T-cell/histiocyte-rich Large B-cell Lymphoma Research Articles

Abstract 4823: Survival outcomes similar in T-cell/histiocyte-rich large B-cell lymphoma between Hispanics and non-Hispanics within the United States

Abstract Background: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare variant of large B-cell lymphoma with features that overlap with Nodular lymphocyte-predominate Hodgkin lymphoma (NLPHL). (Blood PMID: 32871584, PLoS One PMID: 24244368,Haematologica PMID: 20207840). Unlike NLPHL, which has a good prognosis. THRLBCL’s prognosis is worse (Leuk Lymphoma PMID: 31287335). Given its rarity and difficulty to diagnose, limited studies explore prognostic factors for it. This study aims to explore clinical, demographic, and survival outcomes differ in Hispanic (HI) versus non-Hispanic (NH) patients with THRLBCL in the United States (US). Methods: Data were analyzed on THRLBCL patients in the US and reported to the National Cancer Database (NCDB) between 2004 and 2019. Demographic and treatment characteristics were compared between ethnic groups. Kaplan-Meier and Cox regression analyses compared OS between HI and NH. Multivariate analysis and propensity score matching was performed with adjustment for age, stage, co-morbidity score, insurance status, type of facility, and great circle distance. Results: Of 1252 THRLBCL patients, 7% were HI and 93% NH. 67% of HI were male, compared to 68% of NHHI pts were younger at diagnosis 55 vs 57 (p=0.471); the majority of HI and NH were <65, 64% and 66% respectively (p=0.574)Most of HI and NH were white (88% vs 74%). When examining stage, most of HI and NH were stage (IV) (50% vs 57%) (p=0.600)Regarding insurance type, Government-sponsored was the most prevalent in HI (52%), while private insurance was most prevalent for NH (51%) (p=0.001). The most non-Insured group was HI (11% vs 3%).Regarding Census Median Income (2008-2012), the most prevalent bracket (39.5%) for HI was $48,000 - $62,999, and for NH (31%) $>63,000. Charlson-Deyo Score (comorbidities score), HI had a 10% =/> 2 score, vs NH 7%. Regarding treatment facility type Academic/Research Programs were the most prevalent for HI (44%) and NH (38%).The median distance in miles between the patient’s residence and the hospital that reported the case (Great Circle Distance), HI lived at a median of 10 miles, vs NH at a median of 11 miles. On survival analysis, the survival probability at 2, 5, and 10 years of HI vs NH were 83% vs 83%, 77% vs 75%, and 69% vs 62%. The median survival time (MS) was not reached for HI or NH. There was no overall survival difference (OS) between HI/NH (p=0.8). Independently, on multivariate analysis, ethnicity was not associated with worse OS (HR 1.2, CI 0.67-2.17, p=0.54). Conclusion: The MS and OS between HI and NH with THRLBCL within the US were similar. However, due to the rarity of THRLBCL, the size of both populations was small, which reduces the confidence that there are no differences in the outcomes of these two populations. Because of this, more data is needed to evaluate further the clinical and socioeconomic factors that play a role in the survival outcomes of THRLBCL. Citation Format: Ian Mines, Daniela Urueta-Portillo, Qianqian Liu, Joel Michalek, Adolfo E. Diaz Duque. Survival outcomes similar in T-cell/histiocyte-rich large B-cell lymphoma between Hispanics and non-Hispanics within the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4823.

Unique presentation of T-cell/histiocyte-rich large B cell lymphoma complicated with hemophagocytic lymphohistiocytosis: case report and review of the literature


 Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory disorder characterized by dysfunction of NK cells and cytotoxic lymphocytes. We present a rare case of a patient diagnosed with HLH who presented with persistent fever during treatment for refractory T-cell/histiocyte-rich large B-cell lymphoma (TCHRBCL), highlighting the challenges of managing HLH in the context of refractory lymphoma. According to our review of the literature, this is the first case of HLH that developed several months into treatment for refractory TCHRBCL and not in close temporal relation to lymphoma diagnosis.

