Variant histology of pediatric nodular lymphocyte-predominant Hodgkin lymphoma with IgD and CD30 expression.

BACKGROUND: Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), recently known as nodular lymphocyte-predominant B-cell lymphoma (NLPBL), accounts for 5%-10% of Hodgkin lymphoma (HL). Different morphologic patterns of NLPBL are identified and categorized as typical patterns (type A and B) and variant histologic patterns (types C, D, E, and F). PATIENTS AND METHOD: We investigated different morphologic patterns, CD30 and IgD expression in pediatric patients with NLPBL diagnosed at the Children's Cancer Hospital Egypt. RESULTS: Forty-six (53%) of the patients exhibited a typical histologic pattern, whereas the remaining (47%) exhibited variant histologic pattern. Variant histology is associated with unfavorable clinical characteristics, such as advanced stages, B-symptoms, and extranodal involvements, particularly bone marrow and bone infiltration, with p-values of .06, .05, and 0.01%, respectively. Additionally, 39% of patients with variant histology experienced disease progression or relapse, compared to only 15.2% of patients with typical patterns (p = .009). Types C and D are related to decreased event-free survival (EFS), as shown by a p-value of .05. The 5-year EFS for patients with variant histology was 94.4% for the rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone (RCHOP) versus 33.3% for the adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD). IgD expression in lymphocyte-predominant (LP) cells was detected in 44 (50%) patients, while CD30 expression in LP cells was found in 39 (44%) patients. CONCLUSION: Variant histology of NLPBL was associated with advanced disease stages and a poor prognosis, while expression of IgD and CD30 in LP cells was not. The poor outcome of variant histology improved with the RCHOP regimen.

[Nodular lymphocyte predominant Hodgkin lymphoma (paragranuloma of Poppema) in children: Case report, review of the literature and treatment]. / Lymphome de Hodgkin nodulaire à prédominance lymphocytaire (paragranulome de Poppema) chez l'enfant : à propos d'un cas, revue de la littérature et traitement.

We present the case of a 12 year old child with a limp. The diagnostic work-up reveals splenomegaly, multifocal bone involvement and abdominal adenopathies. A biopsy of an intra-abdominal lesion shows a lymphoid mass with a nodular architecture composed of poorly defined nodules. We identify large cells with irregular, sometimes poly-lobulated nuclei with a particular immunohistochemical profile. Those "pop-corn" cells are positive for CD20, CD79a, pax-5 and bcl-6 and are negative for CD15, CD30, bcl-2, TdT, CD56 and EMA. There is a diffuse follicular helper T cell population that is located in between the tumour cells. The overall picture is indicative of a nodular lymphocyte predominant Hodgkin lymphoma. Advanced stage of this disease is rare in children and there is currently little data to guide optimal treatment. Because of a stage IV disease, the patient is treated with chemotherapy after which complete metabolic remission is observed. 3.5 years after the initial diagnosis, our patient relapses. He is treated with chemotherapy and an autologous peripheral blood stem cell transplantation. He remains in complete remission since then. This case illustrates the favorable prognosis of the disease even after relapse.

Characterizing the immune microenvironment for nodular lymphocyte-predominant Hodgkin lymphoma.

The microenvironment of nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) and its relationship to presentation and outcomes has not been widely investigated. In a large cohort of patients with NLPHL, Hartmann and colleagues showed an association between microenvironmental factors and clinical presentation serving to inform future studies evaluating the prognostic impact of the immunoarchitectural patterns and cell types present. Commentary on: Hartmann et al. Tumor cell characteristics and microenvironment composition correspond to clinical presentation in newly diagnosed nodular lymphocyte predominant Hodgkin lymphoma. Br J Haematol 2022;199:392-401.

Epstein-Barr virus infection patterns in nodular lymphocyte-predominant Hodgkin lymphoma.

