T-cell States, Repertoire, and Function in Classical Hodgkin Lymphoma Revealed through Single-Cell Analyses.

The classical Hodgkin lymphoma (cHL) environment is comprised of a dense and complex immune cell infiltrate interspersed with rare malignant Hodgkin-Reed-Sternberg (HRS) cells. HRS cells are actively surveilled by endogenous T cells, but data linking phenotypic and functional T-cell states with clonality at the single-cell level in cHL is lacking. To address this knowledge gap, we performed paired single-cell RNA and T-cell receptor sequencing on 14 cHL and 5 reactive lymphoid tissue specimens. Conventional CD4+ T cells dominated the cHL landscape. However, recurrent clonal expansion within effector and exhausted CD8+ T-cell and regulatory T-cell clusters was uniquely observed in cHL specimens. Multiplex flow cytometric analysis revealed that most lymphoma-resident T cells produced effector cytokines upon ex vivo restimulation, arguing against a profound dysfunctional T-cell state in cHL. Our results raise new questions about the nature of T cells that mediate the antilymphoma response following programmed cell death protein 1 (PD-1) blockade therapy in cHL.

Immune and stromal transcriptional patterns that influence the outcome of classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) is characterized by a rich immune microenvironment as the main tumor component. It involves a broad range of cell populations, which are largely unexplored, even though they are known to be essential for growth and survival of Hodgkin and Reed-Sternberg cells. We profiled the gene expression of 25 FFPE cHL samples using NanoString technology and resolved their microenvironment compositions using cell-deconvolution tools, thereby generating patient-specific signatures. The results confirm individual immune fingerprints and recognize multiple clusters enriched in refractory patients, highlighting the relevance of: (1) the composition of immune cells and their functional status, including myeloid cell populations (M1-like, M2-like, plasmacytoid dendritic cells, myeloid-derived suppressor cells, etc.), CD4-positive T cells (exhausted, regulatory, Th17, etc.), cytotoxic CD8 T and natural killer cells; (2) the balance between inflammatory signatures (such as IL6, TNF, IFN-γ/TGF-ß) and MHC-I/MHC-II molecules; and (3) several cells, pathways and genes related to the stroma and extracellular matrix remodeling. A validation model combining relevant immune and stromal signatures identifies patients with unfavorable outcomes, producing the same results in an independent cHL series. Our results reveal the heterogeneity of immune responses among patients, confirm previous findings, and identify new functional phenotypes of prognostic and predictive utility.

Liquid biopsy: A promising tool for driving strategies and predicting failures in patients with classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) consists of a heterogeneous group of haematological disorders that covers undifferentiated B cell neoplasms originating from germinal centre B cells. The HL molecular characterization still represents an ongoing challenge due to the low fraction of tumour Hodgkin and Reed-Sternberg cells mixed with a plethora of non-tumour haematological cells. In this scenario, next generation sequencing of liquid biopsy samples is emerging as a useful tool in HL patients' management. In this review, we aimed to overview the clinical and methodological topics regarding the implementation of molecular analysis in cHL, focusing on the role of liquid biopsy in diagnosis, follow-up, and response prediction.

Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling.

The scarcity of malignant Hodgkin and Reed-Sternberg cells hampers tissue-based comprehensive genomic profiling of classic Hodgkin lymphoma (cHL). By contrast, liquid biopsies show promise for molecular profiling of cHL due to relatively high circulating tumour DNA (ctDNA) levels1-4. Here we show that the plasma representation of mutations exceeds the bulk tumour representation in most cases, making cHL particularly amenable to noninvasive profiling. Leveraging single-cell transcriptional profiles of cHL tumours, we demonstrate Hodgkin and Reed-Sternberg ctDNA shedding to be shaped by DNASE1L3, whose increased tumour microenvironment-derived expression drives high ctDNA concentrations. Using this insight, we comprehensively profile 366 patients, revealing two distinct cHL genomic subtypes with characteristic clinical and prognostic correlates, as well as distinct transcriptional and immunological profiles. Furthermore, we identify a novel class of truncating IL4R mutations that are dependent on IL-13 signalling and therapeutically targetable with IL-4Rα-blocking antibodies. Finally, using PhasED-seq5, we demonstrate the clinical value of pretreatment and on-treatment ctDNA levels for longitudinally refining cHL risk prediction and for detection of radiographically occult minimal residual disease. Collectively, these results support the utility of noninvasive strategies for genotyping and dynamic monitoring of cHL, as well as capturing molecularly distinct subtypes with diagnostic, prognostic and therapeutic potential.

