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Objective:To investigate the clinical features, imaging findings, pathological phenotype, treatment and prognosis of unicentric Castleman disease in the children's neck, in order to improve the understanding of CD among Otolaryngology Head and Neck Surgery. Methods:Retrospective cross-sectional, observational study was undertaken in Kunming Children's Hospital, from the archival data between January July 2015 and June 2020. Only 6 cases of CD were identified after studying the histomorphological characteristics and neck mass diagnosed. The imaging and pathological features were summarized and the pathogenesis was discussed. Results:Among the 6 cases of Castleman disease, five were male and one was female. Histopathology: Five cases were hyaline vascular subtype, one was mixed type. The uniform clinicopathologic features seen in all hyaline vascular subtype of CD included atrophic germinal centre with lymphocyte depletion, concentric rings of small lymphocytes, increased vascularity and predominance of high endothelial vessels in interfollicular region. Twinning, in which two or more germinal centers are combined and surrounded by lymphocytes in the mantle zone was observed in two cases with lollipop pattern at the same time. All the cases underwent complete surgical resection, the median follow-up time was 48 months（26, 84）, both of them had good prognosis. Conclusion:Most cases of unicentric type CD in children are diagnosed late, which is clinical showed by painless lymphadenopathy. The most common pathological type is hyaline vascular. The overall prognosis of surgical treatment was good.

Asunto(s)

Enfermedad de Castleman , Cuello , Humanos , Enfermedad de Castleman/patología , Masculino , Femenino , Niño , Estudios Retrospectivos , Estudios Transversales , Pronóstico , Adolescente , Centro Germinal/patología , Preescolar

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Introduction: Tertiary lymphoid structures (TLSs) are analogues of secondary lymphoid organs that contain various immune cells. The spatial distribution, maturation and composition of TLSs have differential effects on prognosis, and the roles of TLSs in gastric adenocarcinoma (GA) have not been revealed. Methods: Thus, we evaluated the prognostic value of TLSs in GA through analysis of bulk RNA sequencing(RNA-seq) data from public databases and validated our findings in tumour samples from the Fudan University Shanghai Cancer Center (FUSCC) cohort. The spatial distribution,maturation, and composition of TLSs in GA were analysed by reviewing H&E-stained sections and by multiplex immunofluorescence (mIF) staining. Results: We found that TLSs, especially TLSs with germinal centres (GCs) and TLSs located in the invasive margin (IM), were correlated with prolonged overall survival (OS). Second, analysis of public RNA-seq data showed that high dendritic cell (DC) scores were a favourable prognostic factor in GA patients with high scores for both TLSs and GCs. In the FUSCC cohort, DC-LAMP+ DCs weresignificantly enriched in IM-TLSs with GCs, suggesting a potential correlation between the tumour immune activation milieu and the DC abundance. Third, compared to that in TLSs without GCs, the proportion of FOXP3+CD8+ Treg cells was significantly decreased in IM-TLSs with GCs, and the percentage of PD1+CD20+ B cells was significantly increased in TLSs with GCs. Discussion: Our results demonstrate that the spatial arrangement and maturation of TLSs significantly affect prognosis and indicate that TLSs could be a new additional factor for histopathological evaluation.

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Adenocarcinoma , Neoplasias Gástricas , Estructuras Linfoides Terciarias , Humanos , Neoplasias Gástricas/inmunología , Neoplasias Gástricas/patología , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/genética , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Adenocarcinoma/inmunología , Adenocarcinoma/mortalidad , Adenocarcinoma/patología , Pronóstico , Masculino , Femenino , Persona de Mediana Edad , Células Dendríticas/inmunología , Anciano , Centro Germinal/inmunología , Centro Germinal/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Microambiente Tumoral/inmunología

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This study aimed to analyze the heterogeneity or change in cell of origin (COO) in diffuse large B-cell lymphoma (DLBCLs) using the Hans algorithm including 156 patients with multiple DLBCL specimens. COO was detected via immunohistochemical staining for CD10, BCL6, and MUM1. The COO of the main tumor at initial diagnosis was germinal center B-cell (GCB) and non-GCB type in 50 (32%) and 106 (68%) patients, respectively. It did not change in 126 patients (81%). However, it changed in 30 patients (19%), from GCB to non-GCB in 12 patients and vice versa in 18 patients. The COO was heterogeneous or changed in 14% of simultaneous samples at other sites during the initial diagnosis, in 7% of primary refractory sites, and in 20% of samples obtained in the relapse phase other than the primary site. Changes in CD10, BCL6, and MUM1 expression were observed in 15%, 23%, and 24% samples, respectively. A low incidence of change in COO was observed in DLBCL with CD10+/BCL6+/MUM1- (4%), CD10-/BCL6-/MUM1+ (3%), and CD10-/BCL6-/MUM1- (0%) patterns, whereas DLBCL with other patterns showed COO changes at rates of 20-37%. In conclusion, COO was heterogeneous or changed in 19% of DLBCL cases. The COO should be re-examined in other biopsy samples to determine the optimal treatment.

