A 32-year-old woman presents with a 3-week history of painless lymphadenopathy in the neck and axillae. On examination, she has firm, rubbery, non-tender lymph nodes. A lymph node biopsy is performed. Histopathology shows sheets of large cells with prominent nucleoli and abundant cytoplasm (Reed-Sternberg cells). Immunohistochemistry reveals CD30+ and CD15+ cells. The pathologist notes that many of these malignant cells are surrounded by apoptotic bodies and dying lymphocytes. Which of the following best explains the mechanism by which these neoplastic cells evade immune destruction despite being surrounded by cytotoxic T lymphocytes?

Explanation

## Mechanism of Immune Evasion in Hodgkin Lymphoma ### Pathological Context Reed-Sternberg cells in Hodgkin lymphoma are notorious for their ability to survive in an inflammatory microenvironment despite being surrounded by cytotoxic immune cells. The presence of apoptotic bodies and dying lymphocytes in the biopsy is a key clue. ### The Correct Mechanism: Extrinsic Pathway Activation in Surrounding Cells **Key Point:** Hodgkin lymphoma cells express high levels of **FasL (CD95L) and TNF-α** on their surface. These ligands engage Fas and TNF receptors on surrounding T lymphocytes, triggering the **extrinsic apoptotic pathway** in the immune cells rather than in the malignant cells themselves. **High-Yield:** This is a classic example of **"immunological suicide"** or **"fratricide"** — the tumor turns the immune system against itself by forcing T cells to undergo apoptosis through death receptor signaling. ### Extrinsic Pathway Activation Sequence 1. **Death Receptor Engagement:** FasL (on RS cells) binds Fas (on T cells); TNF-α binds TNFR1 (on T cells) 2. **DISC Formation:** Death-Inducing Signaling Complex assembles at the receptor 3. **Caspase-8 Activation:** Initiator caspase-8 is recruited and auto-activated 4. **Effector Caspase Cascade:** Caspase-8 cleaves pro-caspase-3 and pro-caspase-7 5. **Apoptotic Execution:** Effector caspases cleave PARP, lamin A/C, and activate CAD, leading to DNA fragmentation and cell death ```mermaid flowchart TD A["Hodgkin Lymphoma Cell<br/>(RS cell)"]:::outcome B["FasL & TNF-α<br/>on cell surface"]:::outcome C["Surrounding CD8+ T cell"]:::outcome D["Fas & TNFR1 engagement"]:::action E["DISC formation"]:::action F["Caspase-8 activation"]:::action G["Caspase-3/7 activation"]:::action H["T cell apoptosis<br/>(Extrinsic pathway)"]:::urgent A --> B B --> D C --> D D --> E E --> F F --> G G --> H ``` ### Why This Explains the Histology **Clinical Pearl:** The presence of **apoptotic bodies and tingible-body macrophages** (macrophages filled with apoptotic debris) is a hallmark of Hodgkin lymphoma histology. These represent T cells that have been killed by RS cell-derived death ligands, not the other way around. ### Distinction from Intrinsic Pathway The intrinsic (mitochondrial) pathway would involve: - Bcl-2 family imbalance (pro-apoptotic > anti-apoptotic) - Mitochondrial outer membrane permeabilization (MOMP) - Cytochrome c release - Apoptosome formation - Caspase-9 activation But in this scenario, the RS cells are **resistant** to intrinsic apoptosis (they overexpress Bcl-2), while they actively trigger extrinsic apoptosis in surrounding cells.