Primary Mediastinal Large B-Cell Lymphoma (PMBCL)

Primary mediastinal large B-cell lymphoma (PMBCL) is an aggressive non-Hodgkin lymphoma representing approximately 2-4% of all non-Hodgkin lymphomas, recognized as a distinct entity in the WHO 2017 and 2022 classifications, derived from thymic medullary B-cells (asteroid B-cells of the thymus). Molecular profiling reveals overlap with classic Hodgkin lymphoma including 9p24.1 amplification (PD-L1/PD-L2), JAK-STAT pathway activation (JAK2, STAT6 mutations), NFkB pathway alterations (TNFAIP3, NFKBIE), MHC class I/II loss (CIITA rearrangements), and high tumor mutational burden. Distinct gene expression signature differentiates PMBCL from diffuse large B-cell lymphoma (DLBCL) and supports its classification as a unique biological entity bridging classical Hodgkin lymphoma and DLBCL.

Epidemiology: incidence approximately 0.4 per 100,000 per year, female-to-male ratio 2:1, peak age 30-35 years (young adults), no known predisposing factors. Clinical presentation: bulky anterior mediastinal mass (>10 cm in 70-80%) causing local compressive symptoms — superior vena cava syndrome (40-50% with facial swelling, neck vein distension, headache), dyspnea (50-60%), cough, chest pain, dysphagia, hoarseness (recurrent laryngeal nerve compression), pleural/pericardial effusion (25-35%). B-symptoms (fever >38°C, night sweats, weight loss >10%) in 20-30%. Extrathoracic involvement at diagnosis is uncommon (10-15%) but relapses preferentially involve extranodal sites (kidney, ovary, liver, CNS). Bone marrow involvement is rare (<5%).

Diagnosis requires excisional or core needle biopsy (often by mediastinoscopy or video-assisted thoracoscopy) showing diffuse infiltrate of medium-large B-cells with abundant clear cytoplasm, multilobated nuclei, sclerotic stromal compartmentalization, and immunophenotype CD19+ CD20+ CD22+ CD79a+ CD30+ (variable, weak), CD15-, MAL+ (specific marker), CD23+, BCL6+, IRF4/MUM1+. Staging with PET-CT (essential), CT chest/abdomen/pelvis, bone marrow biopsy (low yield), CSF analysis if neurologic symptoms, echocardiogram (baseline cardiac function). Treatment: dose-adjusted EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, rituximab) for 6 cycles is preferred (NCI study showed 93% event-free survival without radiation); alternative R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) for 6 cycles followed by consolidation mediastinal radiotherapy (30-36 Gy) for residual PET-positive disease. Salvage for relapsed/refractory disease: high-dose chemotherapy with autologous stem cell transplantation, CAR-T cell therapy (axi-cel, tisa-cel, liso-cel approved for r/r LBCL including PMBCL), checkpoint inhibitors (pembrolizumab, nivolumab — high response given PD-L1/PD-L2 amplification), brentuximab vedotin (CD30 expression). Prognosis excellent with first-line therapy: 5-year overall survival 80-90%, progression-free survival 75-85%.