Mediastinal Gray Zone Lymphoma Research Articles

Clinical Features and Treatment Outcomes of Grey Zone Lymphoma (GZL), Unclassifiable B-Cell Lymphoma with Features Intermediate between Diffuse Large B-Cell Lymphoma and Classical Hodgkin Lymphoma - a Real-Life Multicenter Study By the Croatian Cooperative Group for Hematologic Diseases (KroHem)

GZL with features between classical Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma (DLBCL) is a rare entity originally introduced in the 2008 World Health Organization (WHO) classification. GZL has been included in KroHem Lymphoma Treatment Guidelines since 2012. The recommended treatment was induction with escalated BEACOPP (escBEACOPP) in those below 60 y and ABVD in those above 60 y, both in combination with rituximab (R) and consolidation with radiotherapy (RT) for patients with limited or autologous stem cell transplantation (ASCT) in those with advanced-stage disease. We conducted a comprehensive retrospective analysis of GZL patients treated in KroHem centers to evaluate clinical features, treatment outcomes and prognostic factors. GZL diagnoses were confirmed by a hematopathologist from a designated expert center, according to current WHO classification at time of diagnosis. Twenty-three patients were evaluable for analysis, 20 diagnosed de novo, and 3 in relapse (2 after HL, 1 after DLBCL). Fourteen patients (60%) were male; median age was 39 and range 18-78 y. Thirteen (57%) presented with mediastinal GZL (MGZL) and 10 (43%) with non-MGZL (NMGZL). NMGZL patients were older (median 55 versus 31 y, p = 0.0157) and had more frequently high NCCN-IPI scores (9/10 vs 5/13, p = 0.0288). Twelve front-line patients received R-escBEACOPP, 4 DA-R-EPOCH, 1 R-ABVD and 3 R-CHOP-like regimen. Of the 3 patients diagnosed in relapse, 2 were treated with R-ICE and 1 with R-CHOP. Ten patients were irradiated and 9 underwent ASCT as consolidation in 1 st remission. Stem-cell collection was successful in all planned patients, albeit 70% with plerixafor. Sixteen (80%) front-line patients responded to immunochemotherapy, 2 progressed during consolidation. At the end of treatment, 13 patients were in complete and 1 in partial remission for a response rate of 70%. Of the 3 relapsing patients, 2 treated with R-ICE responded, underwent ASCT and are in continuous remission. One patient died of toxicity after ASCT in 1 st remission. After a median survivors follow-up time of 42 months, 6 front-line patients have died and additional 3 progressed. Overall survival (OS) at 4 y is 65% and event-free survival (EFS) 52%. MGZL and NMGZL patients had similar outcomes; OS at 4 y was 69% and 64% (p=0.637) and EFS 52% vs. 50% (p=0.88) respectively. Performance status was a statistically significant prognostic factor (OS at 4 y ECOG grade 0-1 90% vs. ECOG grade 2-4 17%, p<0.001; EFS at 4 y 67% vs. 17% p=0.044). Sex influenced EFS (male 70%, female 33% at 4 years, p=0.050), but not OS (69% vs. 61% p=0.667). Age (< 60 y >), presence of bulky or extranodal disease, stage, anemia, LDH or B2M level did not significantly influence outcomes. Patients treated with R-escBEACOPP had numerically superior outcomes (OS at 4 y 81% vs. 44%, p=0.167; EFS at 4 y 64% vs 38%, p=0.293). Despite the small number of patients, the difference was statistically significant in patients with MGZL; EFS at 4 y was 71% in the group treated with R-escBEACOPP vs 0% in the group treated with other regimens (p=0.021) and OS 100% vs. 0% (p<0.001). In contrast, patients with NMGZL treated with R-escBEACOPP had numerically inferior outcomes in comparison to those treated with other regimens (p=0.127 for OS and p=0.388 for EFS). In conclusion, our data confirm the validity of differentiating between MGZL and NMGZL. MGZL patients might benefit from aggressive therapies designed for HL, such as escBEACOPP, in combination with rituximab. Consolidation with ASCT is feasible, but most patients will need plerixafor to collect sufficient stem cells. Different regimens, as used for DLBCL, should be preferred in NMGZL patients.