Hodgkin Lymphoma: A disease shaped by the tumor micro- and macroenvironment.

The tumor microenvironment (TMicroE) and tumor macroenvironment (TMacroE) are defining features of classical Hodgkin lymphoma (cHL). They are of critical importance to clinicians since they explain the common signs and symptoms, allow us to classify these neoplasms, develop prognostic and predictive biomarkers, bioimaging and novel treatments. The TMicroE is defined by effects of cancer cells to their immediate surrounding and within the tumor. Effects of cancer cells at a distance or outside of the tumor define the TMacroE. Paraneoplastic syndromes are signs and symptoms due to effects of cancer at a distance or the TMacroE, which are not due to direct cancer cell infiltration. The most common paraneoplastic symptoms are B-symptoms, which manifest as fevers, chills, drenching night sweats, and/or weight loss. Less common paraneoplastic syndromes include those that affect the central nervous system, skin, kidney, and hematological autoimmune phenomena including hemophagocytic lymphohistiocytosis (HLH). Paraneoplastic signs such as leukocytosis, lymphopenia, anemia, and hypoalbuminemia are prognostic biomarkers. The neoplastic cells in cHL are the Hodgkin and Reed Sternberg (HRS) cells, which are preapoptotic germinal center B cells with a high mutational burden and almost universal genetic alterations at the 9p24.1 locus primarily through copy gain and amplification with strong activation of signaling via PD-L1, JAK-STAT, NFkB, and c-MYC. In the majority of cases of cHL over 95% of the tumor cells are non-neoplastic. In the TMicroE, HRS cells recruit and mold non-neoplastic cells vigorously via extracellular vesicles, chemokines, cytokines and growth factors such as CCL5, CCL17, IL6, and TGF-ß to promote a feed-forward inflammatory loop, which drives cancer aggressiveness and anti-cancer immune evasion. Novel single cell profiling techniques provide critical information on the role in cHL of monocytes-macrophages, neutrophils, T helper, Tregs, cytotoxic CD8+ T cells, eosinophils, mast cells and fibroblasts. Here, we summarize the effects of EBV on the TMicroE and TMacroE. In addition, how the metabolism of the TMicroE of cHL affects bioimaging and contributes to cancer aggressiveness is reviewed. Finally, we discuss how the TMicroE is being leveraged for risk adapted treatment strategies based on bioimaging results and novel immune therapies. In sum, it is clear that we cannot effectively manage patients with cHL without understanding the TMicroE and TMacroE and its clinical importance is expected to continue to grow rapidly.

Ultra-Deep Sequencing Reveals the Mutational Landscape of Classical Hodgkin Lymphoma.

The malignant Hodgkin and Reed Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL) are scarce in affected lymph nodes, creating a challenge to detect driver somatic mutations. As an alternative to cell purification techniques, we hypothesized that ultra-deep exome sequencing would allow genomic study of HRS cells, thereby streamlining analysis and avoiding technical pitfalls. To test this, 31 cHL tumor/normal pairs were exome sequenced to approximately 1,000× median depth of coverage. An orthogonal error-corrected sequencing approach verified >95% of the discovered mutations. We identified mutations in genes novel to cHL including: CDH5 and PCDH7, novel stop gain mutations in IL4R, and a novel pattern of recurrent mutations in pathways regulating Hippo signaling. As a further application of our exome sequencing, we attempted to identify expressed somatic single-nucleotide variants (SNV) in single-nuclei RNA sequencing (snRNA-seq) data generated from a patient in our cohort. Our snRNA analysis identified a clear cluster of cells containing a somatic SNV identified in our deep exome data. This cluster has differentially expressed genes that are consistent with genes known to be dysregulated in HRS cells (e.g., PIM1 and PIM3). The cluster also contains cells with an expanded B-cell clonotype further supporting a malignant phenotype. This study provides proof-of-principle that ultra-deep exome sequencing can be utilized to identify recurrent mutations in HRS cells and demonstrates the feasibility of snRNA-seq in the context of cHL. These studies provide the foundation for the further analysis of genomic variants in large cohorts of patients with cHL. SIGNIFICANCE: Our data demonstrate the utility of ultra-deep exome sequencing in uncovering somatic variants in Hodgkin lymphoma, creating new opportunities to define the genes that are recurrently mutated in this disease. We also show for the first time the successful application of snRNA-seq in Hodgkin lymphoma and describe the expression profile of a putative cluster of HRS cells in a single patient.

