Short answer: Mediastinal gray zone lymphoma (MGZL) is a rare large B-cell lymphoma of young adults that sits between nodular sclerosis classical Hodgkin lymphoma (cHL) and primary mediastinal B-cell lymphoma (PMBCL). It is a pathology diagnosis that needs expert hematopathology review, it has no single standard regimen, and most centers treat it with an aggressive, PMBCL-style approach such as DA-EPOCH-R. In the only prospective trial (24 patients), DA-EPOCH-R produced 62% event-free survival and 74% overall survival at a median of 59 months, which is worse than what we expect in PMBCL. This guide is written for fellows and residents who need to recognize it, explain it on the boards, and know what the evidence actually says.
Author and disclosure: Roupen Odabashian, MD, FRCPC, Oncologist and founder of MeDucation AI. I am the founder of MeDucation AI, which sells hematology and oncology board preparation. I have no other financial relationships relevant to the studies discussed here. This article is educational and is not a substitute for individualized clinical judgment or tumor board discussion.
What is gray zone lymphoma?
Gray zone lymphoma is a B-cell lymphoma whose morphology and immunophenotype overlap between cHL and a large B-cell lymphoma. The mediastinal form is the one you will be tested on. It typically presents in young adults with a large anterior mediastinal mass, and some patients present with superior vena cava syndrome, pleural or pericardial effusion, or phrenic nerve involvement. A 2024 case series described PET avid bulky masses of 9 to 17 cm with SUVmax values near 20 and noted an estimated incidence of about 0.5 per million person years.
Under the WHO 5th edition, mediastinal gray zone lymphoma is retained as an entity. Similar cases that arise outside the mediastinum are no longer grouped as gray zone lymphoma and are classified as diffuse large B-cell lymphoma, not otherwise specified. Older sources still say "B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma," so know both names for exam day.
The biology supports a true intermediate category rather than simple diagnostic uncertainty. A methylation profiling study found that MGZL cases clustered together and apart from both nodular sclerosis cHL and PMBCL, regardless of whether the morphology looked more Hodgkin-like or more large cell. Shared genetic features across the three entities include 9p24 alterations involving JAK2, PD-L1 and PD-L2, and changes at the CIITA locus.
How does it differ from primary mediastinal B-cell lymphoma and classical Hodgkin lymphoma?
The distinction rests on the combination of morphology and immunophenotype, and the key trap is a discordant pair: Hodgkin-like histology with a B-cell program, or large cell histology with a Hodgkin program. Strong, uniform CD20 in what looks like cHL should trigger a full panel.
Feature | Classical Hodgkin lymphoma (nodular sclerosis) | Mediastinal gray zone lymphoma | PMBCL |
|---|---|---|---|
Typical age | Young adults | Young adults (median about 32 in the largest series) | Young adults, female predominant |
Morphology | Reed-Sternberg cells in a polymorphous, fibrotic background | Sheets of large cells in an inflammatory, fibrotic background, or composite of both | Large cells with clear cytoplasm and compartmentalizing fibrosis |
CD30 | Positive | Positive | Weak and heterogeneous |
CD15 | Usually positive | Variable, can be strongly positive | Usually negative |
CD20 and B-cell program (OCT2, BOB1, PAX5) | CD20 weak or absent, B-cell program usually lost | Often strong CD20 with OCT2 and BOB1 in Hodgkin-like cases; B-cell markers can be lost in large cell cases | Positive |
EBV | Variable | 16% positive in the LYSA series | Usually negative |
Usual treatment | ABVD or BV-AVD | No standard; DA-EPOCH-R most common outside trials | DA-EPOCH-R or R-CHOP with or without radiotherapy |
Treat the table as a study aid rather than a diagnostic algorithm. The final call belongs to hematopathology, and review by an expert with access to a full immunohistochemistry panel is worth requesting.
How is gray zone lymphoma diagnosed?
Diagnosis requires an adequate tissue biopsy, ideally an excisional or generous core biopsy of the mediastinal mass, because fine needle aspirates and small cores often mislead in a fibrotic, necrotic background. The pathology workup usually includes CD20, CD79a, PAX5, OCT2, BOB1, CD30, CD15, CD45, MUM1, BCL6, CD10 and EBV testing. Staging follows lymphoma conventions with PET-CT, and baseline cardiac assessment matters before anthracycline therapy in a patient with a large mass and effusion.
In the Lymphoma Study Association (LYSA) series, 204 cases were centrally reviewed and 165 met pathological criteria for MGZL, which tells you how often local diagnoses are revised on expert review. Among 99 patients in the outcome analysis, 64 had Hodgkin-like morphology with a PMBCL-like phenotype, 30 had PMBCL-like morphology with a Hodgkin-like phenotype, and 5 were composite.
How is mediastinal gray zone lymphoma treated?
There is no consensus standard. Treatment has historically mirrored PMBCL, and the options reflect that uncertainty.