Asunto(s)

Algoritmos , Biomarcadores de Tumor , Factores Reguladores del Interferón , Linfoma de Células B Grandes Difuso , Neprilisina , Proteínas Proto-Oncogénicas c-bcl-6 , Humanos , Linfoma de Células B Grandes Difuso/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Biomarcadores de Tumor/análisis , Anciano de 80 o más Años , Neprilisina/análisis , Proteínas Proto-Oncogénicas c-bcl-6/genética , Factores Reguladores del Interferón/análisis , Adulto Joven , Inmunohistoquímica , Centro Germinal/patología , Adolescente

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Ectopic lymphoid structures (ELSs) in the rheumatoid synovial joints sustain autoreactivity against locally expressed autoantigens. We recently identified recombinant monoclonal antibodies (RA-rmAbs) derived from single, locally differentiated rheumatoid arthritis (RA) synovial B cells, which specifically recognize fibroblast-like synoviocytes (FLSs). Here, we aimed to identify the specificity of FLS-derived autoantigens fueling local autoimmunity and the functional role of anti-FLS antibodies in promoting chronic inflammation. A subset of anti-FLS RA-rmAbs reacting with a 60 kDa band from FLS extracts demonstrated specificity for HSP60 and partial cross-reactivity to other stromal autoantigens (i.e., calreticulin/vimentin) but not to citrullinated fibrinogen. Anti-FLS RA-rmAbs, but not anti-neutrophil extracellular traps rmAbs, exhibited pathogenic properties in a mouse model of collagen-induced arthritis. In patients, anti-HSP60 antibodies were preferentially detected in RA versus osteoarthritis (OA) synovial fluid. Synovial HSPD1 and CALR gene expression analyzed using bulk RNA-Seq and GeoMx-DSP closely correlated with the lympho-myeloid RA pathotype, and HSP60 protein expression was predominantly observed around ELS. Moreover, we observed a significant reduction in synovial HSP60 gene expression followed B cell depletion with rituximab that was strongly associated with the treatment response. Overall, we report that synovial stromal-derived autoantigens are targeted by pathogenic autoantibodies and are associated with specific RA pathotypes, with potential value for patient stratification and as predictors of the response to B cell-depleting therapies.

Asunto(s)

Artritis Reumatoide , Autoantígenos , Chaperonina 60 , Centro Germinal , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Animales , Humanos , Ratones , Autoantígenos/inmunología , Autoantígenos/genética , Centro Germinal/inmunología , Centro Germinal/patología , Chaperonina 60/inmunología , Chaperonina 60/genética , Autoanticuerpos/inmunología , Autoinmunidad , Masculino , Sinoviocitos/inmunología , Sinoviocitos/patología , Sinoviocitos/metabolismo , Artritis Experimental/inmunología , Artritis Experimental/patología , Femenino , Linfocitos B/inmunología , Linfocitos B/patología , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología

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Myasthenia gravis (MG) is an autoimmune disease characterized by muscle fatigability due to acetylcholine receptor (AChR) autoantibodies. To better characterize juvenile MG (JMG), we analyzed 85 pre- and 132 post-pubescent JMG (with a cutoff age of 13) compared to 721 adult MG patients under 40 years old using a French database. Clinical data, anti-AChR antibody titers, thymectomy, and thymic histology were analyzed. The proportion of females was higher in each subgroup. No significant difference in the anti-AChR titers was observed. Interestingly, the proportion of AChR+ MG patients was notably lower among adult MG patients aged between 30 and 40 years, at 69.7%, compared to over 82.4% in the other subgroups. Thymic histological data were examined in patients who underwent thymectomy during the year of MG onset. Notably, in pre-JMG, the percentage of thymectomized patients was significantly lower (32.9% compared to more than 42.5% in other subgroups), and the delay to thymectomy was twice as long. We found a positive correlation between anti-AChR antibodies and germinal center grade across patient categories. Additionally, only females, particularly post-JMG patients, exhibited the highest rates of lymphofollicular hyperplasia (95% of cases) and germinal center grade. These findings reveal distinct patterns in JMG patients, particularly regarding thymic follicular hyperplasia, which appears to be exacerbated in females after puberty.

