Nodular Lymphocyte Predominant Hodgkin Lymphoma Research Articles

IgD expression in various immunoarchitectural patterns of nodular lymphocyte predominant Hodgkin lymphoma in children

Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) consist of lymphocyte predominant cell or LP-cell. Despite their origin from active germinal centers, in some cases LP-cells express IgD, which is characteristic of naive B-lymphocytes of the mantle zone. Due to the rarity of NLPHL, assessing the frequency of IgD-positive cases is difficult. This marker can serve not only for differential diagnosis with other diseases, but also indicate the possible heterogeneity of NLPHL, which is currently represented by six immunoarchitectural patterns. To determine the frequency of IgD-positive cases of NLPHL in children with subsequent assessment of the association with types of immunoarchitectural patterns. The study included 52 cases of NLPHL, which were divided to typical and atypical patterns. Differences between two groups were compared using Fisher's exact tests. IgD expression was found in LP-cells in 26 of 52 cases (50%) and was positively correlated with atypical types (typical - 5/23, 21.7% vs atypical - 21/29, 72.4%, p=0.0003), among which pattern C was most common. Due to the high incidence of IgD-positive cases in NLPHL, this marker may be useful in differential diagnosis with histologic mimics. At the same time, positive IgD status was associated with atypical patterns, which may likely determine the different biology of neoplastic cells within the same form.

Evidence for distinct mechanisms of immune suppression in EBV-positive and EBV-negative Hodgkin lymphoma.

Epstein Barr Virus (EBV) has been recognized for its ability to transform B lymphocytes and for its association with different types of cancers including Hodgkin lymphoma. In addition, EBV may also modulate the microenvironment of HL. In this study, we aimed to investigate the prevalence of EBV among HL cases in Ethiopia and to assess the tissue cellular composition of EBV-related and EBV-unrelated cases. We constructed a tissue microarray (TMA) of 126 consecutive cases of classical HL (CHL) and nodular lymphocyte predominant HL (NLPHL) from a tertiary cancer centre, Tikur Anbessa Hospital, Addis Ababa, Ethiopia, and evaluated a panel of immunohistochemical markers. The quantification of immune cells was performed using HALO 2.3, a platform for image analysis from Indica Lab Inc. A total of 77/126 (61.1%) of HL cases expressed LMP1/EBER. Infiltration of CD8+, T-bet+ and FoxP3+ cells was higher in the microenvironment of EBV-related CHL, with P values of <0.001, <0.001 and <0.016, respectively. In contrast, the expression of PD1 was higher in the microenvironment of EBV-unrelated CHL cases (P < 0.001). Unlike in Western countries, the majority of HL cases in Ethiopia were associated with EBV. As FoxP3+ and PD1-expressing cells are thought to participate in down regulation of the immune response by different mechanisms, this finding highlights the previously unrecognized possibility that distinct immunosuppressive mechanisms may be ongoing within EBV positive and negative HL types. This may have important prognostic and therapeutic implications.

T-Cell-Rich Hodgkin Lymphoma With Features of Classic Hodgkin Lymphoma and Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Borderline Category With Overlapping Morphologic and Immunophenotypic Features.

