3.3 Hematologic Malignancies & Lymphoproliferative Disorders
Key Takeaways
- Acute Leukemias (AML and ALL) are defined by ≥ 20% blasts in the bone marrow or peripheral blood; Acute Promyelocytic Leukemia (APL, AML M3) with t(15;17) PML-RARA translocation carries high risk of fatal DIC and requires immediate All-trans retinoic acid (ATRA) plus arsenic trioxide.
- Chronic Myelogenous Leukemia (CML) is driven by the t(9;22) Philadelphia chromosome creating the BCR-ABL1 fusion tyrosine kinase, presenting with extreme leukocytosis, basophilia, low leukocyte alkaline phosphatase (LAP) score, and dramatic response to imatinib.
- Multiple Myeloma is diagnosed by bone marrow clonal plasma cells ≥ 10% (or biopsy-proven plasmacytoma) plus CRAB end-organ damage: Hypercalcemia (> 11 mg/dL), Renal insufficiency (Cr > 2.0 mg/dL), Anemia (Hgb < 10 g/dL), and Lytic bone lesions.
- Hodgkin Lymphoma is characterized by Reed-Sternberg cells (binucleated "owl-eye" CD15+ CD30+ B-cells) presenting with painless lymphadenopathy and B symptoms (fever, night sweats, weight loss > 10%), demonstrating a bimodal age distribution (ages 20-30 and > 55).
- Chronic Lymphocytic Leukemia (CLL) is the most common adult leukemia in Western countries, characterized by absolute lymphocytosis (> 5,000/µL) of mature CD5+ CD19+ B-cells, peripheral smear smudge cells, and potential transformation into diffuse large B-cell lymphoma (Richter transformation).
Diagnostic Classification of Hematologic Malignancies
Hematologic malignancies on USMLE Step 2 CK are divided into acute leukemias (rapid proliferation of immature blast cells ≥ 20%), chronic myeloproliferative/lymphoproliferative neoplasms (indolent proliferation of mature blood cells), lymphomas (solid tumors of lymphoid tissue), and plasma cell dyscrasias (monoclonal immunoglobulins).
Acute Leukemias: AML vs. ALL
Acute leukemias present with signs of bone marrow failure: anemia (fatigue), thrombocytopenia (petechiae, bleeding), and neutropenia (recurrent infections).
Acute Myeloid Leukemia (AML)
Defined by ≥ 20% myeloblasts in bone marrow or peripheral blood. Blasts stain positive for myeloperoxidase (MPO) and contain crystalline rod-like cytoplasmic inclusions called Auer rods.
- Acute Promyelocytic Leukemia (APL / AML M3 Subtype): Caused by t(15;17) translocation, forming the PML-RARA fusion gene. Translocation disrupts retinoic acid receptor alpha, arresting promyelocyte differentiation. Promyelocytes release tissue factor, causing severe, often fatal Disseminated Intravascular Coagulation (DIC).
- APL Management: Emergency administration of All-Trans Retinoic Acid (ATRA) combined with arsenic trioxide, which induces differentiation of promyelocytes into mature granulocytes, rapidly reversing DIC risk.
Acute Lymphoblastic Leukemia (ALL)
Predominantly a pediatric disease (peak age 2–5 years). Defined by ≥ 20% lymphoblasts staining positive for Terminal Deoxynucleotidyl Transferase (TDT) and B-cell markers (CD10 [CALLA], CD19, CD20) or T-cell markers (CD2, CD3, CD7).
- T-cell ALL: Classic presentation in adolescent males with a large anterior mediastinal mass (causing superior vena cava syndrome or dyspnea).
- Management: Multi-agent chemotherapy including mandatory CNS prophylaxis (intrathecal methotrexate) and testicular surveillance to eradicate occult sanctuaries.