AIMS: To investigate Epstein-Barr virus (EBV) latency types in 19 cases of EBV-positive nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), as such information is currently incomplete. METHODS AND RESULTS: Immunohistochemistry (IHC) for CD20, CD79a, PAX5, OCT2, CD30, CD15, CD3 and programmed cell death protein 1 was performed. For EBV detection, in-situ hybridisation (ISH) for EBV-encoded RNA (EBER) was employed combined with IHC for EBV-encoded latent membrane protein (LMP)-1, EBV-encoded nuclear antigen (EBNA)-2, and EBV-encoded BZLF1. In 95% of the cases, neoplastic cells with features of Hodgkin and Reed-Sternberg (HRS) cells were present, mostly showing expression of CD30. In all cases, the B-cell phenotype was largely intact, and delineation from classic Hodgkin lymphoma (CHL) was further supported by myocyte enhancer factor 2B (MEF2B) detection. All tumour cells were EBER-positive except in two cases. EBV latency type II was most frequent (89%) and type I was rare. Cases with latency type I were CD30-negative. Five cases contained some BZLF1-positive and/or EBNA-2-positive bystander lymphocytes. CONCLUSIONS: As HRS morphology of neoplastic cells and CD30 expression are frequent features of EBV-positive NLPHL, preservation of the B-cell transcription programme, MEF2B expression combined with NLPHL-typical architecture and background composition facilitate distinction from CHL. EBER ISH is the method of choice to identify these cases. The majority present with EBV latency type II, and only rare cases present with latency type I, which can be associated with missing CD30 expression. The presence of occasional bystander lymphocytes expressing BZLF1 and/or EBNA-2 and the partial EBV infection of neoplastic cells in some cases could indicate that EBV is either not primarily involved or is only a transient driver in the pathogenesis of EBV-positive NLPHL.

Lymphocyte predominant Hodgkin lymphoma, antigen-driven after all?

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) was suggested as an entity separate from other types of Hodgkin lymphoma 40 years ago and recognized in the WHO classification in 2001. Based on its relatively benign course with late distant relapses, relation with lymph node hyperplasia with progressively transformed germinal centers, presence of clonal immunoglobulin gene rearrangements with somatic hypermutations and ongoing mutations, and relation with a number of inherited defects affecting the immune system, it has been suspected that NLPHL might be antigen-driven. Recent evidence has shown that cases of IgD-positive NLPHL are associated with infection by Moraxella catarrhalis, a common bacterium in the upper respiratory tract and in lymph nodes. This review summarizes the evidence for NLPHL as a B-cell lymphoma involving follicular T-lymphocytes normally found in germinal centers, its molecular features and relation to inherited immune defects, and its relation and differential diagnosis from similar entities. Finally, it discusses the evidence that in many cases a watch and wait policy might be a viable initial management strategy. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Outcome of relapsed and refractory nodular lymphocyte-predominant Hodgkin lymphoma: a North American analysis.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare entity, with limited data on the outcome in the relapsed/refractory setting. We evaluated the outcome of all patients diagnosed between 04/1979 and 01/2019 with relapsed or progressive NLPHL after initial active therapy at two institutions, refractory disease being defined as lack of response to treatment and/or relapse within three months of treatment. NLPHL patients with histological evidence of transformation at time of first relapse or progression were excluded. In total, 69 patients with recurrent NLPHL were included in the study. After a median follow-up after initial diagnosis of 14 years (range, 0·5-46 years), median progression-free survival after front-line treatment (PFS-1) was four years. Second-line therapy included chemotherapy in 28 (41%) patients, biological therapy (rituximab, lenalidomide or brentuximab vedotin) in 14 (20%), high-dose chemotherapy followed by autologous stem cell transplant in 14 (20%) and radiation therapy (RT) alone in 10 (15%). The five-year PFS after second-line therapy (PFS-2) was 68% [95% confidence interval (CI), 54-79%] but the five-year overall survival (OS) after second-line therapy (OS-2) remained excellent, at 94% (95% CI, 85-99%). Due to excellent outcome in case of recurrence, studies aimed at characterizing its biology to guide therapy de-escalation are needed.

Primary therapy and survival among patients with nodular lymphocyte-predominant Hodgkin lymphoma: a population-based analysis in the Netherlands, 1993-2016.

In this nationwide, population-based study, we assessed trends in primary treatment and survival among 687 patients with nodular lymphocyte-predominant Hodgkin lymphoma (75% males; median age, 40 years; and 74% stage-I/II disease) diagnosed in the Netherlands between 1993-2016. There were no noteworthy changes in the application of primary therapy over time among adult patients across the different disease stages and age groups. Survival among various subgroups of adult patients was largely comparable to the expected survival of the general population. A particularly encouraging finding was that young adult patients experienced virtually no excess mortality, as compared to the general population.

Unfavorable presentation but comparable outcome: Presentation and outcome of children with nodular lymphocyte predominant Hodgkin lymphoma from India.