It is known that a subset of cases of classic Hodgkin lymphoma (CHL) with B-cell-rich nodules (lymphocyte-rich CHL) exhibits morphologic and immunophenotypic features that overlap with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), raising diagnostic difficulties that can be resolved in most cases by performing an adequate battery of immunohistochemical studies. To fully characterize cases of T-cell-rich Hodgkin lymphoma where a specific diagnosis of NLPHL (ie, pattern D) or CHL could not be made even after complete immunophenotypic investigation. The clinical, immunomorphologic, and molecular (when applicable) presentation of 3 cases of T-cell-rich Hodgkin lymphoma was thoroughly investigated. These 3 cases harbored lymphocyte-predominant-like and Hodgkin and Reed-Sternberg-like cells that partially expressed B-cell and CHL markers and were negative for Tiftein-Barr virus-encoded small RNA, in a T-cell-rich background with residual follicular dendritic cell meshworks; 1 case had frequent and the other 2 cases scant/absent eosinophils and plasma cells. Two patients with advanced-stage (III or IV) disease presented with axillary and supraclavicular lymphadenopathy, respectively, and without B symptoms. These patients underwent NLPHL-like therapeutic management with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone) chemotherapy; both are in complete remission 7 years posttherapy. One patient presented with stage I disease involving an internal mammary lymph node without B-symptoms and was treated with surgical excision alone; this patient is also in complete remission 1 year later. These cases illustrate overlapping features of T-cell-rich NLPHL and CHL with neoplastic cells expressing both B-cell program and CHL markers. This underrecognized overlap has not been fully illustrated in the literature, although it portrays a therapeutic challenge. These neoplasms may deserve in-depth investigation in the future that may bring up diagnostic or theragnostic implications.

Diagnostic peculiarities of lymphomas in the cervical region in children

Thisarticle discusses various aspects of pediatric lymphadenopathy, focusing on Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). It outlines common etiologies, diagnostic techniques, and key characteristics of differ- ent lymphoma subtypes. HL is classified into classical HL (CHL) and nodular lymphocytic predominant HL (NLPHL), while NHL includes Burkitt lymphoma (BL), lymphoblastic lymphoma (LBL), diffuse large B-cell lymphoma (DLBCL), and anaplastic large cell lymphoma (ALCL). The text emphasizes the importance of accurate diagnosis through various tests, including imaging modalities such as positron emission tomography (PET) and computed tomography (CT). It also discusses the potential use of ctDNA as a prognostic marker and highlights genetic alterations contributing to lymphoma development. The relevance of these findings for pediatric patients and their impact on treatment strategies is emphasized throughout the text.

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&amp;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&amp;lt;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&amp;lt;0.001). Finally, we identified a strong association between THRLBCL and upregulation of checkpoint genes (P&amp;lt;0.001) and gene expression related to inflammatory response (P&amp;lt;0.001) (Figure 2). Furthermore, NLPHLs with a high checkpoint score (above the 75th percentile) were associated with spleen involvement (P&amp;lt;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.

Performance of Positron Emission Tomography at Diagnosis and Response Assessment in Low and Intermediate-Risk Nodular Lymphocyte Predominant Hodgkin Lymphoma