Asunto(s)

Autoanticuerpos , Miastenia Gravis , Receptores Colinérgicos , Timectomía , Timo , Humanos , Miastenia Gravis/patología , Miastenia Gravis/epidemiología , Femenino , Masculino , Adulto , Francia/epidemiología , Timo/patología , Timo/cirugía , Adolescente , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Receptores Colinérgicos/inmunología , Adulto Joven , Niño , Estudios de Cohortes , Centro Germinal/patología , Centro Germinal/inmunología

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Diffuse large B-cell lymphoma (DLBCL) is the most frequent lymphoma. MIC-A and MIC-B are the natural ligands for NKG2D, a receptor expressed in NK cells. MIC-A soluble isoforms (sMICA) have been described in different malignancies. OBJECTIVES: To analyze lymphocyte subsets and sMIC-A in germinal center DLBCL. MATERIALS AND METHODS: sMICA, sMICB, and peripheral blood lymphocyte subsets (CD4+, CD8+, NK, NKT, γδ T cells, and dendritic cells) were analyzed in 59 patients and 60 healthy donors. RESULTS: Patients had decreased numbers of type 1 and type 2 dendritic cells, NK, iNKT, CD4 T, and CD8 T cells, and higher levels of sMIC-A. The 2-year PFS for high IPI scores and high sMIC-A was 24% and 28%, respectively. The 2-year OS for high IPI scores and high sMIC-A was 42% and 33%. The 2-year PFS and OS for patients not achieving response to treatment were 0% and 10%, respectively. The MICPI score (one point each for high IPI score and high sMIC-A) showed that those patients summing two points had worse PSF and OS. CONCLUSIONS: Patients with DLBCL have decreased numbers of peripheral lymphocyte subsets and high levels of sMIC-A. The addition of sMIC-A to IPI could improve its prognostic relevance.

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Centro Germinal , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/sangre , Femenino , Masculino , Persona de Mediana Edad , Anciano , Pronóstico , Centro Germinal/patología , Centro Germinal/metabolismo , Adulto , Subgrupos Linfocitarios/metabolismo , Subgrupos Linfocitarios/inmunología , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Resultado del Tratamiento , Estadificación de Neoplasias , Inmunofenotipificación , Biomarcadores de Tumor

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To evaluate the effects of gene mutations on Bruton tyrosine kinase inhibitor, zanubrutinib's effectiveness in patients with diffuse large B-cell lymphoma (DLBCL), we examined pooled data from four single-arm studies (BGB-3111-AU-003 [NCT02343120], BGB-3111-207 [NCT03145064], BGB-3111_GA101_Study_001 [NCT02569476], BGB-3111-213 [NCT03520920]; n = 121). Objective response rate (ORR) was higher, though not statistically significant, in patients with activated B-cell-like (ABC)- and unclassified DLBCL (42.9% [21/49]) versus those with germinal-center B-cell-like DLBCL (14.3% [1/7]; p = 0.15). Patients with CD79B mutations had better ORR (60%) versus patients with wild-type alleles (25.9%, p < 0.01). Higher TCL1A expression correlated with better zanubrutinib response (p = 0.03), longer progression-free survival (p = 0.01), and longer overall survival (p = 0.12). TCL1A expression was higher in ABC-DLBCL (p < 0.001) and MYD88/CD79B-mutated subtypes (p < 0.0001). Eighteen patients with high MYC/BCL-2 expression responded better to zanubrutinib (ORR = 61 vs. 29%, p = 0.02). Our results support assessing CD79B mutations, co-expressor DLBCL, and TCL1A expression status to identify patients with DLBCL who will benefit from zanubrutinib.