Results of an Italian Retrospective Clinical Experience on Mediastinal Gray Zone Lymphoma

Introduction and methods: Mediastinal gray zone lymphoma (GZL) emerged as a rare and challenging entity due to its high rate of pathological reclassification and heterogeneous clinical management. The bio-GZL2020 study was designed to centralize histological samples and clinical data of patients (pts) diagnosed with GZL between 2006 and 2020 in 16 Italian hematological centers. We here report the preliminary clinical results of this retrospective analysis. Results: Overall, we collected samples and clinical data of 68 pts with GZL. According to the 2022 WHO and ICC classifications we excluded nine pts for lacking mediastinal involvement, hence 59 pts were analyzed. Pts were mostly stage I-II (62.7%); 57.6% had a mediastinal bulky disease. The site of diagnostic biopsy was the mediastinum in 29 pts. Additional clinical characteristics at baseline are reported in Table 1. One patient died before the start of treatment and was excluded from survival analysis. First line chemotherapy (CHT) consisted in DA-EPOCH in 31 pts, CHOP-like regimens in 17 pts, ABVD in six pts, MACOP-B in three pts and DHAP in only one case. Eight pts did not receive rituximab with CHT (six ABVD pts, two CHOP-like pts). Dose escalation in R-DA-EPOCH was performed in 75% of pts, with 18 pts (64.3%) attaining level 3 or higher. Four advanced stage, high-risk pts received central nervous system prophylaxis. Twenty-two pts performed an interim PET-scan during first line therapy; data on Deauville score was available in 19 cases, with 9 pts obtaining a score 1-3. Restaging after first line CHT showed 37 pts in complete remission (CR; 63.8%), nine pts in partial remission (PR; 15.5%), five pts in stable disease (SD; 8.6%) and seven pts in progressive disease (PD; 12.1%). Thirty-one pts (53.4%) received a consolidative treatment (26 pts radiotherapy (RT) only, seven pts autologous transplant (ASCT) only, two pts both RT and ASCT). Restaging after first line consolidation showed 43 CR (74.1%), four PR (6.9%), two SD (5.2%) and eight PD (13.8%). Nineteen pts underwent a second line CHT, 16 of them with a platinum-based regimen; brentuximab vedotin, BeGEV and HyperCVAD were used in one patient each. Second line consolidation ASCT was performed in seven pts, while one received an allogeneic transplant. Of the 17 restaged pts after second line CHT seven were in CR, 10 were not responsive (four SD, six PD). Considering all salvage lines five pts received a checkpoint inhibitor, nine underwent brentuximab vedotin treatment. Overall survival (OS) was 86.9% at 5 years and 71.3% at 10 years; beta2-microglobulin (available only in 32 pts) and the response after first line therapy were associated to a statistically significant difference in OS in univariate analysis. Progression-free survival (PFS) was 61.9% at 5 and 10 years. The use of rituximab, the Deauville score 1-3 at interim PET during induction, and the response after first line therapy were associated to a statistically significant difference in PFS in univariate analysis. ABVD was associated to poorer results in terms of OS and PFS although no significant difference was observed. No statistically significant difference in term of PFS was observed between pts treated with intensified regimens (DA-EPOCH, MACOP-B, DHAP) and other treatments in first line. Excluding pts directly shifted to salvage therapy, consolidative RT after first line CHT showed no statistically significance in term of both OS and PFS. Conclusions: To our knowledge our study represents the largest retrospective data collection on GZL among hematological Italian centers. This preliminary analysis did not show a clear advantage of intensive therapies such as DA-EPOCH or MACOPB, while the positive prognostic role of rituximab was confirmed in PFS. The prognostic role of interim PET-CT scan seems interesting and should be evaluated in subsequent trials. Further refinement of the reported results is expected in relation of an ongoing central pathological review by a panel of expert hematopathologists.

The pathobiology of select adolescent young adult lymphomas.

Lymphoid cancers are among the most frequent cancers diagnosed in adolescents and young adults (AYA), ranging from approximately 30%-35% of cancer diagnoses in adolescent patients (age 10-19) to approximately 10% in patients aged 30-39 years. Moreover, the specific distribution of lymphoid cancer types varies by age with substantial shifts in the subtype distributions between pediatric, AYA, adult, and older adult patients. Currently, biology studies specific to AYA lymphomas are rare and therefore insight into age-related pathogenesis is incomplete. This review focuses on the paradigmatic epidemiology and pathogenesis of select lymphomas, occurring in the AYA patient population. With the example of posttransplant lymphoproliferative disorders, nodular lymphocyte-predominant Hodgkin lymphoma, follicular lymphoma (incl. pediatric-type follicular lymphoma), and mediastinal lymphomas (incl. classic Hodgkin lymphoma, primary mediastinal large B cell lymphoma and mediastinal gray zone lymphoma), we here illustrate the current state-of-the-art in lymphoma classification, recent molecular insights including genomics, and translational opportunities. To improve outcome and quality of life, international collaboration in consortia dedicated to AYA lymphoma is needed to overcome challenges related to siloed biospecimens and data collections as well as to develop studies designed specifically for this unique population.