Background: Nodular lymphocyte predominant Hodgkin lymphoma (nLPHL) has different histology, clinical presentation, and outcomes than classical Hodgkin Lymphoma (cHL). Positron Emission Tomography (PET) plays an important role in staging and response assessment in cHL, but little is published about the use of PET to guide treatment in nLPHL. A better understanding of the clinical significance of PET response in nLPHL is critical for incorporating PET into prospective trials. Methods: Children's Oncology Group study AHOD03P1 (NCT00107198) enrolled patients with low-risk nLPHL and AHOD0031 (NCT00025259) enrolled patients with intermediate-risk cHL and nLPHL &amp;lt;22 years of age. AHOD03P1 patients with stage IA and &amp;gt;1 lymph node or stage IIA nLPHL were treated with 3 cycles of doxorubicin, vincristine, prednisone, and cyclophosphamide (AV-PC) chemotherapy, given every 21 days. Patients with a complete response (CR) based on anatomic response and qualitative reading (&amp;lt;mediastinal blood pool) of negative PET on central review did not receive radiation therapy while patients with &amp;lt;CR received 21-Gy involved field radiation therapy (IFRT). AHOD0031 patients with stages IB, IAE, IIB, IIAE, IIIA, IVA with or without bulk disease, and IA or IIA with bulk disease received 2 cycles of doxorubicin, bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) followed by response evaluation. Slow early responders were randomized to an additional 2 cycles of ABVE-PC with or without 2 cycles of dexamethasone, etoposide, cisplatin and cytarabine (DECA) and all received IFRT. Rapid early responders (RERs) received 2 additional cycles of ABVE-PC. RERs with CR were randomized to IFRT or no further therapy. RER/non-CRs were non-randomly assigned to IFRT. PET scans from both trials available in the Imaging and Radiation Oncology Core (IROC) were retrospectively reviewed and assigned a score of 1-5 on the Deauville 5-point scale (5PS). Patients who did not have evaluable imaging due to either scans not performed, on CD-ROM and inaccessible, or poor quality, were excluded from this analysis. Three-year event-free survival (EFS) was analyzed by 5PS at end of therapy using the Kaplan Meier method. Results: AHOD03P1 enrolled 135 patients with low-risk nLPHL who received chemotherapy and AHOD0031 enrolled 96 patients with intermediate-risk nLPHL. PET imaging available for review at diagnosis in 99 low-risk patients, 92% 5PS=5, and 55 intermediate-risk patients, 98% 5PS=5. Median age 13.4 years (range 16.5), 84.9% male, 29.9% Stage I, 49.8% Stage II, 18.6% Stage III, and 1.7% Stage IV. After 3 cycles of chemotherapy, 106 low-risk patients had available PET scans, 5PS 1 n=50, 5PS 2 n=35, 5PS 3 n=11, 5PS 4 n=7, and 5PS 5 n=3. Three-year EFS for patients with end of chemotherapy 5PS was: 5PS 1 89.9% (95% CI 77.3-95.7%), 5PS 2 97.1% (95% CI 81.4-99.6%), 5PS 3 90.9% (95% CI 50.8-98.7%), 5PS 4 28.6% (95% CI 1.0-71.1%), 5PS 5 66.7% (95% CI 5.4-94.5%) p=0.0081. When categorized as PET negative (5PS 1-3) and PET positive (5PS 4-5), 3-year EFS was 92.6% (95% CI 85.2-96.4%) for PET negative and 45.0% (95% CI 10.6-75.3%) for PET positive patients, p=0.0036 (Figure 1A). Forty-nine intermediate-risk patients had available PET scans after 2 cycles of chemotherapy, 5PS 1 n=9, 5PS 2 n=26, 5PS 3 n=10, 5PS 4 n=3, and 5PS 5 n=1. Three-year EFS by interim response was: 5PS 1 88.9% (95% CI 43.3-98.4%), 5PS 2 96.0% (95% CI 74.8-99.4%), 5PS 3 100%, 5PS 4 100%, 5PS 5 0%, p&amp;lt;0.0001. Thirty-six patients had available PET scans after 4 cycles of chemotherapy, 5PS 1 n=20, 5PS 2 n=11, 5PS 3 n=3, 5PS 4 n=1, and 5PS 5 n=1. Three-year EFS by response after 4 cycles of chemotherapy: 5PS 1 95.0% (95% CI 69.5-99.3%), 5PS 2 100%, 5PS 3 100%, 5PS 4 100%, 5PS 5 0% p&amp;lt;0.0001. When divided into PET negative (5PS 1-3) and PET positive (5PS 4-5), 3-year EFS 97.0% (95% CI 80.4-99.6%) for PET negative and 50.0% (95% CI 0.6-91.0%) for PET positive patients after 4 cycles of chemotherapy, p=0.1449 (Figure 1B). Conclusions: At diagnosis, low and intermediate-risk nLPHL lesions are almost always PET avid with 5PS=5. PET response following 3 cycles of AV-PC chemotherapy is highly predictive of outcome in pediatric patients with low-risk nLPHL when considering 5PS=3 as PET negative. Intermediate-risk patients with negative PET following ABVE-PC achieved excellent outcomes. Whether PET maintains prognostic significance in patients with nLPHL treated with rituximab needs to be studied.