Unraveling the Transcriptional Landscape of Nodular Lymphocyte-Predominant Hodgkin Lymphoma and T-Cell/Histiocyte Rich Large B-Cell Lymphoma: Impact of Tumor Microenvironment and Checkpoint Gene Expression

Introduction: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare B-cell malignancy with a paucity of malignant cells embedded in a diverse tumor microenvironment (TME). The histological composition of the TME is known to influence outcomes, with nodular B-cell rich TME (classical histology, Fan patterns A&B) associated with indolent clinical course, while T-cell infiltration or diffuse growth (variant histology, Fan patterns C-F) may resemble aggressive T/cell-histiocyte rich large B-cell lymphoma (THRLBCL) to which NLPHL can transform. Molecular features of NLPHL and THRLBCL remain to be discovered. To gain further insights into the biology of these lymphomas, we recruited NLPHL and THRLBCL cases as part of the Atlas of Blood Cancer Genomes (ABCG) initiative, a consortium consisting of 26 institutions. Design: We collected comprehensive clinicopathological, treatment and outcome data from 154 NLPHL and 21 THRLBCL patients, with centralized pathology review performed by a panel of dedicated hematopathologists. Fan patterns of the NLPHL samples were documented in all samples where possible. RNA sequencing was performed on formalin-fixed paraffin-embedded (FFPE) diagnostic tumor samples (n=129 NLPHL; n=17 THRLBCL). Tumor-infiltrating immune cell compositions were enumerated using FARDEEP with signature matrix LM22 from CIBERSORT. Results: Median age at diagnosis for the patients with THRLBCL and NLPHL was 54 years (interquartile ratio [IQR] 43-65) and 40 years (IQR 24-53), respectively. The majority of patients with NLPHL had limited stage (74%), whereas the patients with THRLBCL predominantly had advanced stage at diagnosis (95%). In both diseases, most patients were males (NLPHL, 69%; THRLBCL, 76%). Spleen involvement was present in 11 NLPHL patients (8%) and histological growth pattern was documented in 112 patients (73%). Out of those, 47 (42%) presented with variant histology and 65 with classical histology. Variant histology was enriched in NLPHL patients with splenic involvement. During a median follow-up of 6.4 years (IQR 3.8-10.1), 12 NLPHL patients and 9 THRLBCL patients died. Patients with THRLBCL had worse 10-year overall survival (OS, 31% vs 89%; p<0.001) and progression-free survival (PFS, 30% vs 66%; p=0.002) compared to patients with NLPHL. Moreover, NLPHLs with variant histology had inferior 10-year OS compared to NLPHLs with classical histology (81% vs 91%; P=0.03; Figure 1). According to in silico immunophenotyping, THRLBCL cases had the highest median proportions of M1-macrophages (11.0%) and CD8+ T-cells (17.0%), followed by NLPHLs with variant histology (M1-macrophages, 6.5%; CD8+ T-cells, 14.5%), with the lowest proportion observed in NLPHLs with classical histology (M1-macrophages, 5.2%; CD8+ T-cells, 10.9%). In contrast, the median proportions of naïve B cells followed an opposite trend across subtypes (NLPHL classical histology, 15.5%; NLPHL variant histology, 11.0%; THRLBCL, 2.0%), whereas the median proportion of CD4+ T-cells was similar across both lymphomas (NLPHL classical histology, 33.9%; NLPHL variant histology, 33.9%; THRLBCL, 32.4%). Despite differences in the overall transcriptomic landscape, gene expression patterns posited THRLBCL and NLPHL as comprising a biological continuum. THRLBCL shared more similarities with NLPHL with variant histology, while NLPHLs with classical histology exhibited upregulation of genes related to cell growth and proliferation through the MYC pathway (P<0.001). Finally, we identified a strong association between THRLBCL and upregulation of checkpoint genes (P<0.001) and gene expression related to inflammatory response (P<0.001) (Figure 2). Furthermore, NLPHLs with a high checkpoint score (above the 75th percentile) were associated with spleen involvement (P<0.001) and worse outcome (5-year PFS 61% vs 87%; P=0.02). Conclusion: Our study provides the largest comprehensive clinical and transcriptomic analyses of NLPHL and THRLBCL to-date. The findings suggest that the inferior outcomes observed in THRLBCL and in a subset of NLPHL are attributable to a higher degree of inflammation in the TME, increased expression of checkpoint genes, and a high proportion of macrophages.