[Progressively transformed germinal center-like follicular T-cell lymphoma:a clinicopathological analysis of 14 cases].

Objective: To investigate the clinicopathologic features of progressively transformed germinal center-like follicular T-cell lymphoma (PTGC-like FTCL). Methods: The clinicopathologic data of 14 PTGC-like FTCL cases that were diagnosed at the Beijing Friendship Hospital Affiliated to the Capital Medical University from January 2017 to January 2022 were retrospectively collected. Clinicopathological features, immunophenotype, and Epstein-Barr virus (EBV) infection status were analyzed in these cases. Polymerase chain reaction (PCR) was performed to detect the clonal gene rearrangements of T cell receptor (TCR) and the immunoglobulin (Ig) in 10 and 8 cases, respectively. Results: The male to female ratio was 5∶2. The median age was 61 years (range 32-70 years). All patients had lymphadenopathy at the time of diagnosis. By using the Ann Arbor system staging, seven cases were classified as stage Ⅰ-Ⅱ, and seven cases as stage Ⅲ-Ⅳ. Seven cases had B symptoms, four cases had splenomegaly, and two cases had skin rash and pruritus. Previously, three cases were diagnosed as classic Hodgkin's lymphoma, three cases as small B-cell lymphoma, two cases as atypical lymphoid hyperplasia unable to exclude angioimmunoblastic T-cell lymphoma (AITL), one case as EBV-associated lymphoproliferative disorder, and one case as peripheral T-cell lymphoma (PTCL) associated with the proliferation of B cells. All the 14 cases showed that the large nodules were composed of mature CD20+, IgD+B lymphocytes admixed with small aggregates of neoplastic cells with pale to clear cytoplasm. Moreover, hyperplastic germinal centers (GCs) and Hodgkin/Reed-Sternberg-like (HRS-like) cells were seen within these nodules in two and five cases, respectively. The neoplastic cells expressed CD3 (14/14), CD4 (14/14), PD1 (14/14), ICOS (14/14), CD10 (9/14), bcl-6 (12/14), CXCL13 (10/14), and CD30 (10/14). The HRS-like cells in five cases expressed CD20 (2/5), PAX5 (5/5), CD30 (5/5), CD15 (2/5), LCA (0/5), OCT2 (5/5) and BOB1 (2/5). Moreover, neoplastic T cells formed rosettes around HRS-like cells. EBV-encoded RNA (EBER) in situ hybridization showed scattered, small, positive bystander B lymphocytes in 8/14 cases, including 3/5 cases containing HRS-like cells. All tested cases (including five with HRS-like cells) showed monoclonal TCR gene rearrangement and polyclonal Ig gene rearrangement. Conclusions: PTGC-like FTCL is a rare tumor originated from T-follicular helper cells. It could be distinguished from angioimmunoblastic T-cell lymphoma by the formation of follicular structure, and lack of follicular dendritic cell proliferation outside the follicles and the polymorphous inflammatory background. In addition, it should be differentiated from lymphocyte-rich classical Hodgkin's lymphoma and low-grade B cell lymphoma.

Exophthalmos and ocular pain as clinical debut of intracranial Hodgkin's lymphoma at diagnosis.

Intracranial involvement in Hodgkin's Lymphoma (HL) is extremely unusual, especially at the time of diagnosis. Because of its non-specific radiological behaviour, it can be confused with more common entities with a radically different prognosis. Pathologically, large and bi-nucleated cells, called Reed-Sternberg cells, embedded in an inflammatory network. In this report we describe the clinical case of a patient, with no medical history, with left ocular pain and exophthalmos as presetation of intracranial HL at diagnosis and review the most current literature. Intracranial involvement is often associated with extracranial disease. Therefore, a systemic study including body computed tomography, bone marrow biopsy and ophthalmological evaluation is necessary. Intracranial lesions respond favourably to treatment and the prognosis depends on the extracranial involvement. To date, there is no standardised management scheme for these patients. For us, the primary role of surgery in this context is to perform a biopsy to confirm the histological diagnosis.

Steady-state approximations for Hodgkin-Huxley cell models: Reduction of order for uterine smooth muscle cell model.

