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. 2025 Dec 2;2025(1):547-554. doi: 10.1182/hematology.2025000748C

All shades of gray in the mediastinum: do we have bright ideas about how to diagnose and treat mediastinal gray zone lymphoma in the era of targeted agents?

Clémentine Sarkozy 1,✉, Alexandra Traverse-Glehen 2
PMCID: PMC12897939  PMID: 41347974

Visual Abstract

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Abstract

Mediastinal gray zone lymphoma (MGZL) is defined in the international World Health Organization classification as a B-cell lymphoma with overlapping clinical, morphological, immunophenotypic, and molecular features between primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (CHL), particularly nodular sclerosis CHL (NSCHL). Recent molecular studies have highlighted the similarities between these 3 entities, relying on immune escape, JAK-STAT, and nuclear factor-κB pathway alterations without specific features related to MGZL. These studies shed light on the different pathobiology of extramediastinal cases, leading to the conclusion that these cases are generally better classified as diffuse large B-cell lymphoma (DLBCL)-not otherwise specified. The absence of Epstein-Barr virus (EBV) on the biopsy is also a desirable criterion, leading to the differential diagnosis of EBV-positive DLBCL. Most studies reporting clinical and treatment data suggest that more intensive induction regimens provide greater disease control compared to standard regimens. Given the paucity of dedicated clinical trials, it remains unknown if, and when, the evolving therapeutic options of PMBL and NSCHL will become available to those with MGZL, offering novel immune-based treatments to these patients with a higher risk of primary chemorefractory disease.

Learning Objectives

  • Diagnose mediastinal gray zone lymphoma in the context of a mediastinal mass

  • Discuss first-line treatment strategies

  • Learn end-of-treatment disease assessment methods

  • Discuss the options for patients with relapsed/refractory MGZL

CLINICAL CASE

On 23 November 2020, a case was referred to our pathology department for review. Unfortunately, no clinical information was provided. At the microscopic level, at low magnification the morphology suggested Hodgkin lymphoma with the presence of large Hodgkin and Reed-Sternberg cells. Atypical cells were scattered or grouped in small, sometimes cohesive, clusters. Atypical cells were mixed with a background of small lymphocytes, histiocytes, and rare plasmacytes, without polynuclear eosinophils. The immunohistochemistry performed showed that the atypical cells expressed CD45, CD30, and CD15 with a strong and diffuse expression of CD20 and PAX5 on all tumor cells. A diagnosis of mediastinal gray zone lymphoma (MGZL) with classical Hodgkin lymphoma (CHL)-like features was suggested by the referring pathologist, but some key elements were lacking, preventing the reviewer from confirming this diagnosis. Fortunately, the presence of a large excisional biopsy allowed additional analysis.

The definition of MGZL

Included in the World Health Organization (WHO) classification of hematologic malignancies in 2008 as a provisional and in 2016 as a definitive entity,1 the definition of “Gray Zone lymphomas between Hodgkin lymphoma and large B-cell lymphoma” was refined in 2022 to “mediastinal gray zone lymphoma (MGZL).”2

The clinical and molecular similarities between primary mediastinal B-cell lymphoma (PMBL) and nodular sclerosis CHL (NSCHL) include an anterior mediastinal involvement and comparable gene expression profile (GEP) reflecting JAK-STAT, nuclear factor-κB pathways activation, and features of immune evasion resulting from characteristic abnormalities found at comparable frequencies,3-5 despite distinct morphology and immunophenotype.2 GZL was first described in 1998, when 5 cases of PMBL exhibiting features overlapping with NSCHL were reported,6 later confirmed in a series from the National Institutes of Health.7 The initial classifications (2008-2016) described cases of “B cell lymphoma unclassifiable, with features intermediate between DLBCL [diffuse large B-cell lymphoma] and cHL,” including those mediastinal GZL cases with features intermediate between PMBL and NSCHL.8-10 Approximately 70% of cases were classified as CHL-like (Figure 1), with a morphology more reminiscent of NSCHL but containing clusters of large cells that, importantly, express CD20, CD79a, and other B-cell markers such as the transcription factors PAX5, OCT2, and BOB1. The remaining 30% had a PMBL-like morphology (Figure 2), with a more diffuse infiltration of large tumor cells that have partially lost B-cell markers and strongly express CD30, with or without CD15. Within individual biopsies, heterogeneous areas or transitional zones between these 2 typical morphologies may be observed.8-10 Importantly, these classifications only partially addressed key aspects, such as the presence of cases without mediastinal involvement and/or with Epstein-Barr virus-encoded small RNAs (EBER)-in situ hybridization (ISH) positivity, which raises questions about the differential diagnosis with Epstein-Barr virus (EBV)-positive DLBCL with GZ-like features.11

Figure 1.