Outcomes in Patients with Relapsed Refractory T-Cell/Histiocyte-Rich Large B-Cell Lymphoma Treated with CAR-T Cell Therapies or Salvage Chemotherapy - a Single-Institution Experience

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare and aggressive variant of large B-cell lymphoma. A substantial subset of THRLBCL patients (pts) relapse after frontline anthracycline-based therapy. There is a scarcity of outcome data on therapy options for relapsed/refractory (r/r)THRLBCL, particularly CD19 CAR-T therapy.A recent genetic and spatial analysis provided critical insights into the complex interactions at the tumor-immune interface in THRLBCL. Understanding the mechanisms by which tumor cells evade the immune system is crucial in designing treatment strategies. This retrospective study aims to analyze clinicopathologic data in pts with r/r THRLBCL with the goal of identifying patterns that may influence response rates and long-term survival. METHODS: Pts who were evaluated and treated at MD Anderson Cancer Center (MDACC) with THRLBCL from 1/2005-5/2023 were included in the analysis. We reviewed demographic, clinical and pathological characteristics, treatments, and outcomes through an approved IRB protocol. We excluded cases with ambiguous diagnosis (such as DLBCL with increased infiltrate of T-cells and/or histiocytes), missing treatment, and/or no follow up information. Progression-free survival (PFS) and overall survival (OS) were calculated from start of treatment until progression or death using Kaplan-Meier. Log-rank test was used to evaluate the difference between pt groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for all analyses. RESULTS: A total of 212 pts were reviewed, and we excluded 86 pts who did not meet selection criteria. Out of 126 pts, 63 with biopsy-confirmed relapse after 1st line chemoimmunotherapy were included in the analysis (Table-1). The median age was 49 (20-79 years); and 49 pts (78%) were males. Twenty-one (34%) pts had documented NLPHL at the time of or predating the THRLBCL diagnosis. At relapse, 93 % had advance stage disease (stage 3 and 4). Splenic involvement was documented in 57% and 80% of pts had one or more sites of extra nodal disease. Most pts who relapsed received front line RCHOP (77%) or R-EPOCH (11%). Twenty-six pts (41%) had primary refractory disease, and 24 pts (38%) relapsed within 12 months. The median time to progression from 1st line treatment was 7.4 months(2.2~145.9 months). The most common 2 nd line therapy was salvage chemotherapy (82%) such as R-ICE (n=41), R-DHAP(n=4), R-GemOx (n=3). Overall response rate (ORR) to 2 nd line salvage chemotherapy was 75% with CR of 57%. For pts who received 2nd line salvage chemotherapy with the intent to undergo HSCT, the PFS at 2 years was 53% (95% CI: 0.4-0.68, p< 0.0001) and OS was 64% (95% CI: 0.5- 0.8, p< 0.372). Among pts who received consolidation with HSCT, (n=30, 57%), 5 pts relapsed at the time of last follow up.With a median follow-up time of 60.1 months (95% CI: 33.6~90.3 months), the median PFS from all 2nd line treatments was 11 months (95% CI: 4.7 ~ NA ) and for pts who received salvage chemotherapy with HSCT intent was 50.26 (95% CI: 7 ~ NA months). The median OS from 2nd line for all pts was 77.3 months (95% CI: 22.2 ~ NA months) and for pts who received salvage chemotherapy with HSCT intent OS was not reached (95% CI: 32 ~ NA months). Among 11 pts who received 3 rd line salvage chemotherapy, the median PFS was 2 months, and only one pt received HSCT. All pts eventually had progressive disease. Eleven pts received CD19 CAR-T (Axi-cel-9, Liso-cel-2),(table-1) 6 pts received as 2 nd line, 4 received as 3rd line and 1 pt received as 4 th line. Best ORR to CAR-T at any lines was 45% with CR of 36.4%. At a median follow-up time of 12.3 months (95% CI: 2.4 ~ NA months), all but one pt had disease progression. Median PFS was 1.7 months (95% CI: 1.1 ~ NA months). 6-month PFS was 21% (Figure 1). One pt who had response experienced prolonged remission of 17 months before relapsing. CONCLUSION: Our study highlights the unique biology and poorer prognosis of TCHRBCL compared to other DLBCL subtypes. Despite the success of CD19 CAR-T therapy in DLBCL, TCHRBCL pts have shown limited response to these therapies, demonstrating the challenges of achieving long-term remission in this group. Our study shows the high unmet need for improved therapies that can target the unique biology in TCHRBCL. We plan to report a comparative spatial analysis evaluating the tumor-immune interface that can contribute to resistance to Immune effector cell therapies at the meeting.

