A 42-year-old woman from Mumbai presents with a 2-month history of progressive generalized lymphadenopathy, night sweats, and a 5 kg weight loss. Physical examination reveals firm, matted cervical and axillary lymph nodes. Laboratory studies show hemoglobin 9.2 g/dL, WBC 12,500/μL with eosinophilia, and elevated LDH. An excisional lymph node biopsy shows diffuse infiltration by numerous large atypical cells with multiple nuclei and prominent nucleoli, sparse background lymphocytes, and areas of necrosis. Immunohistochemistry reveals CD30+, CD15+, CD20−, CD3−, and EBV-LMP1+. What is the most likely diagnosis and subtype?

Explanation

## Diagnosis: Hodgkin Lymphoma, Lymphocyte-Depleted Subtype ### Histopathologic Features The key diagnostic findings are: - **Numerous large atypical cells with multiple nuclei and prominent nucleoli** = abundant Reed-Sternberg cells and Hodgkin cells - **Sparse background lymphocytes** = paucity of inflammatory cells - **Areas of necrosis** = indicates aggressive disease - **Diffuse infiltration pattern** = no nodular architecture **Key Point:** The hallmark of lymphocyte-depleted HL is a high number of RS cells with a sparse lymphocytic background—the opposite of lymphocyte-rich disease. ### Immunophenotype - CD30+, CD15+ = RS cells and Hodgkin cells (diagnostic) - CD20−, CD3− = excludes B-cell and T-cell lymphomas - **EBV-LMP1+** = strong association with lymphocyte-depleted HL and indicates poor prognosis ### Subtype Classification | Feature | Lymphocyte-Depleted | Mixed Cellularity | Nodular Sclerosis | Lymphocyte-Rich | |---------|---------------------|-------------------|-------------------|------------------| | **RS cell density** | Numerous (high) | Moderate | Moderate | Few (low) | | **Background lymphocytes** | Sparse | Mixed/abundant | Mixed | Abundant | | **Necrosis** | Common | Occasional | Rare | Rare | | **EBV association** | Strong (LMP1+) | Moderate | Weak | Weak | | **Frequency** | <5% | 15–25% | 60–70% | 5% | | **Prognosis** | Poor | Intermediate | Favorable | Favorable | | **Age of onset** | Older adults, immunocompromised | Older adults | Young adults | Variable | **High-Yield:** Lymphocyte-depleted HL is the rarest and most aggressive subtype, with strong EBV association and poor prognosis. It is more common in older patients and immunocompromised individuals (including those with HIV). ### Clinical Features Supporting Lymphocyte-Depleted HL 1. **Aggressive presentation**: B symptoms (fever, night sweats, weight loss) are prominent 2. **Advanced disease**: Generalized lymphadenopathy suggests stage III–IV disease 3. **Systemic manifestations**: Elevated LDH and eosinophilia indicate high tumor burden 4. **EBV positivity**: Strong predictor of lymphocyte-depleted subtype 5. **Older age**: While HL can occur at any age, lymphocyte-depleted is more common in older patients ### Clinical Pearl EBV-LMP1 positivity is a red flag for lymphocyte-depleted HL and portends a worse prognosis. This subtype requires more aggressive therapy and closer follow-up than nodular sclerosis.