Figure 1.

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Classical Hodgkin lymphoma (CHL)-like case. CHL-like morphology of mediastinal gray zone lymphoma (MGZL) with numerous large, atypical Hodgkin-like cells, sometimes in sheets, in an inflammatory background. (A) growth  ×  1.25; (B), growth  ×  20; (C) growth  ×  20. Tumor cells express by immunohistochemistry CD30 (D), CD20 (E), and CD79A (F).

Figure 2.

Figure 2.

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Primary mediastinal B cell lymphoma (PMBL)-like case. Diffuse infiltration of large, atypical cells with clear cytoplasm. (A) growth  ×  10, with a weak PAX5 expression. (B) absence of CD20 expression on tumor cells (C), but with the expression of CD30 (D) and CD15 (E).

Clarification of diagnosis criterion thanks to molecular biology (Figure 3)

Figure 3.

Figure 3.

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Integration of clinical, immunopathological, and molecular features to refine the diagnosis of MGZL. * There is no consensus on the precise definition of PEMGZL. A diagnosis of PEMGZL should be applied very restrictively. Cases that share morphological and/or immunophenotypic features with MGZL outside the mediastinum are generally better classified as DLBCL-NOS.2 ** These data are derived from a small number of cases and require further studies. CNV, copy number variations; DLBCL, diffuse large B-cell lymphoma; EBER, Epstein-Barr virus-encoded small RNAs; GEP, gene expression profiling; MGZL, mediastinal gray zone lymphoma; NOS, not otherwise specified; NS-CHL, nodulosclerosis classical Hodgkin lymphoma; PEMGZL, primary extramediastinal GZL; PMBL, primary mediastinal B-cell lymphoma; SNV, single nucleotide variant.

In the past 5 years, an international collaborative effort deciphered the molecular landscape of GZL, leading to clarification of the definition now restricted to “Mediastinal GZL, a B-cell lymphoma with overlapping clinical, morphological, immunophenotypic, and molecular features between PMBL and CHL, particularly NSCHL.” Indeed, these different studies highlighted genetic and epigenetic links between NSCHL, MGZL, and PMBL. As PMBL or NSCHL, MGZLs frequently harbor 9p24.1 rearrangements,12,13 leading to programmed cell death 1 ligand 1 and 2 overexpression or 16p13.13 rearrangements involving the CIITA transcription factor, as well as B2M mutations, resulting in the loss of major histocompatibility complex class I and II expression. This places immune evasion at the center of the pathophysiology of these lymphomas. Alterations in the JAK-STAT and NF-κB pathways (such as REL gains) or nuclear transport mechanisms are also commonly observed, with some of the most frequently mutated genes including SOCS1, TNFAIP3, NFKBIE, GNA13, and XPO1. Although no molecular abnormality specific to MGZL has been identified,13 GEP studies highlighted a signature characterized by a macrophage-rich infiltrate, differentiating MGZL from both NSCHL and PMBL.14,15 Mirroring the dichotomy of PMBL vs DLBCL developed a decade before,16 these biological studies have refined the classification of MGZLs, consolidating cases with mediastinal involvement while excluding most cases without, referred to as primary extramediastinal GZL (PEMGZL) for which no clear consensus on the definition currently exists. Indeed, the differences in GEP, as assessed by LymphC3X assay,13,15 and the mutational profiles between mediastinal and extramediastinal cases resemble those observed between PMBL and DLBCL.16 EBV was also highlighted as a strong driver in the GEP and mutational landscape of positive cases, showing a clear distinction with EBV-negative MGZL, PMBL, and NSCHL cases compared to EBV-positive cases, leading to the exclusion of EBV-positive cases in the diagnosis criteria for MGZL. Importantly, in most instances these concern immunodeficiency/dysregulation-associated EBV plus DLBCL and, more rarely, EBV-positive DLBCL-not otherwise specified (NOS).2 A more recent GEP study attempted to classify MGZL cases as PMBL-like or CHL-like using both tumor and tumor microenvironment–related genes,17 but the result was not significant enough to justify its use in clinical practice.