Autologous hematopoietic cell transplantation (autoHCT) for T‐cell/histiocyte‐rich large B‐cell lymphoma (THRLBCL): An EBMT Lymphoma Working Party study

Introduction: THRLBCL is an orphan entity of large B-cell lymphomas (LBCL). It is dominated by stromal and immune components—especially T-cells and histiocytes—with similarities to nodular lymphocyte-predominant Hodgkin lymphoma. This microenvironment can produce immunomodulating molecules with therapeutic implications since recent reports suggest THRLBCL resistance to chimeric antigen receptor T-cells (CART). As CART-based therapies are challenging the role of autoHCT as second line consolidation for relapsed/refractory LBCL, we aimed to study the efficacy of autoHCT in THRLBCL in comparison with diffuse LBCL not other specified (DLBCL). Methods: Eligible for this EBMT registry analysis were adult patients who underwent a first autoHCT for THRLBCL between 2016 and 2020. These were compared to adult patients with DLBCL who received a first autoHCT during the same time period. Statistical analysis was descriptive and employed univariate and multivariate comparisons for the impact of baseline characteristics on survival endpoints. A 1:2 matching comparison was performed to better adjust for baseline differences between THRLBCL and DLBCL, respectively. Results: In total 11,151 patients (10,831 DLBCL, 320 THRLBCL) were identified. THRLBCL patients were younger (52 vs. 58 years), predominantly male (76% vs. 59%), had better performance status (ECOG 0: 97% vs. 92%) and less comorbidity (HCT-CI 0: 78% vs. 68%), and had a longer time from diagnosis to transplant (13 vs. 11 months) than DLBCL patients. In contrast, there were no significant differences regarding the proportion of patients receiving autoHCT during second-line (2L) treatment (87% vs. 82%) and sensitive disease status at autoHCT (95% vs. 92%) between THRLBCL and DLBCL, respectively. On logrank comparisons including all patients, THRLBCL was associated with a better 2-year overall survival (OS; 79% vs. 73%; p = 0.05) and progression-free survival (PFS; 72% vs. 61%) than DLBCL. However, when comparing 139 THRLBCL with 278 DLBCL patients matched for age, sex, disease status, performance status (PS), comorbidities (HCT-CI), and time from diagnosis, the outcome differences were no longer significant. Multivariate analyses adjusting for age, gender, disease status, PS, HCT-CI, and time from diagnosis identified higher age, refractory disease, >12 months from diagnosis, and poorer PS as significant risk factors for reduced OS and PFS. Of note, diagnosis THRLBCL was an independent predictor of reduced relapse risk (HR 0.73; p = 0.04). Conclusions: AutoHCT is an effective salvage therapy for relapsed/refractory THRLBCL sensitive to salvage therapy. Superior outcome of autoHCT for THRLBCL compared to DLBCL may be partly explained by more favorable baseline features of the THRLBCL group in terms of age, and PS. The 72% PFS-benchmark shown for autoHCT here has to be considered when deciding about 2L treatment strategies for THRLBCL. Keywords: Aggressive B-cell non-Hodgkin lymphoma, Stem Cell Transplant Conflicts of interests pertinent to the abstract. S. Renders Honoraria: Gilead P. Dreger Honoraria: Novartis, Kite, BMS, Miltenyi