Patient Characteristics and Outcomes of Nodular Lymphocyte Predominant Hodgkin Lymphoma at a Safety-Net System Compared to an Academic Comprehensive Cancer Center

Purpose: Nodular lymphocyte predominant Hodgkin's lymphoma (NLPHL) is a rare subtype of Hodgkin lymphoma that often follows an indolent course although carries a risk of late recurrence and transformation. Given its rarity, there is significant variability in the treatment patterns at various healthcare centers. The aim of this study was to compare the patient characteristics and outcomes of NLPHL treated at a safety-net system compared to those treated at an academic comprehensive cancer center. Materials and Methods: Parkland Health (PH) is the safety-net system for uninsured/underinsured patients in Dallas County and is affiliated with the UT Southwestern NCI-designated Harold C. Simmons Comprehensive Cancer Center (SCCC). Electronic records of adult patients (age &amp;gt; 18) diagnosed with NLPHL between January 1st, 2007, and December 31st, 2022, at the two centers were reviewed and data on demographics, disease characteristics, treatments, and outcomes were collected. Results: A total of 53 patients were included in the study (25 at PH vs 28 at SCCC). The median age at diagnosis was 42 (IQR 32-54.5) and was not significantly different between the institutions (41.7 at PH vs 46.5 at SCCC). There was a trend towards male predominance at SCCC compared to PH, but this was not statistically significant. PH patients were more likely to belong to racial/ethnic minority groups (Black non-Hispanic 84% at PH vs 32% at SCCC; Hispanic 16% at PH vs 0% at SCCC, p &amp;lt;0.01) and to be uninsured (60% at PH vs 0% at SCCC, p &amp;lt;0.01). Overall, 38% of patients presented at a late stage (stage III-IV) and this was not different based on site of care (11 at PH vs 9 at SCCC; p=0.37). Patients were managed by observation alone (n=4), radiation only (n=11), combination chemotherapy and/or rituximab only (n= 22), or combined modality (n=12). Site of care (PH vs SCCC) or race/ethnicity did not impact the treatment choice. At a median follow up of 60 months (IQR 21-83), 6 recurrences and 5 transformations were noted. Only 3 deaths occurred during the follow up period, for an overall median survival of 62 months (IQR 21.5-84.5). Conclusion: Despite health inequities that typically impact safety-net patients, we did not observe any differences in treatment patterns or outcomes of Nodular lymphocyte predominant Hodgkin lymphoma between patients treated at Parkland Health compared to Simmons Comprehensive Cancer Center.

Comparative Outcome Analysis of Nodular Lymphocyte-Predominant Hodgkin Lymphoma Vs Classical Hodgkin's Lymphoma - a SEER Based Study

Introduction Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a slower-growing variant of Hodgkin lymphoma that is uniquely characterized by its growth pattern and cellular appearance. While patients with NLPHL tend to demonstrate more promising prognoses than their counterparts with classical Hodgkin lymphoma (CHL), recent comparative studies remain limited. The objective of this study was to investigate the disparities in survival rates between NLPHL and CHL patients, accounting for variations in patient demographics and disease attributes. Methodology We utilized Surveillance, Epidemiology, and End Results (SEER) 17 registries database to identify patients diagnosed with NLPHL and CHL between 2000 - 2020. Univariate survival analysis was done using a Kaplan Meir plot with a log-rank test, and the Cox proportion hazard regression model was used for multivariate survival analysis. Results A total of 2,723 NLPHL cases and 42,581 CHL cases were included in the study. The median age of NLPHL patients stood at 44 years, whereas for CHL patients it was observed to be 38 years. Over an 83-month median follow-up, NLPHL demonstrated superior 5-year (92.2%) and 10-year (83.84%) survival rates compared to CHL (82.45% and 75.45%, respectively). When controlled for all available characteristics, NLPHL showed a significantly higher overall survival (HR: 2.373; 95% CI, 2.131 - 2.644; P&amp;lt;.001) than CHL. For those diagnosed with NLPHL, our data indicated that patients who underwent radiation therapy had better survival rate (HR: 1.98; 95% CI, 1.55 - 2.53; p&amp;lt;.001). Additionally, younger age and male gender were associated with a more favorable prognosis. Conclusion Our analysis highlights the superior survival outcomes for NLPHL patients as compared to those with CHL, even when accounting for available patient and disease characteristics. The further enhanced survival rates observed in NLPHL patients undergoing radiation therapy suggests potential for more tailored therapeutic approaches. Factors such as younger age and male gender were also identified as indicative of a more favorable prognosis, underscoring the need for further exploration of demographic and clinical influences on survival outcomes in Hodgkin lymphomas.

