The spleen is noted to be palpable just below the costal margin. A complete blood count shows a hemoglobin level of 19.5 g/dL, a total leukocyte count of 12,000/mm3, and a platelet count of 450,000/mm3. Which of the following sets of abnormalities is most likely present in this patient?

↑ Blood viscosity, ↓ blood flow, ↓ erythropoietin

↑ Blood viscosity, ↓ blood flow with an M-spike of immunoglobulin G

↑ Blood viscosity, ↓ blood flow with blast cells

↑ Blood viscosity, ↓ blood flow with an M-spike of immunoglobulin M

↓ Blood viscosity, ↑ blood flow, ↓ erythropoietin, ↑ ferritin

A 13-year-old girl is brought to the pediatrician due to a 4-month history of heavy vaginal bleeding during menstrual periods. She endorses episodes of bleeding gums after brushing her teeth and experienced prolonged bleeding after tonsillectomy 6 years ago. Her mother states that she bled significantly during childbirth and that the girl’s older brother has similar symptoms including easy bruising. Vitals were stable and physical exam was not revealing. Laboratory studies show: Platelet count: 72,000/mm^3 Bleeding time: 14 min Prothrombin time: 12 secs (INR = 1) Partial thromboplastin time: 40 secs Blood smear demonstrates increased megakaryocytes and enlarged platelets. Platelets do not aggregate to ristocetin. Which of the following is the most likely diagnosis?

Idiopathic thrombocytopenic purpura (ITP)

Myeloproliferative neoplasms for USMLE Step 2 CK: High-Yield Pathology Lessons

MPNs - Proliferation Party!

Clonal proliferation of mature myeloid cells, leading to ↑ peripheral blood counts.
Driven by activating mutations in tyrosine kinases.
- CML: Defined by BCR-ABL1 fusion gene from the Philadelphia chromosome t(9;22).
- PV, ET, PMF: Mostly associated with JAK2 V617F mutation; also CALR or MPL.

Peripheral blood smear in myeloproliferative neoplasm

⭐ All MPNs risk transformation to acute myeloid leukemia (AML) or a spent phase of myelofibrosis.

CML - The Philly Special

Pathogenesis: Defined by the Philadelphia (Ph) chromosome, a t(9;22) translocation.
- Creates the BCR-ABL1 fusion gene, a constitutively active tyrosine kinase.
- Drives massive proliferation of mature granulocytes (neutrophils, basophils, eosinophils).
Presentation:
- Often asymptomatic with incidental leukocytosis.
- Symptomatic: massive splenomegaly, fatigue, weight loss.
Labs:
- WBC > 100,000/μL.
- ↑ Basophils (pathognomonic).
- ↓ Leukocyte Alkaline Phosphatase (LAP) score.
Treatment: Tyrosine Kinase Inhibitors (e.g., Imatinib).

Karyotype with Philadelphia Chromosome t(9;22) translocation)

⭐ CML is distinguished from a benign leukemoid reaction by the presence of the Ph chromosome, ↑ basophils, and a very low LAP score. It can progress to a blast crisis (> 20% blasts), resembling acute leukemia.

Polycythemia Vera - Seeing Red

Pathophysiology: Neoplastic proliferation of mature myeloid cells, especially RBCs. Driven by JAK2 V617F mutation (>95%), leading to growth factor-independent proliferation.
Clinical Features:
- Symptoms: Intense pruritus (especially post-shower), headache, erythromelalgia (burning pain).
- Signs: Plethora (ruddy face), splenomegaly, thrombosis/bleeding.
Lab Findings: ↑ RBC mass/Hct, ↑ Platelets, ↑ WBCs. The key differentiating feature is ↓ serum EPO.
Treatment: Phlebotomy (target Hct <45%), low-dose aspirin; add hydroxyurea for high-risk patients.

⭐ The combination of generalized pruritus after a hot shower and a decreased serum EPO level is highly specific for Polycythemia Vera.

📌 Mnemonic: Plethora, Visual/Vascular, JAK2 (P.V. JAK).

Polycythemia Vera peripheral blood smear

ET & PMF - Platelets & Pipes

Essential Thrombocythemia (ET): ↑ Platelets
- Sustained thrombocytosis (> 450,000/μL) from megakaryocyte proliferation.
- Mutations: JAK2 (~50%), CALR, MPL.
- Clinical: Can cause thrombosis (e.g., stroke) or, paradoxically, bleeding.
- Presents with erythromelalgia (burning pain/redness in hands/feet).
Primary Myelofibrosis (PMF): Clogged Pipes
- Megakaryocytes release fibrogenic factors (PDGF, TGF-β) → marrow fibrosis.
- Leads to severe "B" symptoms & massive splenomegaly (extramedullary hematopoiesis).
- Smear: Leukoerythroblastosis & dacrocytes (teardrop cells).
- 📌 Mnemonic: Fibrosis "Tears" up the RBCs.

⭐ Exam Favorite: Primary Myelofibrosis classically results in a "dry tap" on bone marrow aspiration due to extensive reticulin fibrosis.

Peripheral smear showing dacrocytes (teardrop cells)

High‑Yield Points - ⚡ Biggest Takeaways

All MPNs feature overproduction of mature myeloid cells from activating mutations like JAK2 V617F.

CML is unique with its BCR-ABL fusion (t(9;22)) and is treated with tyrosine kinase inhibitors.

Polycythemia Vera (PV) presents with ↑ RBC mass, aquagenic pruritus, and low erythropoietin (EPO).

Essential Thrombocythemia (ET) is marked by thrombocytosis, leading to thrombosis or hemorrhage.

Primary Myelofibrosis (PMF) causes marrow fibrosis, splenomegaly, and teardrop cells.

All risk transformation to myelofibrosis or acute myeloid leukemia (AML).

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