CLINICAL CASE (continued)

In the presented case, some important features are lacking to confirm a diagnosis of MGZL. First, the presence of an anterior mediastinal involvement and the absence of an immunodeficiency context and, second, EBER ISH to rule out the diagnosis of an EBV-positive DLBCL with GZL-like features.11 Finally, different B-cell markers should be tested, as at least 3 B-cell markers should be positive to assess the diagnosis of MGZL (see below). In this case, positivity for CD79a, OCT2, and/or BOB1 would need to be assessed.

WHO guidance on diagnosis criteria

The recent WHO classification mentioned essential and desirable criteria for the diagnosis of MGZL and provided guides in the differential diagnosis of PMBL and CHL (Supplementary Table 1).18

Table 1.

Prospective and retrospective series on mediastinal gray zone lymphoma treatment strategies

Reference N Age Treatment ORR/CRR EFS/OS Comment
Wilson et ala,34 24 33 (14-59) DA-EPOCH-R 100%/79% 5-y EFS, 63%;
5-y OS, 74%		 Prospective trial: MGZL has poorer outcomes compared to PMBL
Sarkozy et al25 99 32 (13-84) R-CHOP/R-ACVBP/
ABVD/eBEACOPP		 80%/73% 3-y EFS, 63%;
3y OS, 80%		 An intensified regimen provides better outcomes than ABVD
Pilichowska et al26 25 37 (19-72) R-CHOP/ABVD/
DA-EPOCH-R		 60%/56% 3-y PFS, 39%;
3-y OS, 95%		 R-CHOP regimen provides better outcomes than ABVD
Chihara et al27 16 39 (19-64) R-CHOP/ABVD/
DA-EPOCH-R		 69%/69% 2-y PFS, 42%;
2-y OS, 93%		 DA-EPOCH-R regimen provides better outcomes than ABVD
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a

The only prospective study in the first line.

ABVD, adriamycin-bleomycin-vinblastine-dacarbazine; CRR, complete response rate; DA-EPOCH-R, etoposide-prednisone-oncovin-cyclophosphamide-doxorubicin; eBEACOPP, doxorubicin-bleomycin-cyclophosphamide-etoposide-procarbazine-prednisone; EFS, event-free survival; MGZL, mediastinal gray zone lymphoma; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; PMBL, primary mediastinal B-cell lymphoma; R-ACVBP, cyclophosphamide-doxorubicin-vindesine-bleomycin-prednisone; R-CHOP, cyclophospha  mide-doxorubicin-oncovin-prednisone.

  • Essential for CHL-like MGZL: confluent growth of pleomorphic cells within a variably abundant microenvironment and dense fibrotic stroma; uniform strong expression of CD20, PAX5, and at least 1 additional B-cell marker (CD19, CD79a, BOB1, OCT2); positive expression of CD30, with varying intensity.

  • Essential for PMBL-like MGZL: monomorphic sheets of medium- sized to large neoplastic cells within a variably dense fibrotic stroma; strong and uniform positive expression of CD30 and partial or complete loss of B-cell markers or strong CD15 expression.

  • Desirable for both:

    • ◦ Because the complex histological features are often not reliably identifiable in core needle biopsies, a larger excisional biopsy is strongly preferred for the diagnosis.

    • ◦ Absence of EBV.

In routine clinical practice, molecular (GEP or next-generation sequencing) workups are not needed, as they are not helpful for the diagnosis of MGZL.

Clinical presentation and initial staging of MGZL

Patients are typically young, with a median age of 30 years, but without a female predominance as reported in PMBL. They present with a bulky anterior mediastinal mass, often with pleural extension and a not uncommon superior vena cava syndrome. PEMGZL are rare and, as opposed to MGZL, present with a disseminated disease (spleen, liver, and/or bone marrow involvement). Given the absence of consensus on their precise definition,2 the diagnosis of PEMGZL should be applied very restrictively, considering a classification as DLBCL-NOS.