Mediastinal Gray-Zone Lymphoma: Still an Open Issue

The concept of gray-zone lymphoma (GZL) has been progressively refined since its introduction in the literature in 1998. For several years, it was applied to a rather broad spectrum of conditions, posing the problem of the differential diagnosis between any type of Hodgkin lymphoma (HL) and diffuse large B-cell lymphoma, with special reference to primary mediastinal forms (PMBL). Officially recognised as a provisional entity in the 4th and revised 4th editions of the WHO Classification of Tumour of Haematopoietic and Lymphoid Tissues with the term “B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma”, it was limited to tumours showing either morphologic features reminiscent of classic HL (CHL) but carrying a complete B-cell phenotype or conversely provided with a PMBL morphology yet revealing CHL phenotypic characteristics. The definition of GZL has been further revised in the recently published International Lymphoma Classification and 5th edition of the WHO Classification of Haematolymphoid Tumours, which have limited it to mediastinal neoplasms (MGZL) based on emerging molecular evidence. The aim of this review is to critically discuss the issue of MGZL, as well as in light of the suboptimal response to current therapies.

Mediastinal gray zone lymphoma in a pregnant woman presenting with cardiac tamponade

BackgroundMediastinal gray zone lymphoma is a newly recognized rare B cell neoplasm, which is challenging in diagnosis and treatment.Case presentationIn the current study, we aimed to report a 25-year-old pregnant woman at 25 weeks of gestation who presented with chronic cough and progressive shortness of breath, hypotension, tachycardia, and tachypnea. A large circumferential pericardial effusion with compressive effect on the right atrium and right ventricle and a large extracardiac mass with external pressure to mediastinal structures were seen on trans thoracic echocardiography. The emergency pericardiocentesis was performed with the diagnosis of cardiac tamponade. Also, CMR revealed a huge heterogeneous anterior mediastinal mass, and the pathology and the immunohistochemistry of the mass biopsy revealed gray zone lymphoma with positive CD3, CD20, CD30, CD45, PAX5, and negative CD15 expression. Three courses of chemotherapy with the CHOP regimen were performed with an acceptable response every three weeks before delivery. A caesarian section was performed at 37 weeks without any problem for the patient and fetus, and chemotherapy will be started three weeks after delivery.ConclusionCardiac tamponade as an emergency condition occurred in this pregnant patient by malignant pericardial effusion and mediastinal mass pressure. Accurate diagnosis and on time interventions caused a significant improvement and a successful delivery.

Pediatric gray zone lymphoma according to the 2022 WHO classification: An Italian cohort study.

The 2022 World Health Organization (WHO) classification redefines the concept of gray zone lymphoma (GZL), restricting it in practice to cases of mediastinal/thymic origin (mediastinal gray zone lymphoma, MGZL) with overlapping features between primary mediastinal B-cell lymphoma (PMBCL) and classical Hodgkin lymphoma (CHL). Cases with histological characteristics of GZL but occurring without mediastinal involvement are better classified as diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS), with few exceptions. We collected clinical and pathological data about all Italian pediatric patients diagnosed with GZL over a 20-year period. We identified only four cases of bona fide MGZL. All patients were adolescent and presented with a mediastinal disease, always associated with other nodal involvement. B symptoms and increased levels of both erythrocyte sedimentation rate (ESR) and lactate dehydrogenase (LDH) were observed. Only two patients achieved a first complete remission, suggesting a more aggressive clinical behavior than either PMBCL or CHL. Prospective studies evaluating prognostic factors and establishing the most effective first-line therapy for MGZL are highly needed.

Mediastinal Gray Zone Lymphoma

A 50-year-old male presented with cough and breathlessness. A positron emissoin tomography scan revealed FDG (Fluorodeoxyglucose) avid mediastinal mass. Tru-cut biopsy showed fibrotic stromal tissue with cellular infiltrate consisting of abnormal lymphoid cells and few large cells with smudged nucleus. Immunohistochemistry revealed diffuse positivity with CD20, focal positivity for CD30 and rare CD15 positive cells. Histological picture and immune profile showed overlaping features of non-Hodgkin's as well as Hodgkin's lymphoma. A diagnosis of mediastinal gray zone lymphoma was made. The patient showed a complete metabolic response to six cycles of chemotherapy.

Evolution in the definition and diagnosis of the Hodgkin lymphomas and related entities.

Hodgkin lymphoma was the first of the lymphomas to be recognized as a specific disease entity. However, recent studies have highlighted the heterogeneity of the diseases associated with this eponym warranting clarification and refinement of diagnostic terminology. While classic Hodgkin lymphoma (CHL) remains an essentially unchanged diagnostic entity in the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC), nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is now renamed nodular lymphocyte predominant B cell lymphoma (NLPBL) in recognition of the distinct pathologic, biologic, and clinical differences. Fan patterns A, B, and C (sharing the presence of evident follicular structures, and retention of a B cell rich background) will be combined in "typical" or grade 1, while the other "variant" patterns, D, E, and F, are considered grade 2. T-cell/histiocyte-rich large B cell lymphoma (THRBCL) is considered part of the "variant" NLPHL continuum.The entity previously known as "B cell lymphoma, unclassifiable (BCLU), with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL" has been renamed "mediastinal gray zone lymphoma" (MGZL) in recognition of the importance of the thymic niche in the biology of this tumor. The diagnostic criteria for MGZL have been refined and require both a high tumor cell density and a strongly preserved B cell program.This article will describe updates on CHL, NLPBL, and MGZL in the recently published 2022 ICC and provide some useful differential diagnostic clues in cases with atypical morphology or immunophenotype.

