Gray zone lymphoma and aggressive B-cell lymphomas

WHO 2022 / ICC 2022: Updated Aggressive B-cell Lymphoma Categories

• DLBCL/HGBL with MYC + BCL2 rearrangements (with or without BCL6; 'double-hit', 'triple-hit'), renamed in WHO 2022 from the WHO 2016 HGBL with MYC and BCL2 and/or BCL6 rearrangements; MYC + BCL6 alone no longer qualifies in WHO 2022. WHO 2022 retains MYC + BCL2 (with or without BCL6) as the highest-risk; ICC 2022 also recognizes MYC + BCL6 as separate.
• HGBL with 11q aberration, a new WHO 2022 entity. MYC-negative, partial 11q gain/loss; previously called "Burkitt-like with 11q aberration."
• HGBL NOS: cases not meeting double-hit or 11q criteria but with intermediate aggressive features.
• Mediastinal gray-zone lymphoma (MGZL): features intermediate between PMBL and cHL; ICC 2022 term "mediastinal gray zone lymphoma"; WHO 2022 retains it as a separate entity.
• EBV+ DLBCL NOS: formerly "EBV+ DLBCL of the elderly," now any age; worse prognosis.
• Large B-cell lymphoma with IRF4 rearrangement: pediatric/young adult, often tonsillar; favorable outcome with R-CHOP-like therapy.
• T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL): aggressive; treat as DLBCL.
• Primary cutaneous DLBCL, leg type: aggressive, MYD88 L265P common; R-CHOP-like.
• Primary effusion lymphoma (PEL): HHV-8+, often EBV+, body-cavity effusions, HIV-associated; aggressive.
• Plasmablastic lymphoma: HIV+/EBV+ (oral cavity); aggressive; CD20-negative, MYC+ common.

Gray Zone Lymphoma (Mediastinal, MGZL)

• Definition: B-cell lymphoma with features intermediate between DLBCL/primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL), not clearly assignable to either.
• Presentation: large anterior mediastinal mass with or without supraclavicular nodes; more common in males aged 20 to 40 years; thymic origin. Cases formerly called non-mediastinal gray zone lymphoma are now classified as DLBCL, NOS or another defined entity; MGZL is restricted to the mediastinal setting (a mediastinal primary may still disseminate).
• Morphology: large pleomorphic cells in a diffusely fibrous stroma; cells are typically larger and more pleomorphic than in PMBL, sometimes resembling lacunar or Hodgkin-like (Reed-Sternberg-like) cells. Necrosis without a neutrophilic infiltrate is frequent.
• Immunophenotype: CD45+, PAX5+, BOB.1+, OCT-2+, CD30+, CD79a+, CD15 and CD20 variable (often discordant with morphology, see table); CD10-negative, ALK-negative; BCL6 variable; EBV-negative (EBV positivity excludes MGZL; classify such cases as EBV+ DLBCL). The phenotype is atypical and shows transitional features between PMBL and cHL.

• Prognosis: worse than either classical Hodgkin lymphoma or primary mediastinal B-cell lymphoma.
• Treatment: DA-EPOCH-R is generally preferred (Wilson Blood 2014, NCI series); R-CHOP or ABVD are less favored. Consider ISRT for residual, bulky, or localized disease based on response; routine consolidation radiation is not required (the NCI DA-EPOCH-R study omitted planned RT). Treat with R-based therapy if CD20+.

Reduced-Cardiotoxicity Options. Anthracycline-free (for absolute anthracycline contraindication or very low LVEF): R-CEOP, R-CEPP, R-GCVP. Anthracycline-containing but lower cardiac risk (not for absolute contraindication): liposomal doxorubicin (RCDOP), infusional DA-EPOCH-R.

