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According to expert guidelines, lymph node surgical excision is the standard of care for lymphoma diagnosis. However, core needle biopsy (CNB) has become widely accepted as part of the lymphoma diagnostic workup over the past decades. The aim of this study was to present the largest multicenter inventory of lymph nodes sampled either by CNB or surgical excision in patients with suspected lymphoma and to compare their diagnostic performance in routine pathologic practice. We reviewed 32 285 cases registered in the French Lymphopath network, which provides a systematic expert review of all lymphoma diagnoses in France, and evaluated the percentage of CNB and surgical excision cases accurately diagnosed according to the World Health Organization classification. Although CNB provided a definitive diagnosis in 92.3% and seemed to be a reliable method of investigation for most patients with suspected lymphoma, it remained less conclusive than surgical excision, which provided a definitive diagnosis in 98.1%. Discordance rates between referral and expert diagnoses were higher on CNB (23.1%) than on surgical excision (21.2%; P = .004), and referral pathologists provided more cases with unclassified lymphoma or equivocal lesion through CNB. In such cases, expert review improved the diagnostic workup by classifying ∼90% of cases, with higher efficacy on surgical excision (93.3%) than CNB (81.4%; P < 10−6). Moreover, diagnostic concordance for reactive lesions was higher on surgical excision than CNB (P = .009). Overall, although CNB accurately diagnoses lymphoma in most instances, it increases the risk of erroneous or nondefinitive conclusions. This large-scale survey also emphasizes the need for systematic expert review in cases of lymphoma suspicion, especially in those sampled by using CNB.

Leukocyte-associated immunoglobulin (Ig)-like receptor 1 (LAIR1, CD305) belongs to the family of immune-inhibitory receptors and is widely expressed on hematopoietic mature cells, particularly on immune cells. Four different types of ligands of LAIR1 have been described, including collagens, suggesting a potential immune-regulatory function on the extracellular matrix. By modulating cytokine secretion and cellular functions, LAIR1 displays distinct patterns of expression among NK cell and T/B lymphocyte subsets during their differentiation and cellular activation and plays a major negative immunoregulatory role. Beyond its implications in physiology, the activity of LAIR1 can be inappropriately involved in various autoimmune or inflammatory disorders and has been implicated in cancer physiopathology, including hematological neoplasms. Its action as an inhibitory receptor can result in the dysregulation of immune cellular responses and in immune escape within the tumor microenvironment. Furthermore, when expressed by tumor cells, LAIR1 can modulate their proliferation or invasion properties, with contradictory pro- or anti-tumoral effects depending on tumor type. In this review, we will focus on its role in normal physiological conditions, as well as during pathological situations, including hematological malignancies. We will also discuss potential therapeutic strategies targeting LAIR1 for the treatment of various autoimmune diseases and cancer settings.

International audience; Rationale: Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We hence investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Methods: Analysis of PCNSL transcriptomes (sequencing, n = 20; microarrays, n = 34). Integrated correlation analysis and signaling pathway topology enabled us to infer intercellular interactions. Immunohistopathology and digital imaging were used to validate bioinformatic results. Results: Transcriptomics revealed three immune subtypes: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, e.g., IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, i.e., CTLA-4/CD86 and TIM-3/LAGLS9. TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Conclusion: Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.

AimsDiffuse large B-cell lymphoma (DLBCL) is the most common type of aggressive non-Hodgkin's lymphoma that represents a heterogeneous group of disease that is differentially characterised by clinical, molecular and cytogenetic features. MYC, BCL2 and BCL6 gene rearrangements have been identified as prognostic factors in DLBCL, especially for MYC. Nevertheless the frequency and effect of atypical/unbalanced BCL6, BCL2 and MYC translocations in DLBCL is not fully documented. Here, we aimed to analyse those atypical/unbalanced rearrangements in DLBCL and to assess their prognostic impact.MethodsWe collected tumour tissue and clinical data from 97 DLBCL and used interphase fluorescence in situ hybridisation (FISH) with break-apart probe to characterise BCL6, BCL2 and MYC gene pattern.Results19 of 97 (19,6%) cases of DLBCL had atypical/ unbalanced gene rearrangements (14 involving BCL6 gene, 5 involving BCL2 gene and none involving MYC gene). Compared with patients with simple gene rearrangement and patients without cytogenetic abnormality, patients with atypical/unbalanced gene rearrangement were in an unfavourable risk group by the International Prognostic Index (p=0039), died of disease (p=0012), harboured relapse or progression (p=0011) and had shorter overall (p=0,04), relapse free (p=0029) and event free (p=0026) survival.ConclusionsWe showed that patients with DLBCL with BCL2 or BCL6 atypical/unbalanced rearrangements constituted a group of patients with poor outcome. We also underlined the importance of FISH analyses, easily feasible in routine practise, at diagnosis of DLBCL to detect the rather frequent and clinically significant atypical/unbalanced aberrations of these genes.