HL-367 ASCT for Treatment-Resistant Mediastinal Gray Zone Lymphoma

Gray zone lymphoma (GZL) is a rare type of blood cancer with intermediate characteristics of diffuse large cell B lymphoma (DLCBL) and classical Hodgkin lymphoma (cHL). There is no universal approach to the management of GZL, and resistant cases often remain challenging. To describe a potential treatment for mediastinal GZL (MGZL) resistant to standard chemotherapy regimens based on a clinical case report. A 40-year-old woman was admitted to the hospital with recent onset of generalized itchiness, weakness, fevers, and night sweats. Upon initial standard workup, a CT scan demonstrated a 7 × 4 cm mediastinal mass with irregular borders and several enlarged paraaortic (2 cm), parasternal (4 cm), and aortic bifurcation (2 cm) lymph nodes. The excision biopsy specimen from the mass showed high expressivity of CD30 and moderate expressivity of CD20, CD3, MUM-1, Fascin, and CD79a, with Ki67 detected in 75%-80%. CD15, AE1/3, ALK, PAX-5, CD45, CD19, CD 23, CD68, BOB 1, and PD-1 were negative. The patient was diagnosed with stage IIB MGZL with intermediate features of DLCBL and cHL. Interventions and Main Outcomes: Initial treatment with the R-BEACOPP regimen resulted in some shrinkage in lymph node sizes; however, after the fourth cycle of chemotherapy, a PET-CT scan demonstrated disease progression with Ds5 metabolic activities in the left axillary, mediastinal, and bronchopulmonary nodes, along with left lung consolidation. Salvage therapy with 2 courses of R-DHAP regimen was administered without significant success, as the consequent CT scan demonstrated a tumor size of 9.4 × 5.9 × 7.6 cm with extension to the left lung. This was followed by 3 cycles of BV, resulting in 3-4 months of disease remission. Due to subsequent disease progression, 2 cycles of BvB and 2 cycles of BV-ICE were initiated, followed by autologous stem cell transplantation (ASCT). The procedure resulted in pancytopenia and oral mucositis, both of which were resolved with appropriate treatment. The patient is currently in the third week of follow-up for further management. ASCT may ultimately be a candidate for treatment-resistant MGZL. These findings should be validated in larger studies.

Targeted Mutational Profiling Reveals Clonal Relationships in Metachronous Occurrence of Classic Hodgkin and Mediastinal Large B-Cell Lymphomas.

Classic Hodgkin lymphoma (CHL) patients may infrequently present with a prior or recurrent disease with discordant histology resembling non-Hodgkin lymphomas. These include primary mediastinal large B-cell lymphoma (PMBL), diffuse large B-cell lymphoma (DLBCL), or mediastinal gray-zone lymphoma (MGZL). Such patients are often refractory to standard therapy and their diagnosis is hampered by significant morphologic and immunophenotypic overlap and insufficient molecular data. Among 509 CHL patients seen at an academic medical center, 6 patients had a prior or subsequent diagnosis different from CHL. Paired tissue samples were evaluated by targeted mutational analysis using a 164-gene panel. Our findings show multiple shared variants indicative of a clonal relationship between the CHL and the PMBL, DLBCL, or MGZL diagnoses. Most frequent mutated genes included TNFAIP3 (4 of 6, 66.7%), STAT6 (3 or 6, 50%), ARID1A (3 of 6, 50%), and XPO1 (3 of 5, 60%). Three patients showed the same oncogenic variant within the XPO1 gene (E571K), and mutations in TNFAIP3 and B2M were observed in 2 of the 5 patients with shared variants. In addition, differences in the mutation profile between the lymphoma pairs were also observed, which could represent clonal evolution. Mutational profiling could be of benefit in patients with recurrent/refractory disease with discordant histology, where the clonal relationship could be helpful to inform and guide therapeutic decisions. These findings provide further evidence of a true biological continuum surrounding CHL, PMBL, DLBCL, and MGZL and shed light on underlying genetic events and their clinical impact.