Staging should rely on a positron emission tomographic-computed tomographic (PET-CT) exam and a lumbar puncture with cerebrospinal fluid analysis to rule out a meningeal involvement, which is likely associated with a very poor outcome, as in PMBL.19 Fitness and the ability to receive dose-dense chemotherapy regimens should be carefully assessed, particularly in older adult patients.

CLINICAL CASE (continued)

In the clinical case, the patient was a 25-year-old man who presented with a large anterior mass (stage II, bulky). He was referred to our department for first-line treatment and discussed in the lymphoma tumor board.

First-line strategies for MGZL (Figure 4)

Figure 4.

Figure 4.

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How I diagnose and treat MGZLs. ADC, antibody drug conjugate; ASCT, autologous stem-cell transplant; BReCADD, doxorubicin-cyclophosphamide-etoposide-dacarbazine-prednisone; BV, brentuximab-vedotin; BV-AVD, adriamycin-vinblastine- dacarbazine; CAR-T, chimeric antigen receptor T cell; CMR, complete metabolic response; CPI, checkpoint inhibitor; DA-EPOCH-R, etoposide-prednisone-oncovin-cyclophosphamide-doxorubicin; DS, Deaville score; eBEACOPP, doxorubicin-bleomycin- cyclophosphamide-etoposide-procarbazine-prednisone; EOT, end of treatment; ICT, immuno-chemotherapy; IHC, immunohistochemistry; mAB, monoclonal antibody; PET-CT, positron emission tomography-computed tomography; R-CHOP, cyclophosphamide- doxorubicin-oncovin-prednisone; R, rituximab; RR, relapsed and refractory.

The therapeutic strategy for MGZL presents a clear challenge: Should these patients be treated with a CHL-like (eg, ABVD [adriamycin-bleomycin-vinblastine-dacarbazine]/ BEACOPPesc [doxorubicin-bleomycin-cyclophosphamide-etoposide-procarbazine-prednisone],20 eventually incorporating novel strategies such as BrECADD [doxorubicin-cyclophosphamide-etoposide-dacarbazine-prednisone],21 BV-AVD [with brentuximab-vedotin] or nivo-AVD [with nivolumab]) or a PMBL-like regimen,22 incorporating anti-CD20, and eventually novel antibody conjugates such as polatuzumab-vedotin?23 Importantly, these novel approaches have not been assessed or reported in MGZL and may not be widely available.

Given the rarity of this entity (<1% of all B-cell non-Hodgkin lymphomas), prospective and retrospective studies are extremely limited (Table 1).24 However, available data suggest that MGZL carries a worse prognosis compared to NSCHL or PMBL, with 35% to 40% of patients are primary- refractory to immuno-chemo.24-27 This might be partially due to the therapeutic approach employed. Indeed, the 3 largest retrospective series reported lower response rates and progression-free survival (PFS) with ABVD compared to more intensive regimens also incorporating immunotherapy with anti- CD20 antibodies (DA-EPOCH-R [etoposide-prednisone-oncovin-cyclophosphamide-doxorubicin], R-ACVBP [cyclophosphamide-doxorubicin-vindesine-bleomycin-prednisone], or R-CHOP-14 [cyclophosphamide-doxorubicin-oncovin-prednisone]).28 These data echo findings in PMBL,29 in which more intensive strategies such as R-CHOP-14, DA-EPOCH-R,30 or R-ACVBP improve survival compared to R-CHOP-21 (cyclophosphamide-doxorubicin-oncovin-prednisone).31 In a retrospective series, the dose-dense CHL-like escBEACOPP regimen also provided better outcomes compared to ABVD. But importantly, the worse prognosis of MGZL compared to PMBL cannot be attributed solely to the treatment choice, as the prospective study on DA-EPOCH-R reported a complete response (CR) rate of 79% vs 100%, and 5-year event-free survival (EFS) as 63% vs 95% for MGZL and PMBL patients, respectively.24 So far, no data on the efficacy of BrECADD, BV-AVD, or nivo-AVD regimens have been reported; however, given the biological rationale, namely CD30 expression and the presence of 9p24 rearrangement, it can be assumed that these regimens, if available, should be effective for MGZL.