Specific Polo-Like Kinase 1 Expression in Nodular Lymphocyte-Predominant Hodgkin Lymphoma Suggests an Intact Immune Surveillance Program

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare and relatively indolent B-cell lymphoma. Characteristically, the [lymphocyte-predominant (LP)] tumor cells are embedded in a microenvironment enriched in lymphocytes. More aggressive variants of mature B-cell and peripheral T-cell lymphomas exhibit nuclear expression of the polo-like kinase 1 (PLK1) protein, stabilizing MYC (alias c-myc) and associated with worse clinical outcomes. This study demonstrated expression of PLK1 in the LP cells in 100% of NLPHL cases (n=76). In contrast, <5% of classic Hodgkin lymphoma cases (n=70) showed PLK1 expression within the tumor cells. Loss-of-function approaches demonstrated that the expression of PLK1 promoted cell proliferation and increased MYC stability in NLPHL cell lines. Correlation with clinical parameters revealed that the increased expression of PLK1 was associated with advanced-stage disease in patients with NLPHL. A multiplex immunofluorescence panel coupled with artificial intelligence algorithms was used to correlate the composition of the tumor microenvironment with the proliferative stage of LP cells. The results showed that LP cells with PLK1 (high) expression were associated with increased numbers of cytotoxic and T-regulatory T cells. Overall, the findings demonstrate that PLK1 signaling increases NLPHL proliferation and constitutes a potential vulnerability that can be targeted with PLK1 inhibitors. An active immune surveillance program in NLPHL may be a critical mechanism limiting PLK1-dependent tumor growth.

Immunoglobulin light chain transcript detection by ultrasensitive RNA in situ hybridization for B-cell lymphoma diagnosis.

Evaluation of B-cell clonality can be challenging in the interpretation of lymphoid infiltrates on tissue sections. Clonality testing based on IG gene rearrangements analysis by PCR (IG-PCR) is the gold standard. Alternatively, B-cell clonality can be assessed by the recognition of immunoglobulin light chain (IgLC) restriction, by immunohistochemistry (IHC), chromogenic in situ hybridization (ISH) or flow cytometry (FC). IG-PCR requires molecular facilities, and FC requires cell suspensions, both not widely available in routine pathology units. This study evaluates the performance of B-cell clonality detection by IgLC-RNAscope® (RNAsc) in a group of 216 formalin-fixed, paraffin-embedded samples including 185 non-Hodgkin B-cell lymphomas, 11 Hodgkin lymphomas (HL) and 20 reactive samples. IgLC-RNAsc, performed in parallel with FC in 53 cases, demonstrated better performances (93% vs 83%), particularly in diffuse large B-cell lymphoma (98% vs 71%) and follicular lymphoma (93% vs 83%) diagnosis. IgLC-RNAsc was also superior to IHC and ISH especially in samples with limited tumor cell content, where IG-PCR was not informative. Performed for the first time on mediastinal lymphomas, IgLC-RNAsc identified monotypic IgLC transcripts in 69% of primary mediastinal large B-cell lymphoma (PMBCL) and 67% of mediastinal gray zone lymphomas (MGZL). IGK/L double-negative cells were detected in 1 PMBCL, 2 MGZL, and all classical HL, while monotypic IgLC expression appeared to be a hallmark in nodular lymphocyte-predominant HL. IgLC-RNAsc demonstrates to be a powerful tool in B-cell lymphoma diagnosis, above all in challenging cases with limited tumor cell content, ensuring in situ investigations on mechanisms of Ig regulation across lymphoma entities.