The Grey Zones of Classic Hodgkin Lymphoma

Simple SummaryClassic Hodgkin lymphoma (CHL) is a well-defined lymphoid neoplasm with a minority of characteristic neoplastic cells of B cell origin, namely Hodgkin and Reed–Sternberg cells immersed in a rich reactive inflammatory infiltrate in the background. Although CHL has always been set apart from non-Hodgkin lymphomas, cases with morphological and phenotypic features intermediate between CHL and other lymphomas have been described. Whereas some of these lymphomas only represent morphological mimics, others exhibit mutational and gene expression profiles which overlap with CHL, indicating that these cases, frequently termed grey zone lymphomas, reside on the biological boundary between CHL and large B-cell lymphomas. In the present review, we aim to describe the current knowledge of these rare lymphomas, address diagnostic issues and summarize today’s concepts on the classification of grey zone lymphomas and related tumors.Classic Hodgkin lymphoma (CHL) is a well-defined neoplasm characterized by the presence of a minority of pathognomonic Hodgkin and Reed–Sternberg (HRS) cells in a reactive inflammatory background. Although genotypically of B cell origin, HRS cells exhibit a downregulated B cell program and therefore are set apart from other B cell lymphomas in the current WHO classification. However, cases with morphological and phenotypic features overlapping with CHL have been recognized, and the category of B cell lymphoma—unclassifiable—with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL, also termed grey zone lymphoma, was first introduced into the WHO classification in 2008 as provisional entity. These cases, as well as others raising a differential diagnosis of CHL can present diagnostic problems, as well as therapeutic challenges. Whereas some of these lymphomas only represent biologically unrelated morphological mimics, others, especially mediastinal grey zone lymphoma, exhibit genetic and gene expression profiles which overlap with CHL, indicating a true biological relationship. In this review, we address areas of diagnostic difficulties between CHL and other lymphoma subtypes, discuss the biological basis of true grey zone lymphoma based on recent molecular studies and delineate current concepts for the classification of these rare tumors.

Landscape of 4D Cell Interaction in Hodgkin and Non-Hodgkin Lymphomas.

Simple SummaryLittle is known about the motility and interaction of primary human lymphoma cells in lymph nodes. The aim of this study therefore was to analyze for the first time if there are differences in motility and interaction with bystander cells between different lymphoma types and normal lymph nodes. We observed systematic differences between B cells and PD1-positive T cells. Furthermore, most cases of Hodgkin lymphomas had fast moving PD1-positive T cells, whereas there was little movement in other lymphoma types. Some lymphomas, particularly Hodgkin lymphomas, presented enhanced cell contacts between neoplastic and reactive cells, suggesting a dependency of lymphoma growth on cellular interaction.Profound knowledge exists about the clinical, morphologic, genomic, and transcriptomic characteristics of most lymphoma entities. However, information is currently lacking on the dynamic behavior of malignant lymphomas. This pilot study aimed to gain insight into the motility of malignant lymphomas and bystander cells in 20 human lymph nodes. Generally, B cells were faster under reactive conditions compared with B cells in malignant lymphomas. In contrast, PD1-positive T cells did not show systematic differences in velocity between reactive and neoplastic conditions in general. However, lymphomas could be divided into two groups: one with fast PD1-positive T cells (e.g., Hodgkin lymphoma and mantle cell lymphoma; means 8.4 and 7.8 µm/min) and another with slower PD1-positive T cells (e.g., mediastinal grey zone lymphoma; mean 3.5 µm/min). Although the number of contacts between lymphoma cells and PD1-positive T cells was similar in different lymphoma types, important differences were observed in the duration of these contacts. Among the lymphomas with fast PD1-positive T cells, contacts were particularly short in mantle cell lymphoma (mean 54 s), whereas nodular lymphocyte-predominant Hodgkin lymphoma presented prolonged contact times (mean 6.1 min). Short contact times in mantle cell lymphoma were associated with the largest spatial displacement of PD1-positive cells (mean 12.3 µm). Although PD1-positive T cells in nodular lymphocyte-predominant Hodgkin lymphoma were fast, they remained in close contact with the lymphoma cells, in line with a dynamic immunological synapse. This pilot study shows for the first time systematic differences in the dynamic behavior of lymphoma and bystander cells between different lymphoma types.