T-cell/Histiocyte-rich Large B-cell Lymphoma in an Adolescent from Abidjan-Ivory Coast: Case Report

T-cell/Histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare pathology, uncommon in the children population, and the few cases reported had a wide range of clinical presentations, including advanced stage, extranodal involvement, and bad prognosis. The authors report a case of a 16-year-old male patient with no medical history, who presented a single left axillary adenopathy. T-cell/Histiocyte-rich large B-cell lymphoma was diagnosed by immunohistochemistry and was classified good prognosis. RCHOP-based chemotherapy was performed with good progress. The authors hope to contribute to the literature on THRLBCL and draw the attention of practitioners to its occurrence in the pediatric population.

A case report of T cell/histiocyte-rich large B cell lymphoma misdiagnosed as lymphomatoid papulosis.

T cell/histiocyte-rich large B cell lymphoma (THRLBCL) is an uncommon B cell lymphoma characterized by < 10% large neoplastic B cells in a background of abundant T cells and frequent histiocytes. If a skin lesion is the first clinical sign of lymphoma, the diagnosis might be difficult and misdiagnosed. A 60-year-old woman presented with multiple erythematous umbilicated nodules on her left upper back for 3 months. Through punch biopsy of the back lesion and additional excisional right inguinal lymph node biopsy, the patient was diagnosed with cutaneous metastasis of THRLBCL. The patient was referred to the Hemato-oncology Department for chemotherapy. R-CHOP chemotherapy is currently in progress, and some skin lesions show improvement. Skin lesions might be the first clinical sign of THRLBCL and when THRLBCL is suspected, careful further evaluation is essential for accurate diagnosis and treatment.

T-cell/Histiocyte-rich Large B-cell Lmphoma in Pediatric Patients: a Reported Case of a 16-year-old Patient in Clinical Haematology Department of the University Teaching Hospital of Yopougon (Abidjan-Ivory Coast)

T-cell/Histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare pathology, uncommon in children population and the few cases reported, had wide range clinical presentations, including advanced stage, extranodal involvement and bad prognosis. Authors report a case of a 16-year-old male patient with no medical history, who presented a single left axillary adenopathy. T-cell/Histiocyte-rich large B-cell lymphoma was diagnosed by immunohistochemistry and was classified good prognosis. A RCHOP-based chemotherapy was performed with good progress. Authors hope to contribute to the literature on THRLBCL and draw the attention of practitioners to its occurrence in the pediatric population.

The utility of IMP3 immunohistochemical staining in differentiating nodular lymphocyte predominant Hodgkin Lymphoma from T-Cell/Histiocyte-Rich large B-Cell lymphoma

IntroductionNodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have overlapping histological features that make their diagnosis challenging. Insulin-like growth factor II mRNA-binding protein 3 (IMP3) is a recently proposed diagnostic marker for Hodgkin’s lymphoma. The aim of this study was to determine the ability of IMP3 in differentiating NLPHL from THRLBCL.MethodsIn this retrospective study, the formalin-fixed paraffin-embedded blocks from 56 patients (28 NLPHL and 28 large B cell lymphoma (LBCL, including 16 THRLBCL and 12 DLBCL, NOS) cases based on immunohistochemistry (IHC) were included. Sample sections were stained for IMP3 using IHC method. Moderate to strong staining in at least 10% of tumor cells was considered positive IMP3 expression.ResultsThe mean age of the patients was 41.25 ± 16.08 years old. The majority of the patients were male. There was a significant age difference between NLPHL (34.61 ± 16.44 years old) and LBCL (47.89 ± 12.85 years) groups (p = 0.001). No significant difference was seen in gender and site between NLPHL and LBCL groups. The expression of IMP3 was mainly strong in LBCL group, while it was heterogeneously distributed among NLPHL samples ranging from weak to strong (p < 0.001). It was determined that strong IMP3 expression at 55.00% can differentiate LBCL from NLPHL with 71.4% sensitivity and 71.4% specificity.ConclusionOur findings showed that IMP3 may be a good complement in differentiating NLPHL cases from THRLBCL.

