Gray Zone Lymphoma Research Articles

Esophagopleural fistula complicated by pyopneumothorax in a patient with gray zone lymphoma

Esophagopleural fistula complicated by pyopneumothorax in a patient with gray zone lymphoma

Nivolumab PD-1 Blockade as Bridge to Allogeneic Stem Cell Transplant (HSCT) in Gray-Zone Lymphoma: Case Report

Nivolumab PD-1 Blockade as Bridge to Allogeneic Stem Cell Transplant (HSCT) in Gray-Zone Lymphoma: Case Report

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.

Late Failure of Aggressive B-Cell Lymphoma Following CAR T-Cell Therapy: A Lysa Study from the Descar-T Registry

Background. Failure after anti-CD19 Chimeric Antigen Receptor (CAR) T-cells is associated with poor prognosis. Several reports showed 65.5 to 83% of CAR T-cell failures occur in the first 3 months (Early Failure, EF), while late failures (LF), after 3 months, represented only 12.5 to 34.5 %. Longer duration of response to CAR T-cell therapy has been associated with better survival in a real-life setting. Here, we analyzed clinical features, patterns of treatment and outcomes of LF patients (pts) from DESCAR-T, a nationwide registry collecting real-life data for pts treated with approved CAR T-cell therapy in France. Patients and Methods. The present analysis (April 29, 2022) included 977 pts with Relapsed/Refractory (R/R) aggressive B-cell lymphoma (BCL) registered in DESCAR-T from July 2018 and infused with either axicabtagene ciloleucel (axi-cel; n=611) or tisagenlecleucel (tisa-cel; n=365) (infusion data missing for one pt). All pts were informed before being included in DESCAR-T registry. Progression and relapse after CAR T-cells were based on the Cheson 2014 response assessment criteria. Results. Overall, 431/977 pts (44.1%) failed (Progressive Disease or Relapse) after CAR T-cell infusion, of whom 145 (33.6%) were LF. For LF patients, histological subtypes were diffuse large B-cell lymphoma (DLBCL, n=109, 75.2%), primary mediastinal B-cell lymphoma (PMBL, n=6, 4.1%), high-grade B-cell lymphoma (HGBCL, n=6, 4.1%), transformed follicular lymphoma (t-FL, n=15, 10.3%), or other (n=9, 6.2%: primary central nervous system lymphoma [PCNSL, n=1]; transformed marginal zone lymphoma [t-MZL, n=5]; grey zone lymphoma [GZL, n=2]; Richter syndrome, n=1). At time of CAR T-cell eligibility, median age was 62 years (range 19-77), 40% of pts were aged >65 yrs, and 58.6% were male; 120 (85.1%) had advanced disease (stage III/IV) and 78 (57.8%) had an age-adjusted International Prognostic Index (aaIPI) of 2-3. The median number of treatment lines prior eligibility was 3 (range 2-10). Thirty-six (24.8%) pts were transplant recipients (34 auto-HSCT and 2 allo-HSCT). At time of CAR T-cell infusion, 12 pts (8.4%) had ECOG PS >2, 72 (50.7%) elevated LDH level and 34 (23.4%) bulky disease. Median ferritin and C-reactive protein blood levels were 474.5 µg/l and 8 mg/dl respectively. Bridging therapy was administered to 82.8% of pts (chemotherapy-based for 76.7% of pts). Overall Response Rate (ORR) to CAR T-cell therapy among LF pts was 90.3%, among whom 76 (52.4%) were in complete metabolic response (CMR); 14 pts were enlisted as non-responders in the registry despite not showing clear signs of progression at 3 months. Median time from infusion to failure was 4.11 months (3 - 21.5, IQR 3.1). After failure, 104 LF pts (71.7%) received a systemic treatment as follows: 41 (33.1%) IMiDs-based, 22 (17.7%) chemotherapy-based, 18 (14.5%) bi-specific antibodies (BsAb), 16 (12.9%) targeted therapy (BTKi, MALT-1 inhibitors), 7 (5.6%) anti-PD1. Eighteen (14.5%) pts received radiotherapy because expressed localized disease, while 20 (13.8%) were not treated. The ORR after post CAR T-cell failure treatment was 15.4%, with 10.6% of CMR. At a median follow-up from first progression of 15 months (95% CI, 12-17), LF pts had a median PFS of 4.2 months (95% CI, 3.4-6) after treatment for CAR T failure, and a median overall survival (OS) of 12.1 months (95% CI, 6.9-15.7). Between therapy groups, when compared to chemotherapy [6-months PFS and OS of 22% (95% CI, 7.1-42) and 39.4% (95% CI, 18.3-60.1), respectively], only pts treated with BsAb showed a benefit in terms of 6-months PFS [77.5%, HR=0.188 (95% CI, 0.069-0.509), P=0.001] (Figure 1), while 6-months OS was longer in both targeted therapy [76.6%, HR=0.278 (95% CI, 0.093-0.83), P=0.02] and BsAb groups [92.9%, HR=0.167 (95% CI, 0.049-0.572), P=0.004]). For pts treated with radiotherapy, 6-months PFS and OS were 64.2% (95% CI, 36.9-82.1) and 94.1% (95% CI, 65-99.1), respectively. Conclusion. This is the first analysis of pts with R/R aggressive BCL that failed after 3 months from CAR T-cell therapy. Even though the groups were small in size, the best PFS and OS were observed in the BsAb treatment group. Radiotherapy can obtain prolonged responses in selected pts with localized disease. Different biological mechanisms of relapse and sensitivity to adoptive immunotherapy could explain the later loss of response in LF subgroup of pts and should be investigated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Population-Based Study Reveals the Unique Clinical Characteristics and Long-Term Survival of Patients with Gray Zone Lymphoma