BACKGROUND: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is an uncommon subtype of Hodgkin lymphoma (HL) with few published studies in children, entirely from North America and Europe. We analyzed clinical features and treatment outcome of pediatric NLPHL. PROCEDURE: Children less than 18 years of age diagnosed after histopathology review to have NLPHL between June 1998 and August 2016 were retrospectively analyzed. Descriptive details of clinical presentation and treatment were collected, and outcomes analyzed using Kaplan-Meier survival analysis. RESULTS: Of the 42 patients with a confirmed diagnosis of NLPHL during this period, there was complete information on 35. Median age was 11 years (range 6-16 years), male:female ratio was 4.8:1, there were 15, 11, 6, and 3 patients with Stage I, Stage II, Stage III, and Stage IV disease, respectively. Six patients had B symptoms, 10 had bulky disease, and 3 had bone marrow as well as extranodal involvement. Histology was typical NLPHL in 23 and variant in 12. Twenty-nine received chemotherapy, 10 with additional radiation, 3 patients with early stage disease received only radiotherapy and three others underwent complete node resection alone. Median follow-up was 55 months (range 7-165 months), 5 year event-free survival (EFS) was 83.3%, and overall survival 97.1%. Variant NLPHL histology was associated with higher incidence of unfavorable presentation and lower EFS. CONCLUSIONS: NLPHL in India has an excellent outcome, despite a higher incidence of unfavorable presentations such as advanced stage disease, B symptoms, and bulky disease. Variant histology is an adverse prognostic factor.

Relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma in children and adolescents - a report from the United Kingdom's Children's Cancer and Leukaemia Study Group.

There is a paucity of data on the treatment outcome in children with relapsed or poorly responsive nodular lymphocyte predominant Hodgkin lymphoma (nLPHL). This retrospective report evaluates the treatment outcome in a national cohort of children with relapsed or poorly responsive nLPHL. A total of 37 patients, 22 with relapsed and 15 with poorly responding disease, are the subjects of this report. Of the 22 patients with relapsed nLPHL, 11 had relapsed after primary excision biopsy, 10 after chemotherapy and 1 after chemotherapy and involved field radiotherapy. The majority had localized disease at relapse. The median time to relapse was 8 months after chemotherapy and 11 months after excision biopsy. Seven of the 15 patients with poorly responding nLPHL had variant histology. Three patients with initial poor response did not receive any further treatment and have had no disease progression. Transformation to diffuse large B cell lymphoma, in addition to evolution from typical to variant nLPHL occurred in one patient each. Thirty-four patients have been successfully re-treated with second chemotherapy or radiotherapy. Multiple relapses were uncommon but treatable. Relapse or poorly responsive nLPHL is fully salvageable with either additional chemotherapy and or radiotherapy.

Childhood and Adolescent nodular lymphocyte predominant Hodgkin lymphoma - A review of clinical outcome based on the histological variants.

Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) comprises approximately 10-12% of all childhood Hodgkin lymphoma. As the majority have low stage disease recent years have seen a de-escalation of treatment intensity to avoid treatment-related morbidity. This report evaluates treatment outcome in children with histopathological variants of nLPHL after therapy de-escalation. Biopsies from 60 patients were reviewed and histology categorized as typical (n = 47; 78%) or variant nLPHL (n = 13; 22%). Furthermore, presence of immunoglobulin D (IgD) expression by the lymphocyte predominant (LP) cells was assessed in 41 patients. Treatment outcomes were compared according to treatment received and histopathology of nLPHL. Compared to typical nLPHL, children with variant nLPHL had higher stage disease at diagnosis (stage III: 3/13; 23% vs. 3/47; 6%, P = 0·11), lower complete response rates (6/13; 46% vs. 38/47; 81%, P = 0·029) and higher relapse rates (2/13; 15% vs. 2/47; 4%, P = 0·20). Additionally, IgD expression by LP cells was associated with poorer treatment response and was more commonly seen in patients with variant nLPHL. (11/13; 85% vs. 15/28; 54%, P = 0·08). Variant histology appears to be indicative of a poorer prognosis in patients with early stage disease, and may be an important factor to take into account when moving towards reduced intensity treatment for nLPHL.

Microenvironmental immune cell alterations across the spectrum of nodular lymphocyte predominant Hodgkin lymphoma and T-cell/histiocyte-rich large B-cell lymphoma.