Overall, the first-line treatment should comprise a monoclonal antibody targeting the appropriate (ie, present) cell surface antigen (ie, CD20 or CD30) in combination with a dose-dense chemotherapy regimen (Table 2). Prospective data comparing face-to-face immunochemotherapy (ICT) regimens based on anti-CD20 vs anti-CD30 immune agents would be of great value to the community.

Table 2.

First-line options for MGZL

Regimen CHL-like vs PMBL-like regimen Chemotherapy Immunotherapy Chemotherapy intensified regimen
ABVD CHL-like Adriamycin
Bleomycin
Vinblastine
Dacarbazine		 No No
R-CHOP 21 days PMBL-like Cyclophosphamide
Doxorubicin Oncovin
Prednisone		 Anti-CD20 No
R-CHOP 14 days PMBL-like Cyclophosphamide
Doxorubicin Oncovin
Prednisone		 Anti-CD20 Yes
R-ACVBP PMBL-like Cyclophosphamide
Doxorubicin Vindesine
Bleomycin
Prednisone		 Anti-CD20 Yes
DA-EPOCH-R PMBL-like Etoposide
Prednisone
Oncovin
Cyclophosphamide
Doxorubicin		 Anti-CD20 Yes
escBEACOPP CHL-like Doxorubicin
Bleomycin
Cyclophosphamide
Etoposide
Procarbazine
Prednisone		 No Yes
BrECADD CHL-like Doxorubicin
Cyclophosphamide
Etoposide
Dacarbazine Prednisone		 Anti-CD30 Yes
BV-AVD CHL-like Adriamycin
Vinblastine
Dacarbazine		 Anti-CD30
(brentuximab-vedotin)		 No
Nivo-AVD CHL-like Adriamycin
Vinblastine
Dacarbazine		 Anti-PD1 No
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Importantly, among the listed regimens, ABVD should not be considered as a first-line treatment (listed here for comprehensiveness), and some regimens might not be available depending on specific country approvals (such as BReCADD, BV-AVD, and Nivo-AVD).

BV, brentuximab-vedotin; CHL, classical Hodgkin lymphoma; MGZL, mediastinal gray zone lymphoma; Nivo, nivolumab; PMBL, primary mediastinal B-cell lymphoma.

In line with CHL and PMBL, end-of-treatment response assessment should be based on PET-CT evaluation. For patients achieving a complete metabolic remission during first-line treatment, neither high-dose chemotherapy followed by autologous stem cell transplant nor consolidative radiation therapy appears to provide additional benefit,25 similar to the situation for PMBL patients.25,32

As an expert opinion, interim PET-CT imaging and a de-escalated approach for patients treated with eBEACOPP or BrECADD and with a negative PET-2 could be applied (per AHL-2011/HD18-21 in disseminated CHL) but has not been prospectively evaluated in this setting.20 For all patients (ie, whatever the choice of the first line), interim PET-CT imaging should be performed after 4 cycles, to identify refractory patients, and at the end of the treatment schedule (if 6 cycles). Importantly, a positive PET-CT after 4 or 6 cycles should lead to a biopsy to confirm (or rule out) the presence of the lymphoma, given the potential false PET-CT positivity as observed in PMBL. A description of the residual histology and phenotype is needed to guide the second-line options and exclude the diagnosis of a sequential/ composite lymphoma.33

Finally, predictive factors, such as lymphocyte count, Eastern Cooperative Oncology Group - Performance Status, anemia, B symptoms, albumin level, CD15 expression, dendritic cell-specific ICAM-grabbing non-integrin, where ICAM is an intercellular adhesion molecule (DC-SIGN) positive cells, and mutation burden have mainly been reported in univariate analyses and/or in retrospective series and are not currently included in clinical decision-making.13,25,26,34

CLINICAL CASE (continued)

In the lymphoma tumor board, 6 cycles of R-CHOP-14, given the strong positivity of CD20 on tumor B cells, vs 6 escBEACOPP were discussed (BV was not available in this specific situation). R-CHOP-14 was finally decided upon. The disease was initially well controlled, with a reduction of 80% of the SUVmax (maximum standardized uptake value) and a Deauville score of 4 at midinduction (4 cycles), with a residual uptake (SUVmax) lower than 5. Given the high delta SUV and the low residual uptake, the patient was considered in response, and it was decided not to perform a biopsy, following recommendations on PMBL.19 At the end of induction, the residual mass showed a slight increase in the uptake (SUVmax, 5.8). The patient had a needle biopsy that showed necrosis and no vital lymphoma cells. Another PET-CT image 6 weeks afterward showed an increase in the fluorodeoxyglucose uptake (6.8), and a surgical biopsy finally showed the presence of lymphoma cells.