Asunto(s)

Antígenos CD79 , Linfoma de Células B Grandes Difuso , Mutación , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-myc , Proteínas Proto-Oncogénicas , Pirimidinas , Humanos , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/mortalidad , Linfoma de Células B Grandes Difuso/patología , Proteínas Proto-Oncogénicas c-bcl-2/genética , Persona de Mediana Edad , Femenino , Masculino , Anciano , Pirimidinas/uso terapéutico , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Antígenos CD79/genética , Proteínas Proto-Oncogénicas/genética , Adulto , Piperidinas/uso terapéutico , Pirazoles/uso terapéutico , Anciano de 80 o más Años , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacología , Antineoplásicos/uso terapéutico , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Resultado del Tratamiento , Centro Germinal/patología , Centro Germinal/metabolismo , Centro Germinal/efectos de los fármacos

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BACKGROUND: Altered immunological responses in the palatine tonsils may be involved in the pathogenesis of IgA nephropathy (IgAN). The germinal center serves as the site for antigen-specific humoral immune responses in the palatine tonsils. Germinal center involution is frequently observed in the palatine tonsils of IgAN (IgAN tonsils). However, the pathogenic significance of these characteristic changes remains unclear. This study aimed to investigate the morphological changes in secondary lymphoid follicles in IgAN tonsils and to evaluate the correlation between the morphometric results and the clinicopathological severity of IgAN. METHODS: The tonsils of age-matched patients with recurrent tonsillitis (RT tonsils) were used as controls. The correlation between the degree of lymphoid follicular involution and histopathological severities in clinical or kidney biopsy was evaluated. RESULTS: In total, 87 patients with IgAN were included (48% male, median age 35 years, median estimated glomerular filtration rate: 74 mL/min/1.73 m2). Compared to RT tonsils, IgAN tonsils showed smaller median sizes of lymphoid follicles and germinal centers (P < 0.001). The relative areas of lymphoid follicles (%LFA) and germinal centers (%GCA) in the total tonsillar tissue were smaller in the IgAN tonsils than in the RT tonsils (P < 0.001). In contrast, the median proportion of mantle zones in the total tonsillar tissue was comparable between the groups. A lower %LFA was associated with a longer period from the onset of urinary abnormalities to biopsy diagnosis and higher urinary protein excretion (P = 0.01). %LFA showed significant negative correlations with frequencies of glomeruli with both global and segmental sclerosis. CONCLUSIONS: The present study confirmed accelerated germinal center involution in the tonsils of patients with IgAN. This characteristic change in the IgAN tonsil correlates with heavy proteinuria and advanced chronic histopathological changes in the kidneys, thereby suggesting the involvement of repeated tonsillar immunoreactions during IgAN progression.

Asunto(s)

Centro Germinal , Glomerulonefritis por IGA , Tonsila Palatina , Humanos , Glomerulonefritis por IGA/patología , Glomerulonefritis por IGA/inmunología , Tonsila Palatina/patología , Tonsila Palatina/inmunología , Centro Germinal/inmunología , Centro Germinal/patología , Masculino , Femenino , Adulto , Tonsilitis/patología , Tonsilitis/inmunología , Persona de Mediana Edad , Adulto Joven , Riñón/patología , Riñón/inmunología

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The WHO classifications of hematolymphoid malignancies have recognized several distinct entities within the large B cell lymphomas, including the more recently described high-grade B cell lymphoma with 11q aberration (HGBCL-11q). We utilized genomic array to assess for chromosome 11q abnormalities in a broad set of aggressive B cell lymphomas from 27 patients with a focus on younger adults. The findings suggest more frequent alterations of 11q in diffuse large B cell lymphoma (DLBCL)/HGBCL-GC BCL2-, in comparison to cases of Burkitt lymphoma (BL) or DLBCL-GC BCL2+, and confirm a low genomic complexity score of BL. Variability identified in patterns of 11q alterations suggests genomic array studies may afford value over FISH testing as we continue to understand HGBCL-11q as a distinct entity, and interrogate cases of DLBCL/HGBCL-GC BCL2-.