A Population-Based Study Reveals the Unique Clinical Characteristics and Long-Term Survival of Patients with Gray Zone Lymphoma

Allogeneic Transplant As a Curative Option for Relapsed/Refractory Large B-Cell Lymphoma in the Era of CAR T-Cell Therapy: A Monocentric Retrospective Study

Introduction: Large B-cell lymphomas (LBCL) are aggressive but curable subtypes of non-Hodgkin lymphoma (NHL). Patients with multiple relapses or refractory (R/R) LBCL have a very poor prognosis with a median overall survival of about 6 months. Until recently, allogenic stem cell transplantation (allo-SCT) was the only curative option for chemotherapy-refractory patients or relapses after an autologous stem cell transplantation (auto-SCT). However, its efficacy was limited by significant toxicity and high non-relapse mortality (NRM), mainly due to graft-versus-host disease (GVH) and infections. Lately, approval of autologous CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) significantly improved therapeutic management for R/R LBCL after 2 or more lines of systemic therapy, providing long-term remissions in 35 to 40% of patients with manageable toxicity. Most recently, ZUMA-7 and TRANSFORM trials demonstrated the superiority of second-line CAR-T over standard of care chemotherapy with or without auto-SCT for R/R LBCL. To investigate the positioning of allo-SCT in the current therapeutic landscape of R/R LBCL, we performed a retrospective analysis of patients treated with allo-SCT or CAR-T for this indication in our institute. Materiel & Method: All patients who underwent allo-SCT or CAR-T from February 2010 to January 2022 at Institute Paoli-Calmettes (Marseille, France) were included in this retrospective study. LBCL included diffuse large B-cell lymphoma DLBCL, high-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, or Burkitt like-lymphoma (HGBL), Primary Mediastinal B-cell lymphoma (PMBCL), Grey-Zone lymphoma (GZL), and transformed follicular or marginal zone lymphoma (t-FL and t-MZL). Results: We analyzed 95 successive patients with R/R LBLC treated with allo-SCT (from Feb 2010 to Dec 2020; N = 39; median age: 56 (range 20-71); Donor type: matched related donor: 13; mismatched related donor: 15; matched unrelated doner: 9; mismatched unrelated donor: 1 cord blood = 1) or CAR T cell therapy (from Jan 2019 to Jan 2022; N = 56; median age : 58 (range 19-75); Axi-Cel n = 40, Tisa-Cel n = 16). Median number of prior lines received before cellular therapy were 3 and 2 for allo-SCT and CAR-T groups respectively, bridging therapy excluded. The CAR-T group had a significantly greater proportion of patients with primary refractory disease (71,4% vs 38,4%). The two-year OS and PFS rates for the allo-SCT group were 69% [95% confidence interval (CI): (56-85)] and 66% [95% CI: (53-83)] respectively. The cumulative incidence of NRM at 2-year post allo-SCT was 13% [95% CI: (6-30)]. The two-year OS and PFS rates for the CAR-T group were 67% [95% confidence CI: (53-84)] and 43% [95% CI: (31-61)] respectively. At a median follow-up of 23,2 months, 28 patients experienced relapse/progression after CAR-T. 5 patients underwent allo-SCT after CAR-T failure, 1 of whom was in partial response at the time of conditioning and the 4 others with complete responses. With a median follow up of 14 months: 4 patients are still in response after allo-SCT and only 1 patient had an early relapse (<3 months). Conclusion: Our results confirm efficacy and safety of CAR-T in R/R LBCL with durable complete responses in about 40% of patients in the 3rd line setting. However, early failures after infusion require prompt diagnosis and management because they portend a very dismal prognosis. In this context, our data show that allo-SCT remains a curative option for selected LBCL patients relapsing after CAR T-cell therapy with manageable toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Digital Gene-Expression Signature Supports Mediastinal Gray Zone Lymphoma Stratification within Classical Hodgkin or Primary Mediastinal B-Cell Lymphoma

