A 35-year-old woman from Mumbai presents with a 2-month history of progressive dyspnea and chest discomfort. Imaging reveals a large anterior mediastinal mass (8 cm) with bilateral hilar lymphadenopathy. Chest X-ray shows a widened mediastinum with a 'mediastinal widening' sign. A mediastinal mass biopsy is performed. Histology shows diffuse infiltration by large cells with clear cytoplasm, prominent nucleoli, and occasional multinucleated forms. Immunohistochemistry shows CD30+, CD15+, CD45−, CD20−, and CD3− large cells. EBV in situ hybridization (EBER) is positive in the neoplastic cells. What is the most likely diagnosis?

Explanation

## Diagnosis: Classical Hodgkin Lymphoma, Nodular Sclerosis Subtype with Mediastinal Involvement ### Clinical Presentation **High-Yield:** Mediastinal involvement in Hodgkin lymphoma is **highly characteristic of nodular sclerosis subtype** (present in 60–80% of nodular sclerosis cases). The patient presents with dyspnea and chest discomfort due to mass effect from the anterior mediastinal mass. **Key Point:** Nodular sclerosis is the most common subtype of cHL and has a **predilection for mediastinal and supradiaphragmatic lymph nodes**, particularly in young adults and adolescents. ### Histopathology & Immunophenotype **Clinical Pearl:** The biopsy findings are diagnostic of classical Hodgkin lymphoma: - **Large cells with clear cytoplasm and prominent nucleoli** — characteristic of Hodgkin and Reed-Sternberg cells - **Occasional multinucleated forms** — classic RS cells - **CD30+, CD15+** — markers of Hodgkin/RS cells - **CD45−, CD20−, CD3−** — loss of pan-hematopoietic and lineage markers **Mnemonic: CHER** — **C**lassical HL; **H**odgkin/RS cells; **E**BV association (variable, ~40% in developed countries, higher in nodular sclerosis); **R**ich inflammatory background. ### EBV Association **High-Yield:** EBV in situ hybridization (EBER) positivity in Hodgkin/RS cells is present in approximately 40% of cHL in developed countries and up to 80% in nodular sclerosis subtype. EBV is associated with: - Nodular sclerosis and mixed cellularity subtypes - Older age and immunocompromised states (though this patient is 35 years old) - Worse prognosis in some studies **Warning:** EBV positivity does NOT change the diagnosis from cHL to PMBL; it is a prognostic marker within cHL. ### Why Nodular Sclerosis? **Key Point:** Nodular sclerosis is distinguished by: 1. **Mediastinal involvement** — present in 60–80% of cases (this patient has anterior mediastinal mass with hilar involvement) 2. **Nodular fibrosis pattern** — divides lymph node into nodules (not always visible in small biopsies) 3. **Lacunar cells** — RS cell variants in formalin-fixed tissue 4. **Age of presentation** — typically young adults (this patient is 35) 5. **Supradiaphragmatic predominance** — mediastinal and cervical nodes ### Differential Diagnosis: cHL Subtypes | Feature | Nodular Sclerosis | Mixed Cellularity | Lymphocyte-Rich | Lymphocyte-Depleted | | --- | --- | --- | --- | --- | | **Frequency** | 60–70% | 15–25% | 5% | <1% | | **Mediastinal involvement** | 60–80% | <10% | Rare | Rare | | **Age** | Young adults | Older adults | Young adults | Older adults | | **Stage at presentation** | I–II | III–IV | I–II | III–IV | | **RS cell number** | Moderate | Numerous | Few | Very numerous | | **Background** | Rich inflammatory | Numerous RS cells | Predominantly small lymphs | Sparse lymphocytes | | **EBV+ frequency** | ~40–80% | ~40% | ~20% | ~80% | | **Prognosis** | Good | Intermediate | Good | Poor | ### Why NOT Mixed Cellularity? Mixed cellularity presents with **numerous RS cells without nodular fibrosis**, typically in **older patients with advanced-stage disease (III–IV)**. Mediastinal involvement is rare (<10%). This patient's mediastinal presentation is atypical for mixed cellularity. ### Why NOT Lymphocyte-Rich? Lymphocyte-rich subtype is characterized by a **background predominantly composed of small lymphocytes with sparse RS cells**. Mediastinal involvement is rare. The histology described (diffuse infiltration by large cells) is inconsistent with lymphocyte-rich. ### Why NOT PMBL? **Clinical Pearl:** Primary mediastinal B-cell lymphoma (PMBL) can mimic cHL mediastinal involvement but is distinguished by: - **CD20+ neoplastic cells** (this patient's cells are CD20−) - **CD15− neoplastic cells** (this patient's cells are CD15+) - **Lack of typical Hodgkin/RS cells** — PMBL has large cells with clear cytoplasm but lacks the characteristic multinucleated RS cell morphology - **EBV− in neoplastic cells** (PMBL is typically EBV−; this patient is EBER+) **Warning:** Do NOT confuse mediastinal involvement with PMBL. Nodular sclerosis cHL is the most common cause of mediastinal lymphoma in young adults. ### Staging & Management **High-Yield:** Once diagnosed: - **PET-CT** for staging and prognostic assessment - **International Prognostic Score (IPS)** — age, stage, hemoglobin, albumin, lymphocyte count, WBC - **Treatment:** Chemotherapy (ABVD or escalated BEACOPP) ± radiation - **Prognosis:** Nodular sclerosis has favorable prognosis (5-year OS ~90% for early-stage, ~80% for advanced-stage) [cite:Robbins 10e Ch 13]