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Aberraciones Cromosómicas , Cromosomas Humanos Par 11 , Centro Germinal , Linfoma de Células B Grandes Difuso , Fenotipo , Proteínas Proto-Oncogénicas c-bcl-2 , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Cromosomas Humanos Par 11/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Centro Germinal/patología , Adulto , Persona de Mediana Edad , Femenino , Masculino , Anciano , Adulto Joven , Anciano de 80 o más Años , Hibridación Fluorescente in Situ , Adolescente

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Macrophages are abundant immune cells in the microenvironment of diffuse large B-cell lymphoma (DLBCL). Macrophage estimation by immunohistochemistry shows varying prognostic significance across studies in DLBCL, and does not provide a comprehensive analysis of macrophage subtypes. Here, using digital spatial profiling with whole transcriptome analysis of CD68+ cells, we characterize macrophages in distinct spatial niches of reactive lymphoid tissues (RLTs) and DLBCL. We reveal transcriptomic differences between macrophages within RLTs (light zone /dark zone, germinal center/ interfollicular), and between disease states (RLTs/ DLBCL), which we then use to generate six spatially-derived macrophage signatures (MacroSigs). We proceed to interrogate these MacroSigs in macrophage and DLBCL single-cell RNA-sequencing datasets, and in gene-expression data from multiple DLBCL cohorts. We show that specific MacroSigs are associated with cell-of-origin subtypes and overall survival in DLBCL. This study provides a spatially-resolved whole-transcriptome atlas of macrophages in reactive and malignant lymphoid tissues, showing biological and clinical significance.

Asunto(s)

Linfoma de Células B Grandes Difuso , Humanos , Pronóstico , Linfoma de Células B Grandes Difuso/patología , Perfilación de la Expresión Génica , Transcriptoma , Centro Germinal/patología , Microambiente Tumoral/genética

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INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is the most common type of B-cell lymphoma accounting for about 40% of all lymphomas. The international prognostic index (IPI), which relies on clinical and laboratory parameters, is used as a prognostic tool in DLBCL. In this study, we have included cases of DLBCL not otherwise specified (NOS) type to test the usefulness of the biological subclassification of DLBCL by immunohistochemistry (IHC) using the Hans algorithm into the germinal center B-like (GCB) type and nongerminal center (non-GCB) type. We correlated the subtypes with the demographics, site of involvement, IPI scores, and stage. OBJECTIVES: 1. To study the immunohistochemical profile of DLBCL. 2. To classify patients with DLBCL into germinal center and nongerminal center subtypes. 3. To review the clinical presentations, clinical staging, and follow-up data in cases of DLBCL. MATERIALS AND METHODS: A total of 152 cases of DLBCL reported from January 2010 to March 2018 were included in this study. Clinical data, treatment details, and follow-up were reviewed. Apart from the routine IHC markers for DLBCL, additional markers CD10, BCL6, and MUM 1 were performed to classify DLBCL into GCB type and non-GCB type using the Hans algorithm. RESULTS: The median age of presentation was 53 years with male-to-female ratio of 2:1. Most of the patients presented with nodal involvement (56.6%); cervical lymph node is the most common site (46.5%). The majority of the patients presented in Ann Arbor stage 1 (44.8%). According to the international prognostic index, 34.8% had a score of 3 (high intermediate). After IHC studies, GCB subtype (51.5%) of DLBCL emerged as more common than non-GCB type (48.5%). The two subtypes differed significantly with regard to sex (i.e. GCB type was more common in males and non-GCB type in females) and showed no significance with regard to any of the other clinical features and prognostic parameters evaluated. CONCLUSION: Our study showed that IHC was a useful tool to subclassify DLBCL into GCB and non-GCB subtypes and may be easily incorporated in routine clinical practice.

Asunto(s)

Algoritmos , Biomarcadores de Tumor , Inmunohistoquímica , Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/clasificación , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células B Grandes Difuso/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Adulto Joven , Anciano de 80 o más Años , Centro Germinal/patología , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-6/genética , Adolescente , Estudios Retrospectivos , Factores Reguladores del Interferón/genética , Neprilisina

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Linfoma de Células B Grandes Difuso , Humanos , Linfoma de Células B Grandes Difuso/patología , Centro Germinal/patología , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-bcl-6