Mediastinal non-Hodgkin Lymphomas with intermediate features between Primary Mediastinal Large B-cell Lymphoma (PMBCL) and classical Hodgkin Lymphoma (cHL) - also known as mediastinal Gray Zone Lymphomas (mGZL) - represent a unique, diagnostically challenging entity (Khoury et al., Leukemia 2022). They typically exhibit discordant morpho-phenotypical characteristics between cHL and PMBCL, a high rate of diagnostic reclassification and consequent poor therapeutic outcomes. While a comprehensive biological picture of this entity remains to be fully deciphered, recent gene expression profiling of mGZL confirmed their molecular straddling between cHL and PMBCL (Pittaluga et al., Blood Cancer Discov., 2020; Sarkozy et al., BLOOD ADVANCES, 2020). However, the diagnosis of mGZL is still challenging and largely based on the satisfaction of morphological and immunophenotypic criteria. Therefore, there is an urgent need of practical tools exploiting deeper molecular traits of mGZL to facilitate their pathological boundaries between cHL or PMBCL and selection of proper treatment. We applied CIBERSORTx (Newman et al., Nat. Biotechnol., 2019) to public Gene Expression Profiling (GEP) data of a training set comprising 50 cHL (GSE17920) and 31 PMBCL (GSE11318). Such approach purified GEP of both tumor and microenvironment (TME) origin, followed by a Nonnegative Matrix Factorization (NMF)-based selection of 2,913 genes with high discriminating capacity between the two lymphoma subtypes. After a fine-tuned feature selection, a final signature of 168 genes was verified on the training cohort, tested in silico on an independent series of 34 cHL (GSE17920) and 20 PMBCL (GSE87371), and finally validated by NanoString technology on a real-life (RL) cohort including ten cHL and twelve PMBCL to which were added ten mGZL samples. Although we initially gathered 20 GZL, only the mediastinal were included in the study (n=14). Finally, we selected only the ten mGZL that successfully passed Quality Control. The signature produced a successful clustering of cHL or PMBCL cases in all the series analyzed from different technology platforms. Notably, the mGZL broke down into the two clusters, either cHL or PMBCL subtypes on a transcriptomic ground (Figure 1). Moreover, to assess the specificity of the signature in categorizing mGZL within the cHL/PMBCL spectrum, we tested it on ten Follicular Lymphoma samples which, as expected, segregated in a stand-alone subgroup. In conclusion, we provided a proof of concept of a NanoString-based gene signature enabling a transcriptomic stratification of mGZL, adding up to their morpho-phenotypical categorization. If validated on larger cohorts, our approach might prompt the design of a useful molecular assay easily transferable to routine clinical practice. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

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.