Chronic Myeloproliferative & Lymphoproliferative Neoplasms
| Disease | Primary Lineage | Key Cytogenetic / Molecular Finding | Pathognomonic Features |
|---|---|---|---|
| CML | Granulocytes (Neutrophils, Basophils) | t(9;22) BCR-ABL1 (Philadelphia Chromosome) | Low LAP score; Basophilia; Treated with Imatinib |
| Polycythemia Vera | Erythrocytes | JAK2 V617F mutation (> 95%) | Low EPO; Aquagenic pruritus; Erythromelalgia |
| Essential Thrombocythemia | Megakaryocytes | JAK2 V617F, CALR, or MPL mutation | Platelets > 450,000/µL; Digital ischemia |
| Primary Myelofibrosis | Fibroblasts (reactive to megakaryocytes) | JAK2 V617F mutation (~50%) | Teardrop RBCs (dacrocytes); Massive splenomegaly |
| CLL / SLL | Mature B-cells | Trisomy 12, 17p deletion | Smudge cells; CD5+ CD19+; AIHA risk |
| Hairy Cell Leukemia | Mature B-cells | BRAF V600E mutation | TRAP positive; Dry marrow tap; Cladribine therapy |
Chronic Myelogenous Leukemia (CML)
Driven by reciprocal translocation t(9;22)(q34;q11), placing the ABL1 tyrosine kinase gene on chromosome 22 (BCR), creating the constitutively active BCR-ABL1 fusion protein. Presents with extreme leukocytosis (> 100,000/µL), full spectrum of granulocyte precursors (myelocytes, metamyelocytes), and prominent basophilia.
- Differentiating CML from Leukemoid Reaction: CML demonstrates a low Leukocyte Alkaline Phosphatase (LAP) score, whereas a leukemoid reaction (severe infection) demonstrates an elevated LAP score.
- Treatment: Imatinib, a small-molecule tyrosine kinase inhibitor targeting BCR-ABL1.
Chronic Lymphocytic Leukemia (CLL)
Most common leukemia in adults in Western countries (median age 70). Characterized by proliferation of incompetent mature B-cells (CD5+, CD19+, CD23+). Peripheral smear reveals fragile lymphocytes that disrupt during slide preparation, forming smudge cells (gumdrop cells).
- Complications: Immune dysfunction leading to hypogammaglobulinemia (recurrent bacterial infections) and Autoimmune Hemolytic Anemia (AIHA).
- Richter Transformation: Sudden transformation of indolent CLL into aggressive Diffuse Large B-Cell Lymphoma (DLBCL), marked by rapidly enlarging isolated lymph node and B symptoms.
Lymphomas: Hodgkin vs. Non-Hodgkin
[ Patient with Painless Lymphadenopathy ]
│
Excisional Lymph Node Biopsy
│
┌───────────┴───────────┐
▼ ▼
Reed-Sternberg Cells No Reed-Sternberg Cells
(CD15+, CD30+ B-cells) (Non-Hodgkin Lymphoma)
│ │
Hodgkin Lymphoma Flow Cytometry & Cytogenetics
┌──────┴──────┐ ┌──────┼──────┬──────┐
▼ ▼ ▼ ▼ ▼ ▼
Nodular Mixed DLBCL Follicular Burkitt Mantle
Sclerosis Cellularity (BCL6) t(14;18) t(8;14) t(11;14)
(Young women (Elderly / BCL2 MYC Cyclin D1
Mediastinal EBV+)
mass)
Hodgkin Lymphoma (HL)
Characterized by Reed-Sternberg (RS) cells: giant binucleated B-cells with prominent inclusion-like nucleoli ("owl-eye appearance"), immunophenotypically CD15+ and CD30+. Bimodal age distribution (ages 20–30 and > 55). Presents with painless cervical lymphadenopathy and systemic B symptoms (fever > 38°C, drenching night sweats, weight loss > 10% over 6 months).
- Nodular Sclerosis: Most common subtype (65–70%), especially in young females. Biopsy demonstrates fibrous collagen bands circumscribing nodular aggregates; frequently presents with a mediastinal mass.