Background: The clinicopathological spectrum of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL), also known as nodular lymphocyte predominant B-cell lymphoma, partially overlaps with T-cell/histiocyte-rich large B-cell lymphoma (THRLCBL). NLPHL histology may vary in architecture and B-cell/T-cell composition of the tumour microenvironment. However, the immune cell phenotypes accompanying different histological patterns remain poorly characterised. Methods: We applied a multiplexed immunofluorescence workflow to identify differential expansion/depletion of multiple microenvironmental immune cell phenotypes between cases of NLPHL showing different histological patterns (as described by Fan et al, 2003) and cases of THRLBCL. Results: FOXP3-expressing T-regulatory cells were conspicuously depleted across all NLPHL cases. As histology progressed to variant Fan patterns C and E of NLPHL and to THRLBCL, there were progressive expansions of cytotoxic granzyme-B-expressing natural killer and CD8-positive T-cells, PD1-expressing CD8-positive T-cells, and CD163-positive macrophages including a PDL1-expressing subset. These occurred in parallel to depletion of NKG2A-expressing natural killer and CD8-positive T-cells. Discussion: These findings provide new insights on the immunoregulatory mechanisms involved in NLPHL and THLRBCL pathogenesis, and are supportive of an increasingly proposed biological continuum between these two lymphomas. Additionally, the findings may help establish new biomarkers of high-risk disease, which could support a novel therapeutic program of immune checkpoint interruption targeting the PD1:PDL1 and/or NKG2A:HLA-E axes in the management of high-risk NLPHL and THRLBCL.

Aberrant expression of lymphoid enhancer-binding factor 1 in Hodgkin lymphoma.

Lymphoid enhancer-binding factor 1 (LEF1) is a transcription factor involved in T-cell maturation and is usually absent in mature B cells. Previous studies have shown aberrant LEF1 expression as a sensitive and specific marker in chronic lymphocytic leukemia/small lymphocytic lymphoma. Our primary aims were i) to analyze LEF1 expression in classic Hodgkin lymphomas (CHLs), including de novo and Richter syndrome (RS), and to assess if LEF1 can be a surrogate marker to assess clonal relationship in RS and ii) to compare LEF1 expression in CHL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). We included 117 patients: 24 CHL-RS, 66 CHL-de novo, and 27 NLPHL. There was no significant difference in LEF1 expression between CHL-RS and CHL-de novo (79.2% vs 87.9%, P = 0.299) or in type I and type II CHL-RS (75% vs 81.3%, P = 1.000). However, CHL showed a significantly higher LEF1 expression than NLPHL (85.6% vs 44.4%, P < 0.0001). As the Wnt/ß-catenin pathway directly regulates LEF1 expression in a ß-catenin-dependent way, ß-catenin expression was assessed in 76 cases and all were negative. Additionally, no association between Epstein-Barr virus positivity and LEF1 expression was detected. Overall, our findings show high LEF1 expression in CHL, regardless of RS or de novo, indicating LEF1 cannot be utilized as a surrogate marker to suggest clonal relationship in RS. Compared with CHL, LEF1 expression is significantly less common in NLPHL, further attesting that they are biologically distinct entities. The absent ß-catenin expression suggests LEF1 expression is independent of Wnt/ß-catenin signaling pathway in Hodgkin lymphomas.

Nodular Lymphocyte-Predominant Hodgkin Lymphoma: Review of Current Literature and Case Discussion.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare subset of Hodgkin lymphoma (HL). It has a distinct clinical and pathological presentation. Unlike classic HL, where the predominant malignant cells are Reed Sternberg cells, the malignant cells in NLPHL are known as lymphocyte predominant (LP) cells, with their own unique immunohistochemistry antigen expression and staining pattern. Based on risk stratification and staging of the disease, treatment can range from active surveillance in asymptomatic patients with no organ compromise or bulky disease, to aggressive chemotherapeutic agents in advanced disease. Guidelines on which of these chemotherapy regimens would offer the most benefit to our patients are limited due to lack of randomized-controlled studies. Majority of the current prospective data on treatment were inclusive of both HL and NLPHL. Thus, the regimens employed in treatment of NLPHL are similar to the ones used in HL, though NLPHL is often viewed as its own distinct entity. This article aims to review the current literature and future advances on treatment of this rare disease.

The stage-specific roles of radiotherapy and chemotherapy in nodular lymphocyte predominant Hodgkin lymphoma patients: a propensity score-matched analysis of the SEER database.

