What is the most likely diagnosis in a 58-year-old man with a large anterior mediastinal mass, mild normocytic anemia, leukocytosis with eosinophilia, and several weeks of fatigue, retrosternal heaviness, and non‑productive cough?

Hodgkin Lymphoma

The most likely diagnosis in this 58-year-old man with a large anterior mediastinal mass, mild normocytic anemia, eosinophilia, and several weeks of constitutional symptoms is Hodgkin lymphoma (HL), specifically classical Hodgkin lymphoma with nodular sclerosing subtype.

Clinical Reasoning

This patient's presentation is highly characteristic of Hodgkin lymphoma based on several key features:

Supporting Clinical Features

• Age and demographics: The patient is 58 years old, fitting the second peak of HL incidence that occurs after age 55 1
• Anterior mediastinal mass: Large mediastinal masses are classic for HL, particularly the nodular sclerosing subtype which commonly presents with mediastinal involvement 2
• Constitutional symptoms: Several weeks of fatigue and retrosternal heaviness are consistent with B symptoms or early-stage disease
• Eosinophilia (10%): The heterogeneous cellular infiltrate in HL characteristically includes eosinophils, histiocytes, lymphocytes, and other inflammatory cells surrounding the rare malignant Reed-Sternberg cells 1
• Generalized pruritus: This is a recognized symptom in HL and explains his diphenhydramine use
• Mild normocytic anemia: Hemoglobin of 10.8 g/dL without other cytopenias is consistent with chronic disease from lymphoma

Distinguishing from Other Anterior Mediastinal Masses

The differential diagnosis for anterior mediastinal masses includes the "terrible Ts" - thymoma, thyroid, teratoma (germ cell tumors), and lymphoma 2. However:

• Thymoma: Typically presents with an indolent course and is often associated with myasthenia gravis. The acute chest pain after hot shower (likely related to mass effect) and constitutional symptoms favor lymphoma over thymoma 2
• Germ cell tumors: Would require elevated AFP and β-hCG, which should be checked but the age and presentation make this less likely 2
• Thymic carcinoma: More aggressive but less common than lymphoma as a primary anterior mediastinal malignancy 2

Immediate Diagnostic Workup Required

The diagnosis of HL requires tissue confirmation and cannot be made on imaging alone 3, 1:

1. Excisional lymph node biopsy is the gold standard - core needle biopsy may be adequate, but excisional biopsy is preferred 3
2. Immunostaining must include: CD3, CD15, CD20, CD30, CD45, CD79a, and PAX5 for classical HL 3
3. Classical HL immunophenotype: CD15+/CD30+/CD20- (versus lymphocyte-predominant HL which is CD15-/CD30-/CD20+) 1

Complete Staging Workup

Once tissue diagnosis is confirmed 3, 4:

• PET/CT from skull base to mid-thigh - this is now standard for staging and eliminates the need for routine bone marrow biopsy if negative or showing homogenous uptake 3
• Contrast-enhanced CT for anatomic detail 3
• Laboratory tests: Complete metabolic panel, LDH, albumin, ESR, HIV and hepatitis B/C testing (given unusual presentation in older adult) 3, 4
• Cardiac ejection fraction assessment before doxorubicin-based chemotherapy 3
• Pulmonary function tests with DLCO before bleomycin therapy (DLCO threshold ≥60% acceptable) 4

Risk Stratification

Based on the large mediastinal mass, this patient would be classified as early-stage unfavorable if stage I-II, or advanced stage if stage III-IV 1, 4:

• Large mediastinal mass is defined as mediastinal mass ratio (MMR) >0.33 (maximum width of mass/maximum intrathoracic diameter) or any mass >10 cm 4, 5
• This is a major unfavorable prognostic factor requiring combined modality therapy 1, 4

Critical Pitfalls to Avoid

1. Do not perform surgical biopsy if resectable thymoma is strongly suspected - but this patient's presentation favors lymphoma 2
2. Fine-needle aspiration alone is insufficient except in unusual circumstances with expert hematopathology review 3
3. Do not delay tissue diagnosis - the acute chest pain episode suggests potential complications from mass effect
4. Bone marrow biopsy is NOT routinely needed if PET/CT is performed, unless cytopenias are present (this patient has only mild anemia) 3

The combination of anterior mediastinal mass, age >55, eosinophilia, constitutional symptoms, and pruritus makes Hodgkin lymphoma the most likely diagnosis, but tissue confirmation with appropriate immunohistochemistry is mandatory before initiating treatment.