Multi-scale mathematical bioelectrical models of organs such as the uterus, stomach or heart present challenges both for accuracy and computational tractability. These multi-scale models are typically founded on models of biological cells derived from the classic Hodkgin-Huxley (HH) formalism. Ion channel behaviour is tracked with dynamical variables representing activation or inactivation of currents that relax to steady-state dependencies on cellular membrane voltage. Timescales for relaxation may be orders of magnitude faster than companion ion channel variables or phenomena of physiological interest for the entire cell (such as bursting sequences of action potentials) or the entire organ (such as electromechanical coordination). Exploiting these time scales with steady-state approximations for relatively fast-acting systems is a well-known but often overlooked approach as evidenced by recent published models. We thus investigate feasibility of an extensive reduction of order for an HH-type cell model with steady-state approximations to the full dynamical activation and inactivation ion channel variables. Our effort utilises a published comprehensive uterine smooth muscle cell model that encompasses 19 ordinary differential equations and 105 formulations overall. The numerous ion channel submodels in the published model exhibit relaxation times ranging from order 10-1 to 105 milliseconds. Substitution of the faster dynamic variables with steady-state formulations demonstrates both an accurate reproduction of the full model and substantial improvements in time-to-solve, for test cases performed. Our demonstration here of an effective and relatively straightforward reduction method underlines the particular importance of considering time scales for model simplification before embarking on large-scale computations or parameter sweeps. As a preliminary complement to more intensive reduction of order methods such as parameter sensitivity and bifurcation analysis, this approach can rapidly and accurately improve computational tractability for challenging multi-scale organ modelling efforts.

BET inhibitors induce NF-κB and E2F downregulation in Hodgkin and Reed-Sternberg cells.

The prognosis of patients with relapsed and/or refractory classic Hodgkin lymphoma (cHL) continues to be poor. Therefore, there is a continuing need to develop novel therapies and to rationalize the use of target combinations. In recent years there has been growing interest in epigenetic targets for hematological malignancies under the rationale of the presence of common alterations in epigenetic transcriptional regulation. Since Hodgkin and Reed-Sternberg (HRS) cells have frequent inactivating mutations of the CREBBP and EP300 acetyltransferases, bromodomain and extra-terminal (BET) inhibitors can be a rational therapy for cHL. Here we aimed to confirm the efficacy of BET inhibitors (iBETs) using representative cell models and functional experiments, and to further explore biological mechanisms under iBET treatment using whole-transcriptome analyses. Our results reveal cytostatic rather than cytotoxic activity through the induction of G1/S and G2/M cell-cycle arrest, in addition to variable MYC downregulation. Additionally, massive changes in the transcriptome induced by the treatment include downregulation of relevant pathways in cHL disease: NF-kB and E2F, among others. Our findings support the therapeutic use of iBETs in selected cHL patients and reveal previously unknown biological mechanisms and consequences of pan-BET inhibition.

Classic Hodgkin lymphoma in young people.

Classic Hodgkin lymphoma (CHL) is a unique form of lymphoid cancer featuring a heterogeneous tumor microenvironment and a relative paucity of malignant Hodgkin and Reed-Sternberg (HRS) cells with characteristic phenotype. Younger individuals (children, adolescents and young adults) are affected as often as the elderly, producing a peculiar bimodal age-incidence profile that has generated immense interest in this disease and its origins. Decades of epidemiological investigations have documented the populations most susceptible and identified multiple risk factors that can be broadly categorized as either biological or environmental in nature. Most risk factors result in overt immunodeficiency or confer more subtle alterations to baseline health, physiology or immune function. Epstein Barr virus, however, is both a risk factor and well-established driver of lymphomagenesis in a significant subset of cases. Epigenetic changes, along with the accumulation of somatic driver mutations and cytogenetic abnormalities are required for the malignant transformation of germinal center-experienced HRS cell precursors. Chromosomal instability and the influence of endogenous mutational processes are critical in this regard, by impacting genes involved in key signaling pathways that promote the survival and proliferation of HRS cells and their escape from immune destruction. Here we review the principal features, known risk factors and lymphomagenic mechanisms relevant to newly diagnosed CHL, with an emphasis on those most applicable to young people.

The Polyvalent Role of CD30 for Cancer Diagnosis and Treatment.