Study | Design | Patients | Regimen | Key result |
|---|---|---|---|---|
Wilson et al., Blood 2014 (NCI) | Prospective phase 2 | 24 untreated | DA-EPOCH-R | EFS 62% and OS 74% at median follow-up of 59 months; 19 complete and 5 partial responses |
Sarkozy et al., Haematologica 2017 (LYSA) | Retrospective | 99 | Hodgkin-like (ABVD or escBEACOPP) in 43%; DLBCL-like (mainly R-CHOP or R-ACVBP) in 57% | 3-year EFS 63% and OS 80%; dose-intensive 3-year EFS 74% vs 48% with standard regimens (HR 0.38); rituximab did not improve EFS or OS; 28% primary refractory |
Retrospective series summarized in a 2023 review | Retrospective | Not stated | CHOP with or without rituximab, ABVD with or without rituximab, DA-EPOCH-R | Overall response rates of about 65%, 60% and 70% |
Nivolumab plus brentuximab vedotin (CheckMate 436 cohort, as summarized in the same review) | Phase 2 | 10 | Nivolumab and brentuximab vedotin | ORR 70%, complete remission 50% |
The practical reading is this. First, DA-EPOCH-R is the most common choice outside a trial and has the only prospective dataset, but a 62% event-free survival means roughly a third of patients will need further therapy. Second, the LYSA series suggests dose-intensive approaches may do better than standard ABVD or R-CHOP, but it is retrospective and confounded by who received which regimen, so it generates a hypothesis rather than a rule. Third, in the NCI study, nine patients had active disease at a median of 3 months after therapy and all received involved-field salvage radiotherapy; four remained in continuous remission at 3, 73, 91 and 128 months, so radiotherapy has a role in selected residual or early progressive disease.
For relapsed or refractory disease, CD30 positivity makes brentuximab vedotin a rational option (a CD30-positive B-cell lymphoma substudy included a small number of gray zone patients), and PD-1 blockade is under investigation given the 9p24 biology. One cited analysis reported 2-year overall survival of 88% with stem cell transplant versus 67% without in the relapsed setting, though again in a small retrospective group. Referral to a center with lymphoma expertise and a clinical trial is reasonable at relapse.
What is the prognosis?
Gray zone lymphoma behaves worse than either of its neighbors. A 2011 Haematologica editorial summarized the literature as showing a more aggressive course and poorer outcome than cHL or PMBCL, and the later outcome data are consistent with that. In the LYSA series, 3-year overall survival was 80% and 3-year event-free survival was 63% at a median follow-up of 34 months, with 20 deaths among 99 patients (17 from lymphoma and 2 from treatment toxicity). Primary refractory disease occurred in 28%. Long term follow-up of the prospective cohort is limited, and none of these numbers should be applied mechanically to an individual patient.
What should you remember for the boards?
MGZL is a young adult anterior mediastinal mass with features of both nodular sclerosis cHL and PMBCL.
Look for discordance: Hodgkin-like morphology with strong CD20, or large cell morphology with CD30 and CD15 expression.
Non-mediastinal gray zone presentations are classified as DLBCL, NOS in the WHO 5th edition.
DA-EPOCH-R is the best studied regimen (prospective NCI series), with 62% event-free survival at about 5 years.
CD30 positivity supports brentuximab vedotin in relapsed disease.
To test this material, try the free question set at 5 Free Hematology Board Review Questions, or compare resources in the Hematology Oncology Question Bank Comparison 2026. For a study plan built around the exam blueprint, see ABIM Hematology Board Exam 2026: Blueprint, Format, and Which Resources Are Actually Worth It.
Frequently asked questions
Is gray zone lymphoma Hodgkin or non-Hodgkin lymphoma?
It is classified as a B-cell lymphoma with features intermediate between nodular sclerosis classical Hodgkin lymphoma and primary mediastinal B-cell lymphoma. The distinction matters because treatment mirrors the large B-cell lymphoma approach more than the Hodgkin approach in most centers.
What is the best treatment for mediastinal gray zone lymphoma?
There is no consensus standard. DA-EPOCH-R is the most commonly used regimen outside trials and has the only prospective data, while retrospective data suggest more intensive regimens may be associated with better event-free survival.
Does gray zone lymphoma need radiotherapy?
Radiotherapy is not a routine requirement. In the NCI study it was used as salvage for nine patients with early residual or progressive disease, and some of them achieved durable remission.
Is brentuximab vedotin used in gray zone lymphoma?
It is an option mainly in relapsed or refractory disease because the tumor cells express CD30. Evidence comes from small subgroups and early phase studies.
What is the prognosis of gray zone lymphoma?
In the largest retrospective series, 3-year overall survival was 80% and event-free survival was 63%. Outcomes are generally considered worse than for cHL or PMBCL.
References
Wilson WH, Pittaluga S, Nicolae A, et al. A prospective study of mediastinal gray-zone lymphoma. Blood. 2014;124(10):1563 to 1569. doi:10.1182/blood-2014-03-564906
Bath C. First prospective study of rare lymphoma shows promising but inconclusive results with DA-EPOCH-R. The ASCO Post. September 1, 2014. ascopost.com
Sarkozy C, Molina T, Ghesquieres H, et al. Mediastinal gray zone lymphoma: clinico-pathological characteristics and outcomes of 99 patients from the Lymphoma Study Association. Haematologica. 2017;102(1). haematologica.org
Quintanilla-Martinez L, Fend F. Mediastinal gray zone lymphoma. Haematologica. 2011;96(4):496 to 499. haematologica.org
Uczkowski D, Ashraf H, Cherry M, Dimov N. Gray zone lymphoma: a case report and comprehensive review of literature. Leukemia Research Reports. 2023;19:100372. PMC10242558
Boira I, Chiner E, Onrubia JA, Esteban V. Gray zone lymphoma: the overlap between Hodgkin and non-Hodgkin lymphoma. Archivos de Bronconeumologia. 2024;60(9):602 to 603. archbronconeumol.org
Jacobsen ED, et al. Phase 2 study of brentuximab vedotin in relapsed or refractory CD30 positive B-cell non-Hodgkin lymphoma (SGN35-012). Blood. 2015;125(9):1394 to 1402. doi:10.1182/blood-2014-09-598763
HemOnc.org. Mediastinal gray-zone lymphoma regimens. hemonc.org