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

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. 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. 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. 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.

Investigating PET Responses to Treatment in Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

There is no standard treatment for nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Although response by positron emission tomography (PET) for classic Hodgkin lymphoma (cHL) has allowed for response-adapted treatment, similar approaches for NLPHL have not been developed. This is in part due to the lack of data for PET response to treatment. Therefore, we sought to investigate PET responses to management for NLPHL. We retrospectively identified 47 patients who were diagnosed with or treated for NLPHL between 2001-2018 at a single institution and underwent a staging PET. We recorded clinical data and PET metrics for patients who received various forms of management, including chemotherapy (CT), radiation therapy (RT), combined modality therapy (CMT = CT+RT, with rituximab in a subset), rituximab monotherapy, and observation after excision. Metabolic response was scored according to the Deauville 5-point scale criteria, with complete metabolic response defined as a score 1-3. We identified 47 patients with median age of 26 (IQR = 17-50). They predominantly were male (74.5%) and had early stage (23.4% I, 36.2% II) versus advanced stage (29.8% III, 10.5% IV) NLPHL. The majority of patients had their immunoarchitectural pattern scored (n = 36, 76.6%), with typical pattern (A/B) being the most frequent type (58.3%). The median follow-up was 5.7 years (IQR = 2.3-9.3). Overall survival was 100% at 5 years and 92.3% at 10 years. Primary management included CMT (n = 10, 21.3%; with rituximab in a subset n = 1, 10.0%), CT alone (n = 22, 46.8%; with rituximab in a subset n = 5, 22.7%), RT alone (n = 8, 17.0%), rituximab alone (n = 3, 6.4%), and observation after excision (n = 4, 8.5%). On baseline PET, median SUVmax was 10.7 (range = 1.7-35.4). Of the 10 patients who received CMT, the complete metabolic response rates were 42.9% at interim-chemotherapy PET and 75% at post-chemotherapy PET, which improved to 100% after consolidative radiotherapy. There was no difference in complete metabolic response rate to chemotherapy for typical versus variant pattern (P = 0.60). Of the 22 patients who received CT alone, 66.7% had a complete metabolic response at the interim PET and 72.7% at the end of chemotherapy. For RT, rituximab alone, and observation, the complete metabolic response rates at median 3 months (range 1-5 months) after treatment were 87.5%, 66.7%, 75.0%, respectively. Based on our cohort, we found that patients with NLPHL had a lower complete metabolic response to CT (∼75%) compared to cHL (∼85-90%) and PET-response was improved following RT for those receiving CMT. There was no significant difference in PET-response for those with variant versus typical immunoarchitectural patterns. Our findings will allow for the development of PET response-adapted therapy for NLPHL.

Low Dose Involved Site Radiotherapy as Single Modality Treatment for Early-Stage Nodular Lymphocyte Predominant Hodgkin Lymphoma.

Involved site radiotherapy as a single modality is considered standard of care for early-stage non-bulky nodular lymphocyte predominant Hodgkin's Lymphoma (NLPHL) with excellent rates of local control and overall survival. Guidelines suggest a dose of 30 Gy in conventional fractionation, however NLPHL has an indolent course and clinically behaves likes a low-grade lymphoma. Given the good prognosis NLPHL has been treated as low grade non-Hodgkin's lymphoma with a dose of 24 Gy in 12 fractions. Eleven patients with stage I-II non-bulky NLPHL treated with involved site radiotherapy alone to a dose of 24 Gy in 12 fractions between 2010 and 2021 were respectively identified and reviewed. Data on toxicity, post treatment PET, relapse and site of relapse were recorded from multidisciplinary meetings records and regular six monthly clinic reviews. Mean patient age was 45 (range 25-74), 9 were male. 8 were classified as having Ann-Arbor stage IA disease, and the remaining 3 had IIA disease. All patients were prescribed 24 Gy in 12 fractions, 6 patients had 3D-conformal radiotherapy, 1 static IMRT and 4 VMAT. After a median follow up of 32 months (range 12-147) the overall response rate was 100% and all patients had complete metabolic response on PET scan, performed three months following the completion of radiotherapy. All patients remained disease free throughout the follow up period (PFS and OS 100%). There were no late toxicities reported. This is the largest reported series of NLPHL patients treated with low dose involved site modern radiotherapy. Patients had excellent local control rates and survival with no significant toxicity, supporting the use of 24 Gy in early-stage non-bulky disease.