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.

P033: Clinical significance of the severity of THRLBCL-like areas in nodular lymphocyte predominant Hodgkin lymphoma

Table 1: Comparison of clinical parameters in 3 subgroups of patients with non-classical subvariants (non-A/B) depending on the value of THRLBCL areas (0%, 0>%<50%, ≥ 50%) Introduction: According to the WHO 2017 the presence of sites resembling T cell/histiocyte-rich large B-cell lymphoma (THRLBCL) in nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) does not refer to transformation into THRLBCL. Objective: To compare the severity of THRLBCL-like areas in NLPHL with the clinical course of the disease. Materials and Methods: The study group included 59 patients with verified diagnosis (morphology, IHC) of NLPHL (2010–2017, NRCH for hematology): m/f ratio 3.4: 1, median age - 35 (range 17–68), with biopsy material of lymph node/other localization of the primary biopsy in the debut of the disease. The severity of THRLBCL-like areas was analyzed using IHC with CD20 antibodies and empirically selected cut off of these sites in 50%, compared with clinical and instrumental data. Results: Patients with non-classical subvariants (non-A/B, n=42) were divided into 3 subgroups: 1 subgroup 0% (17/42), 2 subgroup - 0>%<50% (11/42), 3 subgroup ≥50% (14/42) THRLBCL-like areas of the area of the lymph node section. In the three analyzed subgroups, there were a significant difference in the frequency of diagnosis of stage IV of the disease (p=0.0507), bone marrow damage (p=0.0005) and spleen (p=0.0101), response to first-line therapy (p=0.0126). Table 1. In the subgroup with the presence of THRLBCL-like areas ≥50%, up to 6 affected extranodal localizations were observed: bone marrow trephine biopsies, spleen, liver, paravertebral soft tissues, bones, thyroid gland. Conclusions: A subgroup of patients with the presence of THRLBCL-like areas ≥50% of the area of the lymph node section is characterized by the most unfavorable clinical course of the disease.

3D analyses reveal T cells with activated nuclear features in T-cell/histiocyte-rich large B-cell lymphoma

AbstractNodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) can show variable histological growth patterns and present remarkable overlap with T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL). Previous studies suggest that NLPHL histological variants represent progression forms of NLPHL and THRLBCL transformation in aggressive disease. Since molecular studies of both lymphomas are limited due to the low number of tumor cells, the present study aimed to learn if a better understanding of these lymphomas is possible via detailed measurements of nuclear and cell size features in 2D and 3D sections. Whereas no significant differences were visible in 2D analyses, a slightly increased nuclear volume and a significantly enlarged cell size were noted in 3D measurements of the tumor cells of THRLBCL in comparison to typical NLPHL cases. Interestingly, not only was the size of the tumor cells increased in THRLBCL but also the nuclear volume of concomitant T cells in the reactive infiltrate when compared with typical NLPHL. Particularly CD8+ T cells had frequent contacts to tumor cells of THRLBCL. However, the nuclear volume of B cells was comparable in all cases. These results clearly demonstrate that 3D tissue analyses are superior to conventional 2D analyses of histological sections. Furthermore, the results point to a strong activation of T cells in THRLBCL, representing a cytotoxic response against the tumor cells with unclear effectiveness, resulting in enhanced swelling of the tumor cell bodies and limiting proliferative potential. Further molecular studies combining 3D tissue analyses and molecular data will help to gain profound insight into these ill-defined cellular processes.

A rare case of bone marrow infiltration by T-cell/ histiocyte-rich large B-cell lymphoma masquerading as hemophagocytic lymphohistiocytosis

T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is an uncommon B-cell non-Hodgkin lymphoma with an aggressive course. Here, we report a case of a 55-year-old lady presenting with fever for 1 month duration with no localizing signs, who underwent bone marrow (BM) examination with the suspicion of hemophagocytic lymphohistiocytosis (HLH). BM examination showed evidence of hemophagocytosis satisfying the criteria for HLH. In addition, there was infiltration by discrete large atypical cells in the BM immunohistochemically compatible with involvement by THRLBCL. The case is presented due to the rarity of the pattern of presentation of an uncommon B-NHL which posed challenges to an accurate diagnosis.