CD30, also known as TNFRSF8 (tumor necrosis factor receptor superfamily member 8), is a protein receptor that is heavily glycosylated inside the Golgi apparatus, as well as a tumor marker that is found on the surface of specific cells in the body, including certain immune cells and cancer ones. This review aims to shed light on the critical importance of CD30, from its emergence in the cell to its position in diagnosing various diseases, including Hodgkin lymphoma, where it is expressed on Hodgkin and Reed-Sternberg cells, as well as embryonal carcinoma, anaplastic large cell lymphoma (ALCL), and cutaneous T-cell lymphoma (CTCL). In addition to its role in positive diagnosis, targeting CD30 has been a promising approach treating CD30-positive lymphomas, and there is ongoing research into the potential use of CD30-targeted therapies for autoimmune disorders. We aim to elaborate on CD30's roles as a tumor marker, supporting thus the hypothesis that this receptor might be the aim of cytostatic treatment.

[The history of Hodgkin lymphoma]. / Historique du lymphome de Hodgkin.

THE HISTORY OF HODGKIN LYMPHOMA. Hodgkin lymphoma was initially considered to be caused by infectious agents. The Hodgkin and Reed-Sternberg tumor cells are derived from mature B cells and transforming events were identified. Staging laparotomy has been discontinued for clinical evaluation with the progress of medical imaging. For seven decades, clinical trials have allowed to define risk factors, to improve standard treatments with the optimal use of chemotherapy and radiotherapy. A risk adapted strategy and early response to chemotherapy are mandatory to reduce long-term consequences of treatment.

HISTORIQUE DU LYMPHOME DE HODGKIN. Une origine infectieuse du lymphome de Hodgkin a été initialement suspectée. L'origine des cellules tumorales, les mécanismes oncogéniques permettant leur survie et leur prolifération sont de connaissance plus récente. Après l'abandon de la laparotomie exploratrice, les progrès de l'imagerie médicale ont été continus. Pendant sept décennies, les essais cliniques ont permis de définir les facteurs de risque, d'améliorer les traitements de référence avec une utilisation optimale de la chimiothérapie et de la radiothérapie. La stratégie adaptée au risque et à la réponse précoce à la chimiothérapie est nécessaire pour limiter les conséquences tardives des traitements.

CD30 induces Reed-Sternberg cell-like morphology and chromosomal instability in classic Hodgkin lymphoma cell lines.

Classic Hodgkin lymphoma (cHL) is characterized by multinucleated cells called Reed-Sternberg (RS) cells and genetic complexity. Although CD30 also characterizes cHL cells, its biological roles are not fully understood. In this report, we examined the link between CD30 and these characteristics of cHL cells. CD30 stimulation increased multinucleated cells resembling RS cells. We found chromatin bridges, a cause of mitotic errors, among the nuclei of multinucleated cells. CD30 stimulation induced DNA double-strand breaks (DSBs) and chromosomal imbalances. RNA sequencing showed significant changes in the gene expression by CD30 stimulation. We found that CD30 stimulation increased intracellular reactive oxygen species (ROS), which induced DSBs and multinucleated cells with chromatin bridges. The PI3K pathway was responsible for CD30-mediated generation of multinucleated cells by ROS. These results suggest that CD30 involves generation of RS cell-like multinucleated cells and chromosomal instability through induction of DSBs by ROS, which subsequently induces chromatin bridges and mitotic error. The results link CD30 not only to the morphological features of cHL cells, but also to the genetic complexity, both of which are characteristic of cHL cells.

New molecular targets in Hodgkin and Reed-Sternberg cells.

Recent discoveries shed light on molecular mechanisms responsible for classical Hodgkin lymphoma (HL) development and progression, along with features of Hodgkin - Reed and Sternberg cells (HRS). Here, we summarize current knowledge on characteristic molecular alterations in HL, as well as existing targeted therapies and potential novel treatments for this disease. We discuss the importance of cluster of differentiation molecule 30 (CD30) and the programmed cell death-1 protein (PD-1) and ligands (PD-L1/2), and other molecules involved in immune modulation in HL. We highlight emerging evidence indicating that the altered function of SWI/SNF-type chromatin remodeling complexes, PRC2, and other epigenetic modifiers, contribute to variations in chromatin status, which are typical for HL. We postulate that despite of the existence of plentiful molecular data, the understanding of HL development remains incomplete. We therefore propose research directions involving analysis of reverse signaling in the PD-1/PD-L1 mechanism, chromatin remodeling, and epigenetics-related alterations, in order to identify HL features at the molecular level. Such attempts may lead to the identification of new molecular targets, and thus will likely substantially contribute to the future development of more effective targeted therapies.