Primary central nervous system diffuse large B-cell lymphoma (PCNSL) is a rare and aggressive entity that resides in an immune-privileged site. The tumor microenvironment (TME) and the disruption of the immune surveillance influence lymphoma pathogenesis and immunotherapy resistance. Despite growing knowledge on heterogeneous therapeutic responses, no comprehensive description of the PCNSL TME is available. We investigated the immune subtypes of PCNSL and their association with molecular signaling and survival. Bulk mRNA-sequencing (n=20) and microarray (n=34) data were exploited to identify three immune subtypes of PCNSL: immune-rich, poor, and intermediate. The immune-rich subtype was associated to better survival and characterized by hyper-activation of STAT3 signaling and inflammatory signaling, e.g., IFNγ and TNF-α, resembling the hot subtype described in primary testicular lymphoma and solid cancer. WNT/β-catenin, HIPPO, and NOTCH signaling were hyper-activated in the immune-poor subtype. HLA down-modulation was clearly associated with a low or intermediate immune infiltration and the absence of T-cell activation. Moreover, HLA class I down-regulation was also correlated with worse survival with implications on immune-intermediate PCNSL that frequently feature reduced HLA expression. A ligand-receptor intercellular network revealed high expression of two immune checkpoints, i.e., CTLA-4/CD86 and TIM-3/LAGLS9. Immunohistopathology and digital imaging showed that TIM-3 and galectin-9 proteins were clearly upregulated in PCNSL. Altogether, our study reveals that patient stratification according to immune subtypes, HLA status, and immune checkpoint molecule quantification should be considered prior to immune checkpoint inhibitor therapy. Moreover, TIM-3 protein should be considered an axis for future therapeutic development.

Le lymphome B diffus à grandes cellules (DLBCL) est le type le plus commun des lymphomes B non Hodgkiniens agressifs et représente un groupe hétérogène de maladies avec des caractéristiques cliniques, moléculaires et cytogénétiques différentes. Les réarrangements des gènes MYC, BCL2 et BCL6 ont été identifiés comme des facteurs pronostiques, spécialement pour MYC. En revanche, la fréquence et les effets des réarrangements complexes/particuliers de BCL6, BCL2 et MYC ne sont pas bien documentés. Notre étude a consisté à analyser ces réarrangements complexes dans les DLBCL et à étudier leurs impacts pronostiques. Matériels et méthodes : nous avons collecté le tissu tumoral et les données cliniques de 97 LBDGC et nous avons utilisé l’hybridation in situ fluorescente (FISH) sur noyaux interphasiques avec des sondes de type break appart pour caractériser les anomalies cytogénétiques des gènes BCL6, BCL2 et MYC.Résultats : 19 des 97 (19,6%) des cas de LBDGC avaient un réarrangement complexe/particulier (14 impliquaient le gène BCL6, 5 impliquaient le gène BCL2 et aucun n’impliquait le gène MYC). Comparés aux patients avec réarrangements simples ou aux patients sans anomalies cytogénétiques de ces gènes, les patients avec un réarrangement complexe/particulier étaient dans un groupe défavorable de risque pour l’index pronostique international (IPI) (P=0,039), le décès dû à la maladie (P=0,012), montraient plus de rechutes ou de progression (P=0,011) et avaient de plus courtes survies globales (P=0,04), survie sans récidive (P=0,04) et survie sans événement (P=0,026).Conclusion : nous avons montré que les patients avec réarrangements complexes/particuliers de BCL6 ou BCL2 constituaient un groupe de patients avec un pronostic péjoratif. Nous avons également souligné l’importance de l’analyse FISH, aisément applicable en pratique quotidienne, pour la mise en évidence des réarrangements complexes de ces gènes, qui sont assez fréquents, et cliniquement significatifs.