The pathobiology of select adolescent young adult lymphomas.

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

ROLE OF GATA3 AND STAT6 IMMUNOHISTOCHEMISTRY IN CLASSIC HODGKIN LYMPHOMA (CHL) AND NODULAR LYMPHOCYTE PREDOMINANT HODGKIN LYMPHOMA (NLPHL)

Objective: The purpose of our study is to investigate the utility of immunohistochemical expression of GATA3 and STAT6 in differentiating Classic Hodgkin Lymphoma (CHL) from Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL). Material and Methods: We approached database of Shaukat Khanum Memorial Cancer Hospital and Research Centre and selected a total of 79 CHLs and 15 NLPHLs diagnosed either on Trucut biopsy or excision biopsy diagnosed during the time 2020-2021. One slide from each of these 94 cases was stained with GATA3 and STAT6 independently and pattern of staining (either nuclear or cytoplasmic or dual nuclear and cytoplasmic) was accessed. Results: 75/79(95%) cases of CHL were positive for GATA3 staining [60/79(75.9%) cases showed nuclear GATA3 staining, 15/79(18.9%) cases showed both nuclear and cytoplasmic staining] and 4/79(5%) CHL cases were negative for GATA3. 15/15(100%) cases of NLPHL were negative for GATA3[12/15(80%) cases showed no staining and 3/15(20%) cases showed only cytoplasmic blush]. 65/79(82%) cases of CHL were positive for STAT6[17/79(21.5%) cases showed nuclear STAT6 expression, 48/79(60.7%) cases showed both nuclear and cytoplasmic staining], and 14/79(18%) cases of CHL were negative for STAT6 expression [8/79(10%) cases showed only cytoplasmic staining and 6/79(8%) showed neither nuclear nor cytoplasmic staining]. 14/15(93.3%) cases of NLPHL were negative for STAT6[5/79(33.3%) cases showed only cytoplasmic staining and 9/15(60%) cases showed no staining] and 1/15(6.7%) case of NLPHL was positive for STAT6[showed nuclear STAT6 staining]. Conclusion: Nuclear staining of GATA3 and STAT6 either alone or in combination with cytoplasmic staining can be used to differentiate CHL from NLPHL. GATA3 effectively excludes NLPHL with 100% negative predictive value. Keywords: GATA3, STAT6, Classic Hodgkin lymphoma, Nodular lymphocyte predominant Hodgkin lymphoma

Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Rare Lymphoma with Isolated Hepatic Presentation.

Differential diagnosis of fever, especially in young patients, is very complex and complete investigation takes time, which can delay the diagnosis of malignancies such as primary hepatic lymphoma (PHL).PHL is very rare, and overlapping symptoms with other liver diseases can make the diagnosis very challenging.When the suspicion of PHL is very high, only the hepatic biopsy can lead to the correct diagnosis because the disease has no extrahepatic involvement.

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

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). We investigated different morphologic patterns, CD30 and IgD expression in pediatric patients with NLPBL diagnosed at the Children's Cancer Hospital Egypt. 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. 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.

