Section 12.3: Hematologic Malignancies (Leukemia, Lymphoma, Multiple Myeloma)

PANCE Blueprint & Clinical Significance

Hematologic malignancies are a high-yield component of the PANCE blueprint. The exam emphasizes key diagnostic features, such as pathognomonic cell types (e.g., Auer rods, smudge cells, Reed-Sternberg cells), staging markers, and classic clinical presentations (e.g., the CRAB criteria for Multiple Myeloma). Candidates must be able to distinguish between acute and chronic leukemias and Hodgkin vs. Non-Hodgkin lymphoma.

Leukemias

Leukemias are clonal malignancies of hematopoietic stem cells in the bone marrow, classified by the lineage (myeloid vs. lymphoid) and rate of progression (acute vs. chronic).

Acute Lymphoblastic Leukemia (ALL)

Pathophysiology & Epidemiology

ALL is characterized by the uncontrolled proliferation of immature lymphblasts. It is the most common pediatric malignancy, peaking between ages 2 and 5.

Clinical Presentation

Abrupt onset of bone marrow failure symptoms: fatigue/pallor (due to anemia), fever/infections (due to neutropenia), and petechiae/bleeding (due to thrombocytopenia). Bone pain (often causing a limp or refusal to walk) and lymphadenopathy, hepatosplenomegaly, or mediastinal mass are common.

Diagnostics

Bone marrow biopsy is definitive, showing > 20% lymphoblasts. Cells are terminal deoxynucleotidyl transferase (TdT) positive.

Management

Combination chemotherapy (induction, consolidation, maintenance). Intrathecal chemotherapy (methotrexate) is mandatory for central nervous system (CNS) prophylaxis to prevent relapse.

Acute Myelogenous Leukemia (AML)

Pathophysiology & Epidemiology

AML involves the clonal expansion of immature myeloid precursors (myeloblasts). It is the most common acute leukemia in adults (median age 65).

Clinical Presentation

Similar to ALL with cytopenias. High blast counts can lead to leukostasis (sludging of blood in microvasculature, causing dyspnea, headache, confusion), which is a medical emergency.

Diagnostics

Bone marrow biopsy shows > 20% myeloblasts. The pathognomonic finding on peripheral smear or bone marrow aspirate is Auer rods (pink, rod-like cytoplasmic inclusions of crystallized peroxidase).

High-Yield Variant: Acute Promyelocytic Leukemia (APL)

APL (AML M3 subtype) is characterized by the t(15;17) translocation, which fuses the PML and RARA genes. APL is high-yield because it presents with severe Disseminated Intravascular Coagulation (DIC) due to the release of procoagulants from promyelocytes. It is treated with all-trans retinoic acid (ATRA), which induces differentiation of promyelocytes into mature cells.

Chronic Myelogenous Leukemia (CML)

Pathophysiology

CML is a myeloproliferative neoplasm driven by the Philadelphia chromosome, a reciprocal translocation between chromosomes 9 and 22: t(9;22). This fuses the ABL1 gene on chromosome 9 with the BCR gene on chromosome 22, producing the BCR-ABL1 fusion oncogene. This gene encodes a constitutively active tyrosine kinase that drives unregulated granulocyte production.

Clinical Presentation

Often asymptomatic initially, or presenting with fatigue, weight loss, and marked splenomegaly. Pruritus (especially after warm showers due to basophil histamine release) is a classic clue. CML progresses through three phases: chronic, accelerated, and blast crisis (which behaves like acute leukemia).

Diagnostics

Leukocytosis is extreme (often > 100,000) with a full spectrum of granulocytic precursors (neutrophils, metamyelocytes, myelocytes, promyelocytes, and blasts < 5% in chronic phase) and prominent basophilia. The leukocyte alkaline phosphatase (LAP) score is low (distinguishing CML from a reactive leukemoid reaction, which has a high LAP score). Cytogenetics or PCR showing BCR-ABL1 is diagnostic.

Management

First-line therapy consists of tyrosine kinase inhibitors (TKIs) such as imatinib, dasatinib, or nilotinib, which target the BCR-ABL1 protein.

Chronic Lymphocytic Leukemia (CLL)

Pathophysiology & Epidemiology

CLL is a clonal proliferation of morphologically mature but immunologically dysfunctional B lymphocytes. It is the most common leukemia in adults overall, typically presenting in older adults (median age 70).

Clinical Presentation

Most patients are asymptomatic, and the condition is discovered incidentally on a routine CBC. When symptomatic, it presents with painless generalized lymphadenopathy, hepatosplenomegaly, and B-symptoms.