HL-047: Mediastinal Gray Zone Lymphoma Successfully Treated with R-BEACOPP

HL-047: Mediastinal Gray Zone Lymphoma Successfully Treated with R-BEACOPP

Determinants of Circulating Tumor DNA Levels across Lymphoma Histologic Subtypes

Background: Cell-free DNA (cfDNA) and circulating tumor DNA (ctDNA) analysis has an emerging diagnostic role in multiple malignancies including lymphomas. As levels of these biomarkers have been correlated with clinical prognosis, knowledge of baseline values could have utility given wide clinical variation among lymphoma subtypes. We examined cfDNA and ctDNA levels for a pooled international cohort representing both classical Hodgkin (cHL) and non-Hodgkin (NHL) lymphomas. In addition, we analyzed corresponding clinical laboratory data for confounding factors.Methods: A total of 196 patients from six centers were analyzed - Stanford University (65), University of Eastern Piedmont (36), the National Cancer Institute (33), Hospital Le Bocage, Dijon (25), MD Anderson Cancer Center (21), and University Hospital Essen (16). Pre-treatment cfDNA concentration was obtained by fluorimetry after DNA extraction. All samples underwent deep sequencing with error correction by CAPP-Seq (Newman et al Nat Biotech 2016). After genotyping, ctDNA levels were calculated as the product of the cfDNA concentration and the mean allelic fraction of somatic single nucleotide mutations. Where available, clinical laboratory data from the time of ctDNA measurement were correlated.Results: Across lymphoma subtypes, total cfDNA levels were observed to distinguish between aggressive and indolent histologies (Fig 1A). The highest cfDNA levels were seen in a statistically distinct subset of aggressive thoracic tumors including mediastinal grey zone lymphoma (MGZL) and primary mediastinal tumors (PMBCL). These did not differ significantly from each other (p>0.999), but were higher than other aggressive lymphomas including diffuse large B cell lymphoma (DLBCL), cHL, and transformed low grade lymphomas (p<0.013 for all comparisons). Follicular lymphoma (FL) and cHL had the lowest median cfDNA levels.Circulating tumor DNA was detected in 97.4% of patients (191/196) with no difference in detection rate by subtype. Median ctDNA level followed a similar distribution to cfDNA, with highest levels in aggressive thoracic MGZL and PMBCL and lowest in FL (Fig 1B). Variation in ctDNA levels was notably broader than cfDNA, with DLBCL varying across a 10-million fold concentration range.To further characterize our DLBCL cohort we separated cases on cell of origin (COO) determined by Hans classification, and by histological transformation status. No difference in cfDNA or ctDNA levels was seen for GCB versus non-GCB histology (Fig 1C), or for de novo versus transformed DLBCL. However, transformed FL had significantly higher levels of both cfDNA and ctDNA than primary FL (Fig 1D, p<0.0001 for cfDNA, p=0.0032 for ctDNA).We correlated our findings with clinical laboratory data for potential confounders. Although cfDNA is renally cleared, we found no significant correlation between serum creatinine and cfDNA level (p=0.77). While the majority of cfDNA originates in the hematologic compartment, we found no significant correlation with WBC (p=0.10) and a negative correlation with hematocrit (p=0.0016) and serum albumin levels (p=0.0003). Confirming prior observations, LDH was positively correlated with cfDNA level (r=0.51, p=0.0004). All described laboratory correlations remained significant after Bonferroni correction.Conclusions: Cell free and ctDNA levels vary significantly across lymphoma histologies, suggesting that both total levels and genotype may play a role in future assays. The highest levels were observed in a subset of aggressive thoracic tumors which may reflect higher disease volumes, proliferative rates, and/or proximity to venous circulation. Minimal variation with renal and hepatic functions reinforces the reliability of cfDNA as a biomarker, while correlations with anemia, hypoalbuminemia, and LDH elevation are likely reflective of inflammatory disease burden.Figure 1: Variation by lymphoma subtype of cfDNA and ctDNA levels.A) A scatter plot demonstrates variation in cell-free DNA (cfDNA) levels across lymphoma subtypes.B) Circulating tumor DNA (ctDNA) levels vary across lymphoma subtypes.C) Neither cfDNA nor ctDNA levels differ significantly between DLBCL cell of origin subtypes.D) Primary and transformed FL display significant variation in cfDNA and ctDNA levels.(hGE/mL: Haploid genome equivalents / mL) [Display omitted] DisclosuresHüttmann:Bristol-Myers Squibb, Takeda, Celgene, Roche: Honoraria; Gilead, Amgen: Other: Travel cost. Casasnovas:BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Westin:Novartis Pharmaceuticals Corporation: Membership on an entity's Board of Directors or advisory committees; Apotex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees. Gaidano:Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Advani:Juno Therapeutics: Consultancy; Bayer Healthcare Pharmaceuticals: Research Funding; Infinity: Research Funding; Gilead: Consultancy; Celgene: Research Funding; Spectrum: Consultancy; Millennium: Research Funding; FortySeven: Research Funding; Kura: Research Funding; Genentech: Research Funding; Cell Medica: Research Funding; Janssen: Research Funding; Seattle Genetics: Research Funding; Nanostring: Consultancy; Regeneron: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pharmacyclics: Consultancy; Merck: Research Funding; Agensys: Research Funding; Sutro: Consultancy; Pharmacyclics: Research Funding. Diehn:Roche: Consultancy; Novartis: Consultancy; Quanticel Pharmaceuticals: Consultancy; Varian Medical Systems: Research Funding. Alizadeh:CiberMed: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Roche: Consultancy; Gilead: Consultancy.

Mediastinal Lymphoproliferative Disorders.