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BACKGROUND: Stromal tumour infiltrating lymphocytes (sTILs) and presence of tertiary lymphoid structures have been proposed as indicators of tumour-related immune response in breast cancer. An increased number of germinal centres (GCs) in lymph nodes is considered a sign of humoral immune reactivity. AIMS: It is unclear whether a relationship exists between number and size of GCs within tumour positive sentinel lymph nodes (SLNpos), sTILs and tertiary lymphoid structures within matched primary breast cancer and breast cancer subtype. METHODS: Axillary SLNpos from 175 patients with breast cancer were manually contoured in digitized haematoxylin and eosin stained sections. Total SLN area, GC number and GC area were measured in SLNpos with the largest metastatic area. To correct for SLN size, GC number and GC area were divided by SLN area. sTILs and presence of tertiary lymphoid structures were assessed in the primary breast cancer. RESULTS: A higher GC number and larger GC area were found in patients with high sTILs (≥2%) (both P < 0.001) and in patients with presence of tertiary lymphoid structures (PGC number = 0.034 and PGC area = 0.016). Triple negative and HER2-positive (N = 45) breast cancer subtypes had a higher GC number and higher sTILs compared to hormone receptor positive, HER2-negative breast cancer (N = 130) (PGC number < 0.001 and PsTILs= 0.001). CONCLUSION: This study suggests GCs measured within SLNpos might be useful indicators of the humoral anti-tumour immune response in breast cancer. Future studies are needed investigating underlying biological mechanisms and prognostic value of GCs in SLNs.

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Neoplasias de la Mama , Ganglio Linfático Centinela , Estructuras Linfoides Terciarias , Humanos , Femenino , Neoplasias de la Mama/patología , Ganglio Linfático Centinela/patología , Linfocitos Infiltrantes de Tumor/patología , Estructuras Linfoides Terciarias/patología , Ganglios Linfáticos/patología , Centro Germinal/patología , Axila/patología

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Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin's lymphoma in adults, is a genetically and metabolically heterogeneous group of aggressive malignancies. The complexity of their molecular composition and the variability in clinical presentation make clinical diagnosis and treatment selection a serious challenge. The challenge is therefore to quickly and correctly classify DLBCL cells. In this work, we show that Raman imaging is a tool with high diagnostic potential, providing unique information about the biochemical components of tumor cells and their metabolism. We present models of classification of lymphoma cells based on their Raman spectra. The models automatically and efficiently identify DLBCL cells and assign them to a given cell-of-origin (COO) subtype (activated B cell-like (ABC) or germinal center B cell-like (GCB)) or, respectively, to a comprehensive cluster classification (CCC) subtype (OxPhos/non-OxPhos). In addition, we describe each lymphoma subtype by its unique spectral profile, linking it to biochemical, genetic, or metabolic features.

Asunto(s)

Linfoma de Células B Grandes Difuso , Adulto , Humanos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Centro Germinal/patología

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ABSTRACT: Follicular lymphoma (FL) is a generally incurable malignancy that originates from developmentally blocked germinal center B cells residing, primarily, within lymph nodes (LNs). During the long natural history of FL, malignant B cells often disseminate to multiple LNs and can affect virtually any organ. Nonmalignant LNs are highly organized structures distributed throughout the body, in which they perform functions critical for host defense. In FL, the malignant B cells "re-educate" the lymphoid environment by altering the phenotype, distribution, and abundance of other cells such as T cells, macrophages, and subsets of stromal cells. Consequently, dramatic anatomical changes occur and include alterations in the number, shape, and size of neoplastic follicles with an accompanying attenuation of the T-cell zone. Ongoing and dynamic interactions between FL B cells and the tumor microenvironment (TME) result in significant clinical heterogeneity observed both within and across patients. Over time, FL evolves into pathological variants associated with distinct outcomes, ranging from an indolent disease to more aggressive clinical courses with early death. Given the importance of both cell-intrinsic and -extrinsic factors in shaping disease progression and patient survival, comprehensive examination of FL tumors is critical. Here, we describe the cellular composition and architecture of normal and malignant human LNs and provide a broad overview of emerging technologies for deconstructing the FL TME at single-cell and spatial resolution. We additionally discuss the importance of capturing samples at landmark time points as well as longitudinally for clinical decision-making.

Asunto(s)

Linfoma de Células B , Linfoma Folicular , Humanos , Linfocitos B/patología , Centro Germinal/patología , Linfoma de Células B/patología , Linfoma Folicular/patología , Microambiente Tumoral