Digital spatial profiling of CD4+ T cells in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (CHL) harbors a small number of Hodgkin-Reed-Sternberg (HRS) cells scattered among numerous lymphocytes. HRS cells are surrounded by distinct CD4+ T cells in a rosette-like manner. These CD4+ T cell rosettes play an important role in the tumor microenvironment (TME) of CHL. To elucidate the interaction between HRS cells and CD4+ T cell rosettes, we completed digital spatial profiling to compare the gene expression profiles of CD4+ T cell rosettes and other CD4+ T cells separated from the HRS cells. Immune checkpoint molecules including OX40, programed cell death-1 (PD-1), and cytotoxic T lymphocyte associated protein 4 (CTLA-4) expression was higher in CD4+ T cell rosettes compared to other CD4+ T cells. Immunohistochemistry confirmed variable PD-1, CTLA-4, and OX40 expression in the CD4+ T cell rosettes. This study introduced a new pathological approach to study the CHL TME, and provided deeper insight into CD4+ T cells in CHL.

Increased STAT expression in Reed-Sternberg cells as a potential positive prognostication biomarker in Hodgkin lymphoma.

Classic Hodgkin lymphoma (cHL) prognostication primarily relies on clinical and radiological factors. Despite this, a subset of patients still progress. Immunohistochemistry (IHC) based biomarkers on diagnostic tissue have not been routinely used for prognostication. A multicentre retrospective analysis identified 62 patients with cHL. IHC on diagnostic tissues was used to stain Reed-Sternberg cells (RS) cells for STAT1, pSTAT3, p53 and tumour microenvironment for CD68 and PD-1. IHC stains were scored by anatomical pathologists blinded to patients and their outcomes and correlated with survival. Strong intensity of STAT1 and pSTAT3 staining correlated with improved overall survival (OS), with hazard ratios (HR) of 0.21 [95% confidence interval (CI) 0.06-0.76] and 0.22 (95% CI 0.06-0.84), respectively. Similarly, the median OS for weak versus strong STAT1 or pSTAT3 staining was 8.8 years versus not reached. Other IHC stains did not correlate with prognosis. In this cohort of cHL patients, downregulation of immunohistochemical STAT1 or pSTAT3 in RS cells is associated with inferior OS, suggesting STAT transcription within the pathognomonic RS cells may have tumour suppressor function and may be a potential biomarker for cHL prognosis.

Diagnostic Utility of STAT6 and pSTAT6 Immunohistochemistry for Distinguishing Classic Hodgkin Lymphoma and Peripheral T-Cell Lymphoma With Hodgkin and Reed-Sternberg-like Cells.

Peripheral T-cell lymphomas (PTCLs), particularly nodal lymphomas of T-follicular helper cell origin, may include Hodgkin/Reed-Sternberg (HRS)-like cells in their microenvironment. These HRS-like cells are morphologically indistinguishable from HRS cells of classic Hodgkin lymphoma (CHL). Therefore, PTCLs with HRS-like cells pose a differential diagnosis vis-à-vis CHL. A previous study reported that, in contrast to HRS cells, programmed death-ligand 1 (PD-L1) expression is rare in HRS-like cells of PTCLs and suggested that PD-L1 immunohistochemistry is useful to differentiate HRS cells and HRS-like cells. In this study, we analyzed 21 patients with PTCL with HRS-like cells and 34 patients with CHL and assessed the diagnostic utility of STAT6, pSTAT6, and pSTAT3 immunohistochemistry in distinguishing HRS cells from HRS-like cells. In addition, we also performed PD-L1 immunohistochemistry to reconfirm its utility in distinguishing the 2 diseases. Compared with HRS cells in CHLs, HRS-like cells in PTCLs showed significantly less positivity for STAT6 (9.6% vs. 70%, P <0.001), pSTAT6 (9.6% vs. 70%, P <0.001), and PD-L1 (9.6% vs. 85%, P <0.001). Thus, we reconfirmed the diagnostic utility of PD-L1 immunohistochemistry in distinguishing CHLs from PTCLs with HRS-like cells. In contrast, both HRS-like and HRS cells were highly associated with pSTAT3 expression, with no significant difference in positive cell frequency (86% vs. 91%, P =0.66). On the basis of these findings, we conclude that, in addition to PD-L1, STAT6 and pSTAT6 immunohistochemistry are helpful diagnostic tools to distinguish CHLs from PTCLs with HRS-like cells.

The characteristically weak PAX-5 staining of Reed-Sternberg cells surrounds distinct negatively stained block-like inclusions in classic Hodgkin Lymphoma.

No abstract available.