Pathology review identifies frequent misdiagnoses in recurrent classic Hodgkin lymphoma in a nationwide cohort: implications for clinical and epidemiological studies.

Patients treated for classic Hodgkin lymphoma (CHL) have a reported 13-fold increased risk of developing subsequent non-Hodgkin lymphoma (NHL). In light of the growing awareness of CHL mimickers, this study re-assesses this risk based on an in-depth pathology review of a nationwide cohort of patients diagnosed with CHL in the Netherlands (2006-2013) and explores the spectrum of CHL mimickers. Among 2,669 patients with biopsy-proven CHL, 54 were registered with secondary NHL. On review, CHL was confirmed in 25/54 patients. In six of these, the subsequent lymphoma was a primary mediastinal B-cell lymphoma/mediastinal gray zone lymphoma, biologically related to CHL and 19/25 were apparently unrelated B-cell NHL. In 29/54 patients, CHL was reclassified as NHL, including T-cell lymphomas with secondary Hodgkin-like B-blasts (n=15), Epstein Barr virus-positive diffuse large B-cell lymphoma (n=8), CD30+ T-cell lymphoma (n=3) and indolent B-cell proliferations (n=3). Higher age, disseminated disease at presentation, extensive B-cell marker expression and association with Epstein-Barr virus were identified as markers to alert for CHL mimickers. Based on these data, the risk of developing NHL after CHL treatment was re-calculated to 3.6-fold (standardized incidence ratio 3.61; confidence interval: 2.29-5.42). In addition, this study highlights the clinicopathological pitfalls leading to misinterpretation of CHL and consequences for the care of individual patients, interpretation of trials and epidemiological assessments.

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.

P1196: DIFFERENT MUTATIONS IN PATIENTS WITH PRIMARY LARGE B-CELL LYMPHOMA

Background: Primary mediastinal large B-cell lymphoma (PMBCL) is a type of aggressive large B-cell lymphoma which affects mainly young patients and is characterized by a local spread and development of a tumor conglomerate in the mediastinum. One of the most important pathogenetic mechanisms of the development of PMBCLs is their genetic heterogenety. There are a lot of similarities between molecular profiles of diffuse large B-cell lymphoma, Hodgkin’s lymphoma, and gray zone lymphoma, which are described in the literature. However, there is no clear molecular-genetic characteristic of PMBCL. Despite the successful treatment of patients with modern methods of immunochemotherapy, a large number of patients are resistant to the therapy due to the tumor heterogeneity. The aim of this study was the detection of a clinically significant mutation for patients with PMBCL by next-generation sequencing. Aims: To identify significant mutations in the genes in patients with PMBCL for the further studies. Methods: The study included 47 patients diagnosed with different stages of PMBCL who received treatment from 2013 to 2021. NGS was performed using the AVENIO Tumor Expanded Panel, Roche, USA, which includes 77 genes. DNA was isolated using the Gene Read DNA FFPE Kit panel, Qiagen, USA. The data were processed using the AVENIO Oncology Analysis Software to search for clinically significant mutations. The mutations were also confirmed by Sanger sequencing. Results: The genetic material of selected patients was analyzed for the presence of clinically significant mutations among the known databases: COSMIC: v83, TCGA 9.0, ExAC:1.0, dbSNP:150, 1000 Genomes: phase_3_v5b, SnpEff:4.2. A missense variant of clinically significant mutations in the FGFR3, PIK3CA, ALK, EZH2, RNF43, MET genes was identified in patients with refractory PMBCL. For example, an activating driver mutation in the FGFR3 gene was detected in the 9th exon (rs121913479), which is pathogenic. The frequency of alleles was 25.54%. An activating driver mutation in the PIK3CA gene was detected in the 10th exon (rs121913273), which is also pathogenic. The frequency of alleles was 10.88%. The aim of the study was to identify signaling pathways which were related to mutated genes. They were PI3K-AKT, JAK-STAT, RAP1, RAS, MAPK, stem cell regulation signaling pathway, which were also interpreted. According to the bioinformatics analysis, FGF/FGFR3 was the most significant signaling pathway for PMBCL in our study, because it is able to activate all listed pathways via FGFR-receptor activation. Summary/Conclusion: NGS revealed clinically significant mutations in the genes in patients with PMBCL, the therapeutic potential of which requires the further studies.