RESUMEN

ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is a highly aggressive subtype of lymphoma with clinical and biological heterogeneity. The International Prognostic Index (IPI) shows great prognostic capability in the era of rituximab, but the biological signatures of IPI remain to be discovered. In this study, we analyzed the clinical data in a large cohort of 2592 patients with newly diagnosed DLBCL. Among them, 1233 underwent DNA sequencing for oncogenic mutations, and 487 patients underwent RNA sequencing for lymphoma microenvironment (LME) alterations. Based on IPI scores, patients were categorized into 4 distinct groups, with 5-year overall survival of 41.6%, 55.3%, 71.7%, and 89.7%, respectively. MCD-like subtype was associated with age of >60 years, multiple extranodal involvement, elevated serum lactate dehydrogenase (LDH), and IPI scores ranging from 2 to 5, whereas ST2-like subtype showed an opposite trend. Patients with EZB-like MYC+ and TP53Mut subtypes exhibited poor clinical outcome independent of the IPI; integrating TP53Mut into IPI could better distinguish patients with dismal survival. The EZB-like MYC-, BN2-like, N1-like, and MCD-like subtypes had inferior prognosis in patients with IPI scores of ≥2, indicating necessity for enhanced treatment. Regarding LME categories, the germinal center-like LME was more prevalent in patients with normal LDH and IPI scores of 0 to 1. The mesenchymal LME served as an independent protective factor, whereas the germinal center-like, inflammatory, and depleted LME categories correlated with inferior prognosis for IPI scores of 2 to 5. In summary, our work explored the biological signatures of IPI, thus providing useful rationale for future optimization of the IPI-based treatment strategies with multi-omics information in DLBCL.

Asunto(s)

Linfoma de Células B Grandes Difuso , Humanos , Persona de Mediana Edad , Pronóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Rituximab/uso terapéutico , Centro Germinal/patología , Microambiente Tumoral

RESUMEN

AIMS: Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is not recognized as a separate entity by the current classification systems. Here we define and highlight its distinctive clinical presentation, morphology, phenotype, gene expression profile (GEP), and molecular genetics. METHODS: We collected 27 respective cases and investigated their phenotype, performed gDNA panel sequencing covering 172 genes, and carried out fluorescence in situ hybridization to evaluate MYC, BCL2, and BCL6 translocations. We attempted to genetically subclassify cases using the Two-step classifier and performed GEP for cell-of-origin subtyping and in silico comparison to uncover up- and downregulated genes as opposed to other DLBCL. RESULTS: Most cases (n = 22) were germinal centre B-cell-like (GCB) by immunohistochemistry and all by GEP. Additionally, PB-DLBCL had a mutational profile similar to follicular lymphoma and nodal GCB-DLBCL, with the exception of more frequent TP53 and B2M mutations. The GEP of PB-DLBCL was unique, and the frequency of BCL2 rearrangements was lower compared to nodal GCB-DLBCL. The Two-step classifier categorized eight of the cases as EZB, three as ST2, and one as MCD. CONCLUSION: This study comprehensively characterizes PB-DLBCL as a separate entity with distinct clinical and morpho-molecular features. These insights may aid in developing tailored therapeutic strategies and shed light on its pathogenesis.

Asunto(s)

Linfoma de Células B Grandes Difuso , Humanos , Hibridación Fluorescente in Situ , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Mutación , Centro Germinal/patología , Pronóstico , Proteínas Proto-Oncogénicas c-bcl-2/genética

RESUMEN

ABSTRACT: Follicular lymphoma (FL) is an indolent yet incurable germinal center B-cell lymphoma retaining a characteristic follicular architecture. FL tumor B cells are highly dependent on direct and indirect interactions with a specific and complex tumor microenvironment (TME). Recently, great progress has been made in describing the heterogeneity and dynamics of the FL TME and in depicting how tumor clonal and functional heterogeneity rely on the integration of TME-related signals. Specifically, the FL TME is enriched for exhausted cytotoxic T cells, immunosuppressive regulatory T cells of various origins, and follicular helper T cells overexpressing B-cell and TME reprogramming factors. FL stromal cells have also emerged as crucial determinants of tumor growth and remodeling, with a key role in the deregulation of chemokines and extracellular matrix composition. Finally, tumor-associated macrophages play a dual function, contributing to FL cell phagocytosis and FL cell survival through long-lasting B-cell receptor activation. The resulting tumor-permissive niches show additional layers of site-to-site and kinetic heterogeneity, which raise questions about the niche of FL-committed precursor cells supporting early lymphomagenesis, clonal evolution, relapse, and transformation. In turn, FL B-cell genetic and nongenetic determinants drive the reprogramming of FL immune and stromal TME. Therefore, offering a functional picture of the dynamic cross talk between FL cells and TME holds the promise of identifying the mechanisms of therapy resistance, stratifying patients, and developing new therapeutic approaches capable of eradicating FL disease in its different ecosystems.