Digital pathology in pediatric nodular lymphocyte-predominant Hodgkin lymphoma: correlation with treatment response

Early-stage pediatric nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) can be treated effectively with low-intensity chemotherapy, most frequently cyclophosphamide in combination with vinblastine and prednisone (CVP). Descriptive histological risk factors based on the disease-defining lymphocyte predominant cells (LP cells) as used within the Fan classification, are less predictive in early-stage patients. We used deep learning-based cell detection and spatial analysis on digitized biopsy slides from 53 early-stage pediatric NLPHL patients to quantitatively assess LP cell histomorphometry. We found that poor responding patients had significantly fewer LP cells per cluster and lower LP cell density than good responding patients. In our exploratory analysis, we found no correlation between Fan classes or B cell pattern variables and therapy response. We hypothesize that the relationship between poor treatment response and decreased LP cell density may be explained by differences in LP cell proliferation.

Treatment Approaches for Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare variant of Hodgkin lymphoma characterized by a persistent risk of relapse but an excellent overall survival. Historically, it was treated similarly to classic Hodgkin lymphoma, but efforts have been made to deintensify treatment due to risk of late toxicity associated with intensive therapy. For patients with completely resected stage IA NLPHL, no further treatment may be considered, particularly for pediatric patients. For those with stage I-II NLPHL without risk factors such as B symptoms, sites>2, or variant pattern histology, lower intensity treatment with radiotherapy or chemotherapy alone may be sufficient. However, combined modality therapy is a standard treatment for favorable and unfavorable risk stage I-II NLPHL associated with excellent progression-free and overall survival rates. For patients with advanced stage NLPHL, the optimal chemotherapy is not defined, but R-CHOP appears to be an effective treatment. Efforts to study NLPHL through multicenter collaborative efforts are crucial to develop evidence based and individualized treatments for patients with NLPHL.

Relapsed nodular lymphocyte-predominant Hodgkin lymphoma presenting as severe paraneoplastic hepatitis: a case report

BackgroundHematological malignancies are an infrequent but important cause of liver dysfunction. There are several mechanisms by which this can occur, including direct malignant infiltration of the hepatic parenchyma and/or vasculature, vanishing bile duct syndrome, and paraneoplastic hepatitis. Paraneoplastic hepatitis is an extremely rare mechanism by which a hematological malignancy can cause liver dysfunction, and we present the first case, to our knowledge, of paraneoplastic hepatitis caused by nodular lymphocyte-predominant Hodgkin lymphoma in the literature.Case presentationA 28-year-old Caucasian male presented with 3 weeks of fatigue, epigastric pain, and jaundice. His medical history was significant for early stage nodular lymphocyte-predominant Hodgkin lymphoma in the cervical region in remission for 5 years after primary treatment with involved-field radiotherapy. Liver biochemistry was normal at the time of treatment for lymphoma and there was no known liver disease before the current presentation. On physical examination, there was scleral icterus and ecchymoses, but no evidence of hepatic encephalopathy, other stigmata of chronic liver disease, or lymphadenopathy. A computed tomography scan of his neck, chest, abdomen, and pelvis showed heterogeneous enhancement of the liver, multiple enlarged upper abdominal lymph nodes, and an enlarged spleen with multiple rounded lesions. Portal and hepatic veins were patent. Initial workup for viral, autoimmune-, toxin-, and medication-related hepatitis was negative. A transjugular liver biopsy was performed with histology showing a predominantly T-cell mediated hepatitis with very extensive multiacinar hepatic necrosis, but no evidence of lymphoma within the liver. Retroperitoneal lymph node biopsy revealed nodular lymphocyte-predominant Hodgkin lymphoma. The patient’s symptoms, bilirubin, and transaminases improved significantly after treatment with oral prednisolone and a staged introduction of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy.ConclusionsNodular lymphocyte-predominant Hodgkin lymphoma may cause paraneoplastic hepatitis. Physicians should be aware of the possibility of this life-threatening presentation and the importance of early liver biopsy and treatment before acute liver failure occurs. Interestingly, paraneoplastic hepatitis did not occur when nodular lymphocyte-predominant Hodgkin lymphoma was first diagnosed and confined to the cervical region, but was the presenting feature of the recurrence below the diaphragm.