Salvage options for MGZL

In cases of refractory disease, even if localized, radiation does not appear to provide sufficient disease control in more than half of patients,34 and if a biopsy highlights an active disease, a systemic salvage option should be preferred.

The field lacks evidence-based data for MGZL, and recommendations rely on expert opinion (Figure 4). In relapsed or refractory disease, ICT regimens incorporating platinum-based agents, followed by autologous stem-cell transplant in cases of chemosensitive disease, appear to result in long-term responses in nearly 70% of chemosensitive cases in a retrospective series performed almost 10 years ago.25

Importantly, the recent advances in the pathophysiological understanding of MGZL, reinforcing its classification within the “mediastinal” lymphoma group, provide a rationale for combination strategies based on checkpoint inhibitors (CPI) approved in NSCHL and PMBL and/or anti-CD30 antibody-drug conjugate (BV), depending on the treatment applied in the first line. Initially reported in case studies, responses to nivolumab or pembrolizumab are highly encouraging, prompting a prospective trial (NCT03255018).35 As in PMBL, BV has shown responses when used as monotherapy, but of limited duration.36 However, the combination of CPI with BV appears extremely promising, with a 70% overall response rate and a 50% CR rate in a recent phase 2 study,37 making this strategy a treatment of choice in the context of chemorefractory disease for MGZL (this combination has not been approved by the European Union in second line, but is part of National Comprehensive Cancer Network guidelines for PMBL). The efficacy of anti-CD19 chimeric antigen receptor (CAR) T-cell–based therapy for relapsed and refractory (RR) PMBL patients supports its potential as a treatment option for CD19-positive MGZL.38,39 In the future, the discussion of T-cell engager (anti-CD20-CD3 bispecific) and CAR-T cell therapy will likely rely on the precise phenotype (CD19, CD20, CD30) of the MGZL considered and on their potential access. Importantly, phase 2 studies assessing the activity of novel agents should allow the inclusion of MGZL based on a specific immunohistochemistry and/or genomic criteria to be able to generate guidelines based on evidence data, and not only biologically driven assumptions. For localized RR disease, a consolidation (in case of response after a systemic salvage) based on involved site radiation, as in RR PMBL, is also an option, if not previously administered.

CLINICAL CASE (continued)

The relapse biopsy showed a CD20−, CD79a+, OCT2+, BOB1+, CD30+ MGZL with CHL-like morphology despite a previously “negative” core-needle biopsy, highlighting the need the perform a surgical biopsy whenever possible. At that time, data on BV and CPI combinations were not available, and the patient was salvaged with BV combined with ifosfamide-carboplatin- etoposide,40 reached a CR, and received an intensification by BCNU (carmustine), etoposide, ara-C, melphalan (BEAM regimen) followed by autologous stem-cell transplant. Four years later, he remains in CR.

Conclusion

MGZL is a rare entity, in which recent molecular analyses have led to a better understanding of the pathogenesis and a consensual classification relying on clinical and immunopathological criteria that excludes EBV-positive and extramediastinal cases from the spectrum. Given the rarity of the disease, the diagnosis should still rely on an expert opinion and a surgical biopsy. Treatment should be discussed based on IHC features and should comprise a monoclonal antibody targeting the appropriate cell surface antigen (ie, CD20 or CD30, keeping in mind that the availability might vary in different countries) in combination with a dose-dense chemotherapy regimen. It is to be hoped that recent advances in the treatment of first-line CHL and/or PMBL will soon reach the field of MGZL.

Conflict-of-interest disclosure

Clémentine Sarkozy: none to disclose.

Alexandra Traverse-Glehen: none to disclose.

Off-label drug use

Clémentine Sarkozy: nothing to disclose.

Alexandra Traverse-Glehen: nothing to disclose.

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