Asunto(s)

Linfoma de Células B , Linfoma Folicular , Humanos , Linfoma Folicular/patología , Ecosistema , Recurrencia Local de Neoplasia/patología , Linfocitos B/patología , Centro Germinal/patología , Linfoma de Células B/patología , Microambiente Tumoral

RESUMEN

BACKGROUND: Studies suggested that the immunophenotype of hyaline vascular type Castleman disease (HVCD) lacked characteristics, which was easy to be confused with other diseases. METHODS: From January 2010 to June 2022, 17 cases of HVCD were selected from the Department of Pathology of Shaanxi Provincial People's Hospital and the Department of Pathology of Shaanxi Provincial Cancer Hospital. 13 cases of reactive hyperplastic lymph nodes (RHL) and 11 cases of follicular lymphoma (FL) were selected as the control group. All cases were performed CD3, CD20, CD21 and BCL2 immunohistochemical staining. RESULTS: (i) In 17 cases of HVCD, the negative area of BCL2 of germinal center was significantly smaller than the negative area of CD3 of germinal center. However, in 13 cases of RHL, the negative area of CD3 of germinal center was basically consistent with the negative area of germinal center of BCL2 of germinal center. In 11 cases of FL, in neoplastic follicles, the negative area of CD3 was basically consistent with the positive area of BCL2. The difference between HVCD group and other two groups of diseases was statistically significant (P < 0.05). (ii) In 17 cases of HVCD, the negative area of BCL2 of germinal center was significantly smaller than the follicular dendritic cell (FDC) meshworks expressed by CD21. However, in 13 cases of RHL, the FDC meshworks expressed by CD21 were basically consistent with the negative area of BCL2 of germinal center. In 11 cases of FL, in neoplastic follicles, the FDC meshworks expressed by CD21 was basically consistent with the positive area of BCL2. The difference between HVCD group and other two groups of disease was statistically significant (P < 0.05). CONCLUSIONS: HVCD has unique immunophenotypic characteristics. The negative area of BCL2 of germinal center is significantly smaller than the negative area of CD3. The negative area of the BCL2 of germinal center is significantly smaller than the FDC meshworks expressed by CD21. These two immunophenotypic features in HVCD are very important in diagnosis and differential diagnosis.

Asunto(s)

Enfermedad de Castleman , Linfoma Folicular , Humanos , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/patología , Hialina , Inmunohistoquímica , Centro Germinal/patología , Linfoma Folicular/diagnóstico , Linfoma Folicular/patología , Proteínas Proto-Oncogénicas c-bcl-2

RESUMEN

B-cell lymphomas are a group of heterogeneous neoplasms resulting from the clonal expansion of mature B cells arrested at various stages of differentiation. Specifically, two lymphoma subtypes arise from germinal centers (GCs), namely follicular lymphoma (FL) and GC B-cell diffuse large B-cell lymphoma (GCB-DLBCL). In addition to recent advances in describing the genetic landscape of FL and GCB-DLBCL, tumor microenvironment (TME) has progressively emerged as a central determinant of early lymphomagenesis, subclonal evolution, and late progression/transformation. The lymphoma-supportive niche integrates a dynamic and coordinated network of immune and stromal cells defining microarchitecture and mechanical constraints and regulating tumor cell migration, survival, proliferation, and immune escape. Several questions are still unsolved regarding the interplay between lymphoma B cells and their TME, including the mechanisms supporting these bidirectional interactions, the impact of the kinetic and spatial heterogeneity of the tumor niche on B-cell heterogeneity, and how individual genetic alterations can trigger both B-cell intrinsic and B-cell extrinsic signals driving the reprogramming of non-malignant cells. Finally, it is not clear whether these interactions might promote resistance to treatment or, conversely, offer valuable therapeutic opportunities. A major challenge in addressing these questions is the lack of relevant models integrating tumor cells with specific genetic hits, non-malignant cells with adequate functional properties and organization, extracellular matrix, and biomechanical forces. We propose here an overview of the 3D in vitro models, xenograft approaches, and genetically-engineered mouse models recently developed to study GC B-cell lymphomas with a specific focus on the pros and cons of each strategy in understanding B-cell lymphomagenesis and evaluating new therapeutic strategies.

Asunto(s)

Linfoma Folicular , Linfoma de Células B Grandes Difuso , Humanos , Animales , Ratones , Linfocitos B , Linfoma de Células B Grandes Difuso/patología , Centro Germinal/patología , Diferenciación Celular , Microambiente Tumoral