BACKGROUND: The stage-specific roles of radiotherapy (RT) alone, chemotherapy alone, and combined RT and chemotherapy (CRT) for patients with nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) have not been adequately evaluated. METHODS: We analyzed patients with all stages of NLPHL enrolled in the Surveillance, Epidemiology, and End Results (SEER) registry from January 2000 to December 2015. Propensity score (PS) analysis with 1:1 matching (PSM) was performed to ensure the well-balanced characteristics of the comparison groups. Kaplan-Meier and Cox proportional-hazards models were used to evaluate the overall survival (OS), cancer-specific survival (CSS), hazard ratios (HRs), and corresponding 95% confidence intervals (95% CI). Restricted mean survival times (RMST) were also used for the survival analyses. RESULTS: For early-stage patients, CRT was associated with the best survival, the mean OS was significantly improved by approximately 20 months (20 m), and the risk of death was reduced by more than 80%, both before and after PSM (p < 0.05). For advanced-stage patients, none of RT alone, chemotherapy alone, or CRT had a significant effect on survival. Chemotherapy alone and CRT might be more beneficial for long-term survival (RMST120 m : neither RT nor chemotherapy vs. chemotherapy alone vs. CRT = 104 m vs. 111 m vs. 108 m). Subgroup analysis of patients with early-stage NLPHL showed that CRT was associated with better survival of elderly patients (improved OS = 43.8 m, HR = 0.14, p < 0.05). However, the survival benefits of treatments for young patients were not statistically significant. The efficacy of RT was significantly different between the age groups (pfor interaction  = 0.020). CONCLUSIONS: These results from SEER data suggest that CRT may be considered for early-stage NLPHL, especially for elderly patients. Further studies are needed to identify effective treatments in patients with advanced-stage NLPHL.

Hodgkin Lymphoma-Review on Pathogenesis, Diagnosis, Current and Future Treatment Approaches for Adult Patients.

Hodgkin lymphoma (HL) is a rare malignancy accounting for roughly 15% of all lymphomas and mostly affecting young patients. A second peak is seen in patients above 60 years of age. The history of HL treatment represents a remarkable success story in which HL has turned from an incurable disease to a neoplasm with an excellent prognosis. First-line treatment with stage-adapted treatment consisting of chemotherapy and/or radiotherapy results in cure rates of approximately 80%. Second-line treatment mostly consists of intensive salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Novel approaches such as antibody drug conjugates and immunomodulatory drugs have shown impressive results in clinical trials in refractory and relapsed HL and are now increasingly implemented in earlier treatment lines. This review gives a comprehensive overview on HL addressing epidemiology, pathophysiology and current treatment options as well as recent developments and perspectives.

SUMO1 modification of histone H4 is involved in the pathogenesis of nodular lymphocyte predominant Hodgkin lymphoma.

BACKGROUND: Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a distinct and rare subtype of Hodgkin lymphoma (HL) that can be differentially diagnosed from classical Hodgkin lymphoma (cHL). Because of its low prevalence rate and undefined pathogenic mechanisms, a specific treatment for NLPHL has yet to be determined. In NLPHL, which is a malignant B-cell lymphoma, antigen stimulation results in the formation of germinal centers by secondary lymphoid follicles, which promotes the differentiation of germinal center B cells (GCBs) into long-lived plasma cells and memory B cells. Any abnormality during the differentiation can lead to the occurrence and development of NLPHL. METHODS: The GDS4977 data set was selected from the Gene Expression Omnibus (GEO) repository. Differentially-expressed genes (DEGs) were detected with GEO2R. Gene Ontology (GO) enrichment analysis of biological processes (BP) and Reactome pathways was performed withg:Profile. Cytoscape software was employed to screen hub genes, while the core genes were determined using the STRING and Reactome databases. RESULTS: In total, 623 DEGs, 68 GO-BP pathways, 70 Reactome pathways, 19 hub genes, and 12 core genes were identified. CONCLUSIONS: Histone expressions differ between NLPHL and GCBs, and HIST1H4B, HIST1H4C, HIST1H4E, HIST1H4L, HIST1H2AE, H2AFZ, HIST1H2BM, and H3F3A jointly form the core histones. During the development of NLPHL, histones are transported by NPM1. The pathogenesis of NLPHL involves SUMO-1 modification of histone H4.