Non-Hodgkin Lymphoma (NHL)
- Diffuse Large B-Cell Lymphoma (DLBCL): Most common high-grade NHL in adults. Aggressive, rapidly enlarging nodal mass. Stains positive for BCL6 and CD20. Treated with R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone).
- Follicular Lymphoma: Indolent B-cell lymphoma caused by t(14;18) translocation, overexpressing BCL2 (anti-apoptotic protein). Presents with painless, waxing-and-waning lymphadenopathy.
- Burkitt Lymphoma: Highly aggressive B-cell tumor caused by t(8;14) translocation overexpressing c-MYC (transcription activator). Histology shows "starry sky" appearance (macrophages ingesting apoptotic tumor cells against a dark background of lymphocytes). Strongly linked to EBV (endemic jaw tumor in Africa; sporadic abdominal/ileocecal mass in US).
Plasma Cell Dyscrasias
Multiple Myeloma
Neoplastic proliferation of monoclonal plasma cells in bone marrow producing excess monoclonal immunoglobulin (M-spike on SPEP/UPEP, usually IgG or IgA). Diagnosed by clonal bone marrow plasma cells ≥ 10% (or plasmacytoma) plus CRAB end-organ criteria:
- Calcium elevated (hypercalcemia > 11 mg/dL)
- Renal insufficiency (serum creatinine > 2.0 mg/dL due to Bence Jones light chain cast nephropathy)
- Anemia (normocytic, Hgb < 10 g/dL)
- Bone lytic lesions (punched-out lesions on skull/spine radiograph caused by osteoclast-activating factors IL-6 and RANKL)
Key Diagnostic Note: Monoclonal Gammopathy of Undetermined Significance (MGUS) features serum M-spike < 3 g/dL and marrow plasma cells < 10% WITHOUT CRAB symptoms. Waldenström Macroglobulinemia features IgM M-spike leading to hyperviscosity syndrome (retinal vein engorgement, headache, bleeding) without lytic bone lesions.
A 64-year-old male presents for a routine physical examination. He reports mild fatigue over the past 4 months but denies fever or weight loss. Physical examination demonstrates non-tender bilateral cervical and axillary lymphadenopathy. Laboratory studies show hemoglobin 11.2 g/dL, platelet count 165,000/µL, and white blood cell count 68,000/µL with 88% mature-appearing lymphocytes. Peripheral blood smear demonstrates numerous cell fragments resembling crushed gumdrops ('smudge cells'). Flow cytometry identifies a monoclonal population of CD5+ and CD19+ B-lymphocytes. Which of the following complications is this patient at highest risk of developing?
A 48-year-old male is admitted to the hospital due to severe epistaxis, bleeding gums, and extensive ecchymoses across his trunk. Laboratory evaluation demonstrates hemoglobin 8.4 g/dL, platelet count 22,000/µL, WBC 3,200/µL, fibrinogen 90 mg/dL (normal 200–400), and D-dimer 4,800 ng/mL. Bone marrow biopsy reveals 35% immature cells packed with coarse magenta cytoplasmic granules and stacked crystalline rod inclusions. Cytogenetics confirm a t(15;17)(q24;q21) translocation. What is the mechanism of the definitive first-line pharmacotherapy for this patient's underlying malignancy?
A 68-year-old male presents with persistent low back pain and worsening fatigue over 5 months. Laboratory studies show hemoglobin 9.2 g/dL, serum calcium 11.8 mg/dL, serum creatinine 2.4 mg/dL, and total protein 10.2 g/dL. Serum protein electrophoresis (SPEP) demonstrates a dense monoclonal spike (M-spike) of 3.8 g/dL in the gamma globulin region. Plain radiographs of the pelvis and skull reveal multiple sharp, non-sclerotic 'punched-out' radiolucent lesions. Which bone marrow examination finding confirms the definitive diagnosis?