An Update on the Pathology and Molecular Features of Hodgkin Lymphoma.

Simple SummaryHodgkin lymphomas (HLs) include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular findings in HLs have contributed to dramatic changes in the treatment and identification of tumor characteristics. For example, PD-1/PD-L1 blockade and brentuximab vedotin, an anti-CD30 antibody bearing a cytotoxic compound, are now widely used in patients with CHL. Biological continuity between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma has been highlighted. An era of novel therapeutics for HL has begun. The aim of this paper is to review the morphologic, immunophenotypic, and molecular features of CHL and NLPHL, which must be understood for the development of novel therapeutics.Hodgkin lymphomas (HLs) are lymphoid neoplasms derived from B cells and consist histologically of large neoplastic cells known as Hodgkin and Reed–Sternberg cells and abundant reactive bystander cells. HLs include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular analyses have revealed that an immune evasion mechanism, particularly the PD-1/PD-L1 pathway, plays a key role in the development of CHL. Other highlighted key pathways in CHL are NF-κB and JAK/STAT. These advances have dramatically changed the treatment for CHL, particularly relapsed/refractory CHL. For example, PD-1 inhibitors are now widely used in relapsed/refractory CHL. Compared with CHL, NLPHL is more characterized by preserved B cell features. Overlapping morphological and molecular features between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have been reported, and biological continuity between these two entities has been highlighted. Some THRLBCLs are considered to represent progression from NLPHLs. With considerable new understanding becoming available from molecular studies in HLs, therapies and classification of HLs are continually evolving. This paper offers a summary of and update on the pathological and molecular features of HLs for a better understanding of the diseases.

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.

Phase 2 Study of Acalabrutinib Window Prior to Frontline Therapy in Untreated Aggressive B-Cell Lymphoma: Preliminary Results and Correlatives of Response to Acalabrutinib

Phase 2 Study of Acalabrutinib Window Prior to Frontline Therapy in Untreated Aggressive B-Cell Lymphoma: Preliminary Results and Correlatives of Response to Acalabrutinib

A Rare Case of T-Cell Histiocyte Rich Large B-Cell Lymphoma of the Thyroid in a Patient With Hashimotos

Introduction: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare form of large B-cell lymphoma, which usually involves the lymph nodes exclusively. We describe a patient with Hashimoto’s thyroiditis who was discovered to have THRLBCL arising from the thyroid. Clinical Case: A 78-year-old female with a history of Hashimoto’s thyroiditis noted increase in the size of her left thyroid lobe for two months despite normal TSH on Levothyroxine, prompting an ultrasound which revealed several enlarged left sided cervical lymph nodes and an enlarged left thyroid gland. Cytology from an FNA of a left level 3 lymph node showed atypical lymphoid infiltrate featuring scattered large atypical cells in a background of small lymphocytes. Immunohistochemical testing was PAX5+, CD30- and CD15-. Cytology from an FNA of left thyroid revealed identical changes and immunohistochemistry demonstrated PAX5+ and CD20+. Concurrent flow cytometric studies demonstrated increased CD4 to CD8 ratio among T cells. Excisional biopsy of a left cervical lymph node confirmed a diagnosis of THRLBCL. PET/CT exhibited lymphadenopathy above her diaphragm and splenic involvement. Her bone marrow biopsy was negative for involvement. She was deemed Stage III with international prognostic index (IPI) of 2 corresponding with low-intermediate risk. She was commenced on chemotherapy R-CHOP with plan to complete 6 cycles. Discussion: THRLBCL is characterized by scattered atypical B lymphocytes on a background of T lymphocytes and histiocytes. Usually, T-cells are predominantly CD8+, in contrast to our patient. Some studies identified cases of predominant CD4+ and PD1+ T cells. Cytology revealed scattered small B-cells and large B-cells, a feature that is not typically seen in THRLBCL. A diagnosis of diffuse transformation of nodular lymphocyte predominant Hodgkin lymphoma was considered but the diffuse proliferation outside of CD21+ and involvement of the thyroid is not compatible with such diagnosis. Similarly, a diagnosis of follicular helper T-cell lymphoma with admixed large B-cells was considered but while PD1+ CD4+ T cells are present, there was no aberrant antigen expression by flow cytometry or T cell clonality. THRLBCL mainly involves lymph nodes and presents at advanced Ann Arbor stages with high IPI. Malignant lymphomas of the thyroid gland are exceedingly rare, accounting for 2% of thyroid cancers, out of which the literature reveals a single case report of THRLBCL arising from the thyroid. THRLBCL represents an aggressive form of lymphoma and is treated according to stage-matched DLBCL, although the effects of Rituximab in this population is variable. Conclusion: Hashimoto’s is considered a risk for thyroid lymphoma usually diffuse large B-cell lymphoma and MALT lymphoma. We present a rare case of THRLBCL occurring in the setting of Hashimoto’s with acute thyroid gland enlargement.

Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma

T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.

Nodular Lymphocyte Predominant Hodgkin’s Lymphoma with T Cell/ Histiocyte Rich Large B Cell Lymphoma Like Transformation

Nodular lymphocyte predominant Hodgkin’s lymphoma (NLPHL) is an uncommon variant form of Hodgkin’s lymphoma with a worldwide incidence of 5%. 1 It has long been recognized that NLPHL can have varied growth patterns, including some with diffuse areas and/or numerous T cells.2 NLPHL may evolve to a completely diffuse T-cell–rich proliferation lacking any follicular dendritic cells which would be consistent with a T-cell histiocyte-rich large B-cell lymphoma (THRLBCL) or can be associated with such a proliferation at a separate site. Recent data indicate that progression to a process with features of THRLBCL is associated with a more aggressive clinical course, and requires different management, hence the significance of diagnosing correctly THRLBCL-like transformation of NLPHL. We report a case of THRLBCL-like transformation of NLPHL in an 11-year old male child.

PD-1 and PD-L1 Immunohistochemistry as a Diagnostic Tool for Classic Hodgkin Lymphoma in Small-volume Biopsies.

It is becoming increasingly important to obtain detailed diagnostic information on small-volume tissue biopsies, such as core needle biopsies. This is particularly crucial in the workup and diagnosis of classic Hodgkin lymphoma (CHL) and other morphologically similar lymphomas such as T-cell/histiocyte-rich large B-cell lymphoma (THRLBL), where small-volume lymph node biopsies often represent the frontline tissue source, and the differential diagnosis includes a reactive process. Immunohistochemical markers could be helpful to differentiate CHL from reactive lymph node changes (RLN) in this setting. The use of programmed cell death-1 (PD-1) and its ligand (PD-L1) immunohistochemistry has historically focused on prognostic and therapeutic value when evaluating CHL. However, the present study seeks to determine the diagnostic utility of these markers in core needle biopsies of CHL (25), THRLBL (3), and RLN (31). The cases of CHL and THRLBL were previously diagnosed and confirmed with standard immunohistochemistry, allowing the utility of PD-1 and PD-L1 to be tested in this setting. Different PD-1 and PD-L1 expression patterns were observed between the reactive process of RLN and the malignant lymphomas (CHL and THRLBL). CHL cases overall showed the greatest expression of PD-L1 within the malignant Reed-Sternberg cell population, with 40% of CHL cases exhibiting >50% PD-L1 expression. This degree of PD-L1 expression was not seen in the lymphocytic cell population of any RLN (P<0.001). Conversely, CHL cases showed an overall lower expression of PD-1, as 96% of CHLs had <5% PD-1 expression in Reed-Sternberg cells compared with only 10% expression within the lymphocytic population of RLN (P<0.001). THRLBL cases followed a similar trend to CHL. These results demonstrate that upfront PD-1 and PD-L1 immunohistochemistry can aid in the diagnosis of CHL in small-volume tissue biopsies.