Primary mediastinal B-cell lymphoma (PMBCL)

Epidemiology and Presentation

• Demographics: young adults; median age about 35; female predominance (roughly F:M 2:1).
• About 2 to 4% of NHL; arises from thymic medullary B cells.
• Presentation: rapidly enlarging bulky anterior mediastinal mass; SVC syndrome and thrombosis are common at diagnosis; cough, dyspnea, chest pain. About 80% have a mass >10 cm.
• Spread: contiguous to lung, pleura, pericardium; B symptoms in about 40%; LDH often very elevated. Distant nodal or extranodal disease is uncommon at presentation but common at relapse (kidney, adrenal, CNS, ovary).

Pathology and Genetics

• Distinct WHO 2022 / ICC 2022 entity (separate from DLBCL NOS).
• PMBL arises from thymic medullary B cells; its gene-expression and genetic profile overlap with classical Hodgkin lymphoma. Rituximab-containing regimens (DA-EPOCH-R, R-CHOP) are established and effective.
• IHC: CD20+, CD79a+, CD30+ (variable, about 80%, often weak and heterogeneous), CD15−, CD23+, MAL+, BCL6+ (variable), MUM1+; c-REL and TRAF-1 positive. Coexpression of TRAF-1 and c-REL is very specific for mediastinal lymphoma. Gene expression overlaps with classical HL.
• Genetics: 9p24.1 amplification drives PD-L1 and PD-L2 overexpression (the basis for PD-1 inhibitor activity); JAK2 amplification; REL amplification; NF-κB pathway mutations (TNFAIP3, NFKBIA); B2M and CIITA alterations.
• Mediastinal gray-zone lymphoma (MGZL): a separate WHO 2022 entity with features intermediate between PMBL and classical HL; treat with DA-EPOCH-R.

Workup

• PET-CT (highly FDG-avid), CT chest/abdomen/pelvis, bone marrow biopsy (often skipped if PET is clean), echo, MUGA.
• Mediastinal MRI to assess SVC and airway involvement.
• HBV/HCV/HIV; pregnancy test; fertility counseling.
• Stage is typically I to II (bulky mediastinal disease); stage III to IV is less common.

Frontline Treatment

• Two accepted options: (1) DA-EPOCH-R x6 cycles; (2) R-CHOP x6 with PET-guided involved-site RT (a negative end-of-treatment PET allows RT omission).

DA-EPOCH-R (preferred US standard)

• Rationale for the infusional design: continuous infusion of chemotherapy helps prevent resistance; the dose is adjusted based on the ANC nadir; vincristine does not escalate. Start at dose level 1 and escalate up to level 6 as the patient tolerates.
• Dunleavy NEJM 2013 (PMID 23574119): N=51, 5-year EFS 93%, OS nearly 100%, and only 2 of 51 patients (4%) received radiation. ANC <500 occurred in ~50% of cycles; the 6% figure was cycles with platelets <25,000; fever/neutropenia hospitalization occurred in ~13% of cycles, and >50% escalated to at least dose level 4. This avoids long-term mediastinal RT toxicity (breast cancer in young women, cardiac disease).

R-CHOP plus involved-site RT and the radiation debate

• R-CHOP x6 plus ISRT is the older standard: effective, but it exposes young women to mediastinal RT with increased breast cancer and cardiac disease at 15 to 20 years.
• IELSG-37 (Martelli JCO 2024; PMID 39159403): PET-driven RT omission; patients achieving complete metabolic response (Deauville 1 to 3) after immunochemotherapy could safely omit RT (non-inferior PFS, less toxicity). This supports omitting radiation in PET-CR responders.
• R-MACOP-B / R-VACOP-B: European third-generation regimens; also effective.
• Bottom line of the debate: DA-EPOCH-R avoids RT up front in most young patients; when R-CHOP is used, a negative end-of-treatment PET now allows RT to be omitted.

PD-L1 Biology and Checkpoint Inhibitors

• 9p24.1 amplification leads to constitutive PD-L1/PD-L2 expression, making PMBL highly sensitive to PD-1 blockade.
• Pembrolizumab: FDA Jun 2018 for R/R PMBL (KEYNOTE-170; PMID 31609651), ORR 45% (CR 13%) after ≥2 lines; durable responses.
• Nivolumab plus brentuximab vedotin: CheckMate 436, ORR about 73% (leverages both PD-1 and CD30).

Relapsed / Refractory

• For primary-refractory disease or relapse <12 months, second-line CD19 CAR-T is preferred in eligible patients (liso-cel; TRANSFORM included PMBL). Salvage chemo (R-ICE, R-DHAP) then auto-HSCT remains appropriate for later chemosensitive relapse.
• Checkpoint inhibitors: pembrolizumab, nivolumab plus/minus brentuximab (above).
• CAR-T: axi-cel and liso-cel are included in the DLBCL approvals and are effective in R/R PMBL.
• Allo-HSCT: rare; reserved for chemo- or CAR-T-refractory young fit patients.

High-Yield Pearls

• Young woman with a bulky anterior mediastinal mass and SVC syndrome equals PMBL until proven otherwise.
• TRAF-1 plus c-REL coexpression is very specific for mediastinal lymphoma; overlap with classical HL is expected.
• 9p24.1 / PD-L1 amplification makes PD-1 inhibitors highly active.
• DA-EPOCH-R cures about 93% and omits mediastinal RT, preferred over R-CHOP plus RT in young women.
• IELSG-37: a PET complete response allows safe RT omission.
• Long-term breast cancer screening if mediastinal RT is given, especially if exposed before age 30.
• Distinguish from classical HL and MGZL on IHC and morphology; treatment differs.