• Relevant when a large-cell lymphoma requires anthracycline-based therapy but cardiotoxicity is a concern. Options include:
  • RCDOP (rituximab, cyclophosphamide, liposomal doxorubicin, vincristine, prednisone): liposomal doxorubicin has less cardiac toxicity.
  • DA-EPOCH-R: anthracycline is infused over several days, mitigating cardiac risk.
  • RCEPP (rituximab, cyclophosphamide, etoposide, prednisone, procarbazine).
  • RCEOP (rituximab, cyclophosphamide, etoposide, vincristine, prednisone).
  • RGCVP (rituximab, gemcitabine, cyclophosphamide, vincristine, prednisolone).
• Document baseline ejection fraction (MUGA or TTE). Doxorubicin cardiotoxicity risk rises from ~1 to 2% at cumulative doses of 300 mg/m² to 6 to 20% at 500 mg/m²; total lifetime dose is generally limited to 450 mg/m². Avoid anthracyclines at baseline LVEF below 30%.

Double-Hit / Triple-Hit HGBL

• FISH for MYC, BCL2, BCL6 should be performed on ALL DLBCL; the Hans algorithm / GCB phenotype alone misses it.
• Frequency: ~5 to 10% of DLBCL have MYC + BCL2/BCL6 rearrangements.
• Clinical: aggressive, high LDH, BM/CNS involvement, advanced stage.
• Treatment: DA-EPOCH-R generally preferred over R-CHOP (Petrich Blood 2014; Howlett Br J Haematol 2015, retrospective benefit; awaiting prospective definitive data). CNS prophylaxis recommended (high CNS-IPI). Outcomes worse than DLBCL-NOS.
• Distinguish from "double-expressor": MYC (≥40%) and BCL2 (≥50%) protein overexpression by IHC, independent of rearrangement status (FISH defines double-hit); not a separate entity, remains DLBCL, NOS, intermediate prognosis, treated as DLBCL.

HGBL with 11q Aberration

• Formerly called Burkitt-like with 11q.
• MYC-negative, partial 11q gains and telomeric losses ("dual-pattern").
• More pleomorphic morphology than classic Burkitt; often nodal.
• Treated as Burkitt or aggressive B-cell disease: DA-EPOCH-R or CODOX-M/IVAC-R.

EBV+ DLBCL NOS

• Historically considered elderly; the WHO 2016 revision removed the age restriction, so any age.
• EBER+ in most tumor cells (ICC 2022 uses a >80% cutoff; WHO-HAEM5 requires EBV in the majority without a fixed threshold).
• Often non-GCB phenotype; worse prognosis than EBV-negative DLBCL.
• R-CHOP standard; outcomes inferior; emerging strategies (venetoclax/daratumumab, PD-1 inhibitors).

Plasmablastic Lymphoma

• HIV-associated (especially oral cavity) or post-transplant; EBV+ in ~75%.
• Phenotype: CD20-negative, CD138+, MUM1+, MYC+ in ~50%, Ki-67 high.
• Aggressive; rituximab adds no benefit (CD20-negative) and CHOP alone is suboptimal, so prefer more intensive therapy such as DA-EPOCH.
• DA-EPOCH or CODOX-M/IVAC; bortezomib plus chemo (V-EPOCH); CD38-targeted (daratumumab) emerging.

Primary Effusion Lymphoma (PEL)

• HHV-8 (KSHV)+, often EBV+, HIV+; serous-cavity effusions (pleural, pericardial, peritoneal) without a solid mass.
• CD20-negative, CD30+, CD45+, MUM1+; very aggressive (median OS ~6 months).
• CHOP-based (or DA-EPOCH) therapy with concurrent antiretroviral therapy; IL-6/HHV-8-directed strategies (rituximab less effective because CD20 is absent).

High-Yield Pearls

• Always FISH MYC, BCL2, BCL6 in newly diagnosed DLBCL to identify double-/triple-hit HGBL.
• HGBL with 11q = new WHO 2022 entity, MYC-negative, treat like Burkitt.
• DA-EPOCH-R preferred for double-hit HGBL, MGZL, and primary mediastinal lymphoma; for CD20-negative plasmablastic lymphoma use DA-EPOCH without rituximab.
• MGZL: between cHL and PMBL; young males with anterior mediastinal mass; CD30+, variable CD15/CD20; prognosis worse than either parent entity.
• Plasmablastic: CD20-negative, so rituximab is ineffective; HIV/oral-cavity association.
• PEL: HHV-8+ body-cavity effusions typically without a mass (extracavitary PEL can form tissue masses), very aggressive.
• Double-expressor (IHC) is not the same as double-hit (FISH); distinct entities, different prognoses.