Treatment of B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin’s lymphoma (gray zone lymphoma) in children and young adults: a case series

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin’s lymphoma (cHL) is a rare malignant disease that develops from mature B cells. This disease was first recognized as a distinct entity in 2008. It is most common in the 20 to 40 age group and rare in children. Currently, there are no clear criteria for diagnosis and standard therapy for such patients. According to the literature, it is possible to use treatment regimens applied for both aggressive B-cell lymphomas and Hodgkin's lymphoma. The addition of anti-CD20/CD30 targeted agent to standard therapy may be effective, given the expression of these markers by tumor cells. In this article, we present the clinical and morphological characteristics of patients with unclassifiable B-cell lymphoma with features intermediate between DLBCL and cHL, diagnosed at our center, including 4 patients at the onset of the disease in childhood. Patients and/or their legal representatives have consented to the use of information, including photographs, in scientific research and publications.

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.

Grey zone lymphoma - diagnostic and therapeutic challenge

Introduction. ?Grey zone Lymphoma?? is associated with various entities. The last published classification of lymphoproliferative neoplasms includes mediastinal grey zone lymphoma. Precise diagnostic criteria are insufficient and establishing a diagnosis is as complex as deciding on treatment options. In this article pathologist and hematologist discuss issues on this topic through case presentation and literature review. Clinical characteristics. It presents in the younger population usually with a mediastinal mass, sometimes large, with compressive symptoms. Pathologic characteristics. Some cases can?t be classified neither as Hodgkin nor Primary mediastinal B-cell lymphoma. Morphology resembles Hodgkin, but with a positive immunophenotype for primary mediastinal or diffuse large B-cell lymphoma, and vice versa. Case report. We presented a case of a 33-year-old male with cervical lymphadenomegaly, B symptoms and clinical deterioration during the diagnostic period. After the first biopsy, differential diagnosis was Epstein-Barr virus-associated lymphoproliferative disorder or classical Hodgkin lymphoma. The second biopsy confirms Epstein-Barr virus-positive diffuse large B-cell lymphoma. The World Health Organization Classification of lymphoproliferative neoplasms - clinical perspective. The term ?grey zone lymphoma? is associated with overlapping diagnosis or uncertainty in diagnosis in more clinical settings than the ones provided in the 5th World Health Organization Classification. Discussion. For now, chemotherapeutic regimen (rituximab-cyclophos phamide, doxorubicin, vincristine, prednisone) stays the standard first line therapy for diffuse large B-cell lymphoma regardless of the Epstein- Barr virus status. Mediastinal grey zone lymphoma treatment varies: chemotherapeutic regimen (rituximab-cyclophos phamide, doxorubicin, vincristine, prednisone) was linked with better outcomes than chemotherapeutic regimen (adriablastin, bleomycin, vinblastine, dacarbazine) +/-R, but for some patients chemotherapeutic regimen (dose adjusted-etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin) might be beneficial. Conclusion. Grey zone lymphoma is a rare hematologic malignancy that needs extensive sampling for correct diagnosis and is still subject to inter-observer variability.