Diagnostics

Absolute lymphocytosis (> 5,000/mcL). The classic peripheral smear finding is smudge cells (mature lymphocytes that ruptured during slide preparation due to increased fragility). Flow cytometry is diagnostic, demonstrating a clonal B-cell population expressing CD19, CD20, and co-expressing CD5 (a T-cell marker).

Management

CLL is indolent. Asymptomatic patients are managed with a "watch and wait" strategy. Treatment (e.g., targeted agents like ibrutinib, venetoclax, or chemotherapy) is reserved for symptomatic disease, rapid doubling time of lymphocytes, or progressive bone marrow failure.

Lymphomas

Lymphomas are solid tumors of the lymphatic system, divided into Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL).

Hodgkin Lymphoma

Pathophysiology & Epidemiology

Characterized by a bimodal age distribution (peaks in 20s and again in 60s). It is strongly associated with Epstein-Barr Virus (EBV) infection.

Clinical Presentation

Painless, firm, rubbery lymphadenopathy, typically cervical or supraclavicular. Alcohol-induced lymph node pain is a rare but classic symptom. B-symptoms (fever, drenching night sweats, weight loss > 10% in 6 months) indicate advanced stage.

Diagnostics

Lymph node excisional biopsy (not fine-needle aspiration [FNA]) is required. The pathognomonic finding is the Reed-Sternberg cell (a giant, multinucleated B-cell with a prominent "owl-eye" nucleolus; CD15+ and CD30+). Spread is contiguous, moving orderly from one lymph node group to the next.

Management

Chemotherapy (ABVD regimen: Adriamycin, Bleomycin, Vinblastine, Dacarbazine) and/or radiation.

Non-Hodgkin Lymphoma

Pathophysiology & Epidemiology

A heterogeneous group of lymphoid malignancies that are more common than HL, with incidence rising with age. Risk factors include immunosuppression (HIV, post-transplant), autoimmune diseases, and chronic infections (e.g., H. pylori associated with gastric MALT lymphoma).

Clinical Presentation

Painless lymphadenopathy that is diffuse and non-contiguous (spreads unpredictably). Extranodal involvement (gastrointestinal tract, skin, CNS) is common.

Diagnostics

Lymph node excisional biopsy. Staging involves CT imaging of chest, abdomen, and pelvis, and bone marrow biopsy.

Management

Varies by subtype. Indolent types (e.g., Follicular Lymphoma) may be monitored. Aggressive types (e.g., Diffuse Large B-cell Lymphoma) require chemo-immunotherapy, typically R-CHOP (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisone).

Multiple Myeloma (MM)

Pathophysiology

MM is a malignant proliferation of clonal plasma cells in the bone marrow. These cells produce large quantities of a single monoclonal immunoglobulin (most commonly IgG or IgA) or immunoglobulin light chains, known as the M-protein.

Clinical Presentation

The clinical presentation is defined by the CRAB criteria:

• Calcium: Hypercalcemia due to osteoclast activation, presenting as confusion, constipation, weakness, and polyuria.
• Renal insufficiency: Caused by light-chain deposition in renal tubules (myeloma kidney), presenting as elevated creatinine.
• Anemia: Normocytic, normochromic anemia due to bone marrow crowding by plasma cells.
• Bone pain: Caused by lytic bone lesions, particularly in the spine and ribs, leading to pathologic fractures and vertebral collapse.

Diagnostics

• Initial Screen: Serum Protein Electrophoresis (SPEP) shows an M-spike (monoclonal protein band). Urine Protein Electrophoresis (UPEP) detects Bence-Jones proteins (free light chains).
• Peripheral Smear: Reveals Rouleaux formation (RBCs stacked like coins due to increased serum protein neutralizing their negative surface charges).
• Imaging: Skeletal survey (plain radiographs) reveals punched-out lytic bone lesions (skull, long bones, spine). PANCE Trap: Avoid radionuclide bone scans (technetium-99m), as they detect osteoblastic activity, which is minimal or absent in MM (lytic lesions are purely osteoclastic). Use plain films, CT, or MRI instead.
• Bone Marrow Biopsy (Definitive): Reveals > 10% clonal plasma cells.

Management

Chemotherapy (e.g., immunomodulators like lenalidomide, proteasome inhibitors like bortezomib, and dexamethasone) followed by autologous stem cell transplantation in eligible patients. Bisphosphonates (e.g., zoledronic acid) are critical to manage bone disease.

Diagnostic Distinctions of Leukemia Types