Lymphoproliferative disorders comprise 50% to 60% of all mediastinal malignancies in both children and adults. Primary mediastinal involvement is rare (∼5%), whereas secondary mediastinal involvement by systemic disease is more common (10% to 25%). Primary mediastinal disease is defined as involvement by a lymphoproliferative disorder of mediastinal lymph nodes, the thymus, and/or extranodal mediastinal organs without evidence of systemic disease at presentation. In this review, the clinical, radiologic, histopathologic, immunohistochemical, and genetic features of some of the most characteristic mediastinal lymphoproliferative disorders are presented. The entities discussed here include: classic Hodgkin lymphoma with emphasis on nodular sclerosis and mixed cellularity types, and non-Hodgkin lymphomas, including primary mediastinal (thymic) large B-cell lymphoma, mediastinal gray zone lymphoma, mediastinal diffuse large B-cell lymphoma, thymic marginal zone lymphoma, mediastinal plasmacytoma, T-lymphoblastic lymphoma, and anaplastic large cell lymphoma. Although not a malignant process, hyaline vascular Castleman disease is also discussed here as this disorder commonly involves the mediastinum. Despite multiple advances in hematopathology in recent decades, the day-to-day diagnosis of these lesions still requires a morphologic approach and a proper selection of immunohistochemical markers. For this reason, it is crucial for general pathologists to be familiar with these entities and their particular clinicoradiologic presentation.

Primary Mediastinal (Thymic) Large B-Cell Lymphoma: Fidelity of Diagnosis Using WHO Criteria

PurposeDiagnosing primary mediastinal (thymic) large B-cell lymphoma (PMBCL) is challenging because it is a clinicopathologic entity that shares characteristics with other lymphomas and lacks pathognomonic features. We sought to investigate the fidelity between a working diagnosis of PMBCL at our institution and the clinicopathologic criteria established within the 2017 World Health Organization (WHO) classification. Patients and MethodsMedical records and archived tissue of patients treated for stage I-II PMBCL from 1998 to 2018 were retrospectively reviewed for clinical and pathologic conformity with current WHO criteria. Disease was characterized as definitely PMBCL if all of the following were present: anterior mediastinal mass with or without lymph node involvement, no extranodal disease, B-cell antigen expression, Epstein-Barr virus negativity, and at least one supportive feature: female gender under age 40, bulky primary tumor, CD30 weakly positive, compartmentalizing alveolar fibrosis, lack of surface immunoglobulin expression, and MUM1 or CD23 positivity. Disease without supportive features or other pathologic findings more suggestive of other entities was characterized as equivocal for PMBCL. Lack of an anterior mediastinal mass, presence of distant lymph node involvement or extranodal disease, lack of B-cell antigen expression, or Epstein-Barr virus positivity were characterized as definitely not PMBCL. Clinical management and outcomes were also assessed. ResultsOf 63 patients treated for presumed stage I-II PMBCL, 58 (92%) met the criteria for PMBCL. The most common reason for a discordant diagnosis was lack of an anterior mediastinal mass (n = 3). Two additional patients were characterized as having disease equivocal for PMBCL. In retrospect, one patient most likely had a mediastinal gray zone lymphoma due to CD15 positivity and another diffuse large B cell, not otherwise specified, at pathologic review. Five-year progression-free and overall survival were 67% (95% confidence interval, 54-77) and 81% (95% confidence interval, 68-89), respectively, for all patients. ConclusionDespite the complexity of the clinicopathologic criteria of PMBCL, most patients (92%) who were treated for stage I-II PMBCL at our institution appear to have been accurately diagnosed.

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study

Nivolumab Combined with Brentuximab Vedotin for Relapsed/Refractory Mediastinal Gray Zone Lymphoma: Primary Efficacy and Safety Analysis of the Phase 2 CheckMate 436 Study

The Role of CD3, CD20, CD30, and Ki67 Immunohistochemistries in Establishing Mediastinal Gray Zone Lymphoma Diagnosis in 24-years-old Female Patient

Title: The Role of CD3, CD20, CD30, and Ki67 Immunohistochemistries in Establishing  Mediastinal Gray Zone Lymphoma Diagnosis in 24-years-old Female PatientAuthor: Frenky Hardiyanto, MD. Pulmonology and Respiratory Medicine Department, Brawijaya University, Malang, Indonesia. Supervisor: Suryanti Dwi Pratiwi, MD, Pulmonologist Consultant, Artono I, MD, Cardiovascular and Thorax Surgeon, Dini Rachma Erawati, MD, Radiologist Consultant, Diah Prabawati R, MD, Patology Anatomy Specialist, Herwindo P, MD, Internal Medicine Specialist.Introduction:. A woman with complaints of shortness of breath, cough, fever, night sweating, decrease of body weight and swelling in face, neck and right arm. Chest x-rays and ct thorax revealed a mass in mediastinum.Case Description: Patient is a 24 years old female with complaints of shortness of breath, cough, fever, night sweating, decrease of body weight and swelling in face, neck and right arm. Chest x rays and CT thorax revealed a mass in mediastinum. Open biopsy on right neck mass and transthoracic FNAB resulting of chronic inflammation, so the patient was diagnosed with glandular tuberculosis and Mediastinal Tumor. Patient was getting worse after one month consuming OAT. Patient was consulted to Cardiovascular and thorax Surgery Department. Patient was performed thoracotomy and debulking. Anatomical pathology was examined from debulking mass, the result of immunohistochemistry was found nodular mediastinal gray zone lymphoma.Discussion: this case it is very difficult to enforce the diagnosis. Patients have done neck FNAB, transthoracic FNAB, open biopsy right neck mass and FOB have not been able to establish diagnosis. Until finally done thoracotomy and debulking in this patient, from immunohistochemistry results obtained nodular sclerosis Hodgkin lymphoma. Collaboration from pulmonologist, radiologist, cardiovascular and thorax surgeon, and patology anatomy specialist is needed to confirm the diagnosis in these patients.Keywords: mediastinal tumor, mediastinal gray zone lymphoma