Combined use of pathological and genomic alteration analyses for the diagnosis of gray zone lymphoma

Histiocytic sarcoma (HS) is a rare malignancy showing morphologic and immunophenotypic features of histiocytes. HS has morphologic overlap with many other diseases, including various kinds of lymphomas. Gray zone lymphoma (GZL) is a rare B-cell lymphoma subtype characterized by overlapping features between diffuse large B-cell lymphoma and classic Hodgkin lymphoma. The histologic overlap with other diverse diseases of HS and the pathological diversity of GZL make it difficult to render a diagnosis. A 44-year-old woman who was initially diagnosed with HS was diagnosed with GZL after reexamination, including a genetic alteration test. After 6 cycles of brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine, she achieved a complete response. Genomic alteration assessment may be useful for the accurate diagnosis of malignant lymphomas, which are difficult to diagnose, such as GZL.

Pembrolizumab as a bridge to autologous stem cell transplantation in refractory gray zone lymphoma

Gray zone lymphoma (GZL), a rare type of B-cell lymphoma (BCL), has features between diffuse large BCL and classical Hodgkin lymphoma (cHL) and an unfavorable outcome. The expression of PD-L1, encoded by chromosome 9p24.1, has been positively correlated with the copy number alteration of 9p24.1, and it has been associated with a high response rate to anti-PD-1 treatment in cHL and primary mediastinal large BCL (PMBCL). GZL shares similar genomic alterations with cHL and PMBCL, and thus, it may also respond well to anti-PD-1 treatment. However, little is known about the efficacy of anti-PD-1 treatment and the predictive role of PD-L1 expression in GZL. Here, we present a case of GZL refractory to first-line chemotherapy. The patient had a high expression of PD-L1 and was successfully treated with pembrolizumab as a salvage treatment, followed by autologous stem cell transplantation (ASCT) in January 2018. The patient still had a complete metabolic response 42 months after ASCT.

Treatment Selection and Survival in Patients with Gray Zone Lymphoma: A Comprehensive Population-Based Analysis.

There are no treatment guidelines for gray-zone lymphoma (GZL), given the disease's rarity and being a relatively new entity. Our objective was to assess factors affecting treatment selection in GZL and its effect on survival, focusing on combined modality treatment (CMT) versus chemotherapy alone. We identified 1047 patients with GZL treated with CMT or chemotherapy alone between 2004 and 2016 from the National Cancer Database (NCDB). We excluded patients without histologic confirmation of the diagnosis, those who did not receive chemotherapy, and those who started chemotherapy >120 days or radiation >365 days from diagnosis to account for immortal time bias. Factors affecting treatment selection were investigated using a logistic regression model. A propensity score-matched methodology was used to compare survival outcomes. Only 164 patients (15.7%) received CMT, while 883 (84.3%) received chemotherapy alone. Treatment selection was affected by clinical factors (age, odds ratio [OR] 0.99, 95% confidence interval [CI] 0.98-0.997, p-value 0.01 and advanced stage, OR for stage 4: 0.21, 95% CI 0.13-0.34, p-value < 0.001) but not socioeconomic factors. Higher median income was associated with better survival, while increased age, higher comorbidity score, and B symptoms were associated with worse survival. The use of CMT had a survival advantage over chemotherapy alone (hazard ratio [HR] 0.54, 95% CI 0.351-0.833, p-value 0.005). CMT is associated with survival advantage in our analysis. Careful selection of patients is essential to achieve the best outcomes with minimal toxicity. Socioeconomic factors affect treatment selection in patients with GZL that can alter outcomes. Future work should focus on strategies that access disparities without compromising survival.

