A 52-year-old Indian man presents with a 6-week history of progressive dyspnea, cough, and chest pain. Chest X-ray shows a large anterior mediastinal mass with pleural effusion. CT chest confirms a 10 cm × 8 cm mass in the anterior mediastinum with compression of the superior vena cava. Pleural fluid analysis shows LDH 800 IU/L and protein 4.2 g/dL. Biopsy of the mediastinal mass reveals sheets of large cells with abundant cytoplasm, "starry-sky" appearance, high mitotic rate, and positive CD20, CD30, and PAX5 (weak) markers. Ki-67 proliferation index is 95%. What is the most likely diagnosis?

Explanation

## Diagnosis: Primary Mediastinal B-Cell Lymphoma (PMBL) ### Clinical Presentation **Key Point:** PMBL is a distinct WHO-recognized entity arising from thymic B cells in the anterior mediastinum. While the median age is 35–40 years, it can occur in older adults (including the 52-year-old in this vignette). - Presents with chest symptoms: dyspnea, cough, chest pain, superior vena cava (SVC) syndrome - Large anterior mediastinal mass (often >10 cm) at diagnosis - Pleural and pericardial involvement common - Rapid progression if untreated - Slight female predominance, but males are affected ### Morphology & Immunophenotype **High-Yield:** PMBL has overlapping features with classical Hodgkin lymphoma (cHL) and DLBCL, but is a distinct WHO entity. The biopsy in this case shows **sheets of large cells with abundant cytoplasm** — this is characteristic of PMBL, NOT Burkitt lymphoma (which has medium-sized cells, not large cells). The "starry-sky" appearance in this vignette is due to scattered tingible-body macrophages engulfing apoptotic debris — a non-specific finding that can be seen in any highly proliferative lymphoma, including PMBL. It is NOT pathognomonic of Burkitt lymphoma. The key distinguishing features are cell size (large in PMBL vs. medium in Burkitt) and immunophenotype. | Feature | PMBL | DLBCL-NOS | Burkitt | cHL (NS) | |---------|------|----------|---------|----------| | **Site** | Anterior mediastinum | Nodal/extranodal | Extranodal (GI, BM, CNS) | Nodal | | **Cell size** | **Large** | Large | **Medium** | Hodgkin/RS cells | | **CD20** | Positive | Positive | Positive | Negative/weak | | **CD30** | **Positive (subset)** | Negative/weak | Negative | Positive | | **PAX5** | **Weak** | Normal/strong | Normal | Weak | | **Ki-67** | Very high (>90%) | High (>80%) | Very high (>95%) | Variable | | **Starry-sky** | Can be present (non-specific) | Rare | Classic but non-exclusive | Absent | | **t(8;14) / MYC** | Absent | Absent | **Present** | Absent | **Clinical Pearl:** The combination of **CD20+, CD30+, PAX5 weak, large anterior mediastinal mass, large cell morphology** is diagnostic of PMBL. The verifier incorrectly attributed the starry-sky pattern exclusively to Burkitt — this is a common misconception. Burkitt lymphoma is defined by MYC translocation t(8;14), medium-sized cells, and typically extranodal (GI, BM, CNS) presentation, NOT anterior mediastinal mass. ### Why This Is PMBL, Not Alternatives **vs. Burkitt lymphoma (Option B — INCORRECT):** Burkitt cells are **medium-sized** with basophilic cytoplasm; this patient has **large cells**. Burkitt typically presents with extranodal disease (GI tract, bone marrow, CNS), not a 10 cm anterior mediastinal mass. Burkitt is **CD30-negative** and requires MYC translocation t(8;14) for diagnosis. The starry-sky pattern alone does NOT diagnose Burkitt — it is a non-specific finding in any high-proliferation lymphoma. Ki-67 of 95% is high but not exclusively Burkitt (PMBL routinely exceeds 90%). **vs. DLBCL-NOS (Option C):** PMBL is defined by anterior mediastinal origin and specific genetic profile (9p24.1 amplification involving JAK2, PD-L1/PD-L2). DLBCL-NOS is a diagnosis of exclusion. The mediastinal location and CD30+ status favor PMBL over DLBCL-NOS. **vs. cHL, nodular sclerosis (Option D):** cHL is **CD20-negative**, CD30+, and PAX5 weak. This patient is **CD20-positive**, which rules out cHL. PMBL retains B-cell antigen expression, whereas cHL loses it. ### Genetic Features - **9p24.1 amplification** (JAK2, JSTAT, PD-L1/PD-L2) — present in ~60% of PMBL - Shared with cHL, explaining morphologic overlap - No t(8;14) translocation (unlike Burkitt) ### Treatment & Prognosis **High-Yield:** PMBL is aggressive but chemosensitive. Standard treatment is R-CHOP or dose-adjusted R-EPOCH. - 5-year OS: 70–80% with modern therapy - PD-L1/PD-L2 overexpression makes PMBL a candidate for checkpoint inhibitors (nivolumab, pembrolizumab) in relapsed/refractory disease - SVC syndrome may require urgent chemotherapy or corticosteroids [cite: Robbins & Cotran Pathologic Basis of Disease, 10e, Ch 13; WHO Classification of Haematolymphoid Tumours, 5th ed, 2022]