Clinical Characteristics and Prognosis of 56 Lymphoma Patients with Mediastinal Masses

To analyze the incidence, clinical characteristics, treatment efficacy and prognosis of lymphoma patients with mediastinal masses. The clinical data of 56 lymphoma patients with mediastinal masses treated in our hospital from February 2007 to January 2018 were collected, and the clinical characteristics, typing, staging, treatment efficacy as well as prognosis analyzed retrospectively. Among the 56 patients, male and female were 25 (45%) cases and 31(55%) cases, respectively. The median age was 31 (17-72) years old, out of them 48 (86%) patients aged below 40 years old. According to pathological classification, 9 (16.1%) cases were diffuse large B cell lymphoma, not otherwise specified (DLBCL-NOS), 26(46.4%) cases were primary mediastinal large B cell lymphoma (PMBCL), 17 (30.4%) cases were classical Hodgkin's lymphoma (cHL), and 4 (7.1%) cases were primary mediastinal grey zone lymphoma (MGZL). All the patients were treated with chemotherapy or immuno-chemotherapy.The median follow-up time was 54.5(11-149) months. In cHL group, 10 cases received involved field radiotherapy (IFRT), 10 (58.8%) cases achieved complete remission (CR), 2 (11.8%) cases achieved partial remisson (PR), and 5 (29.4%) patients experienced progressive disease (PD) , 6 patients with relapsed/refractory disease received autologous hematopoietic stem cell transplantation (auto-HSCT), the 1, 2, and 5 year overall survival (OS) rates of cHL group were 94.1%, 88.2%, and 67.2%, respectively. In MGZL group, 3 cases combined with IFRT, 1 case with auto-HSCT, 2 (50%) cases achieved CR, 2 (50%) cases experienced PD, the 1, 2, 5 year OS rates of MGZL group were 66.7%, 66.7%, and 33.3%, respectively. In PMBCL group, 8 cases combined with IFRT, 7 cases with auto-HSCT, 22 (84.0%) cases achieved CR, 2 (8.0%) cases achieved PR, 1 (4.0%) case was stable disease (SD) and 1 (4.0%) case experienced PD, the 1, 2 year OS rates of PMBCL group were both 100%, and 5 year OS rate was 95.7%. In DLBCL-NOS group, 3 cases combined with IFRT, 2 cases with auto-HSCT, 4 (44.5%) cases achieved CR, 2 (22.2%) cases achieved PR, 1 (11.1%) case was stable disease (SD) and 2 (22.2%) cases experienced PD, the 1 year OS rate of DLBCL-NOS cohort was 100%, 2, and 5 year OS rates were both 77.8%. There was a significant difference of OS rate among these 4 group (P＜0.05). In intra-group comparison, OS rate in PMBCL group were significantly longer than both MGZL group (P＜0.01) and cHL group(P＜0.05), and showed no significant difference from DLBCL-NOS group (P＞0.05). Mediastinal masses are characterized by unique clinical features due to their unique anatomical location. Several B cell originated lymphomas including cHL,MGZL,PMBCL and DLBCL-NOS, manifested primary or secondary mediastina involvement, tend to occur in young adults and have similar clinical features. However, their therapeutic response was significantly different. The prognosis of PMBCL is prior to MGZL and cHL.

Gene Expression Profiling of Mediastinal Gray Zone Lymphoma and Its Relationship to Primary Mediastinal B-cell Lymphoma and Classical Hodgkin Lymphoma

Mediastinal gray zone lymphoma (MGZL) has immunopathologic features between classical Hodgkin lymphoma (cHL) and primary mediastinal thymic B-cell lymphoma (PMBL), leading to uncertainty regarding its biological relationship to these entities. We performed gene expression profiling from patients with MGZL (20), cHL (18), and PMBL (17) and show MGZL clusters between cHL and PMBL. Expression signatures reveal germinal B-cell and IFN regulatory factor 4 (IRF4) signatures were relatively low in MGZL and cHL compared with PMBL, indicating downregulation of the B-cell program in MGZL, a hallmark of cHL. T-cell and macrophage signatures were higher in MGZL and cHL compared with PMBL, consistent with infiltrating immune cells, which are found in cHL. The NFκB signature was higher in MGZL than PMBL, and like cHL, MGZL and PMBL express NFκB inducing kinase (NIK), indicating noncanonical signaling. These findings indicate that while MGZL has distinctive clustering, it is biologically closer to cHL.