Efficacy and Safety of Pola-BR Combination in Relapsed/Refractory Aggressive В-Cell Non-Hodgkin’s Lymphomas: A Russian Multi-Center Study

Aim. To analyze the first experience of administering polatu-zumab vedotin combined with bendamustine and rituximab (Pola-BR) in clinical practice at some specialized institutions in the Russian Federation. Materials &amp; Methods. The prospective multi-center study enrolled 39 patients with relapsed/refractory aggressive В-cell non-Hodgkin’s lymphomas (B-NHLs): 31 (79 %) patients with diffuse large B-cell lymphoma, 7 (18 %) patients with primary mediastinal (thymic) large B-cell lymphoma, and 1 (3 %) patient with gray zone lymphoma. There were 20 men and 19 women aged 19-69 years (median 43 years). All the patients were treated with Pola-BR protocol: bendamustine 90 mg/m&lt;sup&gt;2&lt;/sup&gt; on Days 1 and 2, rituximab 375 mg/m&lt;sup&gt;2&lt;/sup&gt; on Day 1, and polatuzumab vedotin 1.8 mg/kg on Day 1 of each 21-day cycle. Full treatment with 6 cycles was completed by 19 patients. PET-CT was performed prior to therapy and after the 2nd, 4th, and 6th Pola-BR cycles. The tumor response was evaluated according to the Lugano 2014 criteria. The toxicity profile was assessed by means of reporting adverse events according to the NCI CTCAE, version 5.0. Results. Objective response to the therapy, according to the Lugano 2014 criteria, was identified in 24 (61.5 %) patients: 19 (48.7 %) of them showed the complete response, and 5 (12.8 %) of them showed the partial one. Stable disease as best response to the therapy was reported in 3 (7.7 %) patients, disease progression was observed in 12 (30.8 %) patients. By the time of data analysis, the median follow-up duration was 16.8 months (range 5.3-24.2 months). The 2-year overall survival (OS) was 44 % (95% confidence interval [95% CI] 24-62 %), the median OS was 20.8 months. The 2-year progression-free survival (PFS) was 27 % (95% CI 12-43 %), the median PFS was 7.3 months. Adverse events of grade 3/4 included anemia (n = 4; 10.3 %), neutropenia (n = 15; 38.5 %), thrombocytopenia (n = 3; 7.7 %), and febrile neutropenia (n = 2; 5.1 %). In 2 patients with history of hepatitis B, the virus reactivation was identified on Pola-BR therapy. No cases of peripheral neuropathy were observed. Conclusion. Results obtained in real-world clinical practice correspond to the previously published data and demonstrate that polatuzumab vedotin therapy (Pola-BR protocol) has a controllable toxicity profile and is, therefore, a promising chemotherapy method of relapsed/refractory aggressive B-NHL treatment.

EBV-positive Diffuse Large B-Cell Lymphoma, NOS in a Filipino Patient: Mimickers and Essential Ancillary Studies

Epstein-Barr virus positive diffuse large B-cell lymphoma (EBV+ DLBCL) is prevalent among Asians but is underreported in the Philippine setting. We report the case of an 88-year-old male who presented with difficulty swallowing. CT scan showed an ill-defined soft tissue focus with calcifications in the supraglottic to hypopharyngeal region measuring approximately 2.6 x 1.7 x 1.5 cm, and multiple lymphadenopathies in the head and neck. Biopsy of the masses at the left tonsil, left arytenoid mucosa, pyriform sinus, and aryepiglottic fold showed large lymphoid cells with several Reed-Sternberg-like cells in a background of small lymphocytes, neutrophils, few eosinophils and histiocytes. A panel of immunohistochemical stains and EBER-ish were performed to differentiate among six entities that were morphologically similar to the patient’s case, namely, classic Hodgkin lymphoma, T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL), DLBCL, NOS, anaplastic variant, B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic HL (gray zone lymphoma), and infectious mononucleosis (IM). The neoplastic cells expressed CD20, CD30, CD45, PAX5, CD10, MUM-1, BCL6, BCL2, and c-myc, while CD3, CD15 and ALK-1 were negative. The cells of interest also showed nuclear staining (30-40%) on Epstein-Barr virus encoding RNA in-situ hybridization (EBER-ish). The Ki-67 showed a proliferation index of 40-50%. Given the differences in prognosis and treatment among these diseases, judicious use of immunostains and EBER-ish is recommended for accurate diagnosis.