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The Role of Inflammation in Lymphoma
Abstract
Human lymphomas usually develop in specialized tissue microenvironments characterized by different populations of accessory stromal and lymphoid cells that interact with malignant cells. A clinical role of the tumor microenvironment has recently emerged, bringing new knowledge and suggesting new ideas and targets for treatment. This chapter analyzes the microenvironment in human lymphomas highlighting the role of inflammation in their pathogenesis. Microenvironmental specificity is detailed according to different models including classic Hodgkin lymphoma (HL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), peripheral T-cell lymphoma, unspecified and angioimmunoblastic T-cell lymphoma (AITL).
... [12][13][14][15][16] Inflammation has been reported to be a hallmark of tumorigenesis and is associated with neutrophilia, whereas lymphopenia has been associated with systemic immunodeficient processes. [17][18][19] The relation between neutrophilia and lymphopenia, in the context of inflammation, seems to be associated with specific molecular and cytokine profiles. [20][21][22][23][24] In this context, the NLR might be a biomarker of underlying inflammatory and immunodeficient processes in patients with cancer. ...
... Good examples are hematologic malignancies (eg, Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma), in which the neoplastic lymphocyte is surrounded by a milieu of inflammatory cells that, in turn, has a direct influence in the neoplastic cell survival. [18][19][20] From the concept of a local-tosystemic inflammatory process, a high expression of different cytokines secreted by the tumor microenvironment, such as interleukin (IL)-6, IL-8, IL-10, interferon gamma, and vascular endothelial growth factor, have been described in DLBCL. 21 A recent report showed that CXCL-10 is secreted by inflammatory cells of the tumor microenvironment, which increases cell proliferation, as well as cell migration and neoplastic infiltration. ...
Introduction:
We aimed at investigating the prognostic role of the neutrophil-to-lymphocyte ratio (NLR) in 2 independent cohorts of Latin American patients with diffuse large B-cell lymphoma (DLBCL) treated with chemoimmunotherapy.
Patients and methods:
The learning cohort was composed of 274 patients and the validation cohort of 323 patients, for a total of 597 patients. An optimal NLR cutoff ≥ 4 was determined using receiver operating characteristic analysis.
Results:
In multivariate models, NLR ≥ 4 was independently associated with lower odds for complete response to chemoimmunotherapy in the learning (odds ratio, 0.46; P = .006) and the validation cohort (odds ratio, 0.49; P = .01), and independently associated with worse survival in the learning (hazard ratio, 1.55; P = .04) and the validation cohort (hazard ratio, 1.80; P = .003).
Conclusions:
The adverse prognostic value of NLR ≥ 4 was independent of the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index score. Based on the results of this multi-institutional study, NLR ≥ 4 emerges as an adverse prognostic factor in Latin American patients with DLBCL treated with chemoimmunotherapy.
... The neutrophil-to-lymphocyte ratio (NLR) is as an adverse prognostic factor in different types of solid tumors, such as breast, lung, hepatocellular, pancreatic, gastric and lung cancers (6)(7)(8)(9)(10)(11). In hematological neoplasms, several studies have suggested a prognostic role for the NLR in patients with classical Hodgkin lymphoma (CHL), multiple myeloma and Tcell lymphoma (12)(13)(14)(15)(16). Inflammation has been reported to be a hallmark of tumorigenesis and is associated with neutrophilia, while lymphopenia has been associated with systemic immunodeficient processes (17,18,19). The relation between neutrophilia and lymphopenia, in the context of inflammation, seems to be associated with specific molecular and cytokine profiles (20)(21)(22)(23)(24). ...
... One of these hallmarks is inflammation. In 1863, Rudolf Virchow (18,19,20). From the concept of a local-tosystemic inflammatory process, a high expression of different cytokines secreted by the tumor microenvironment, such as interleukin (IL)-6, IL-8, IL-10, interferon gamma, and vascular endothelial growth factor, have been described in DLBCL (21). ...
Introduction: Diffuse Large B-Cell Lymphoma (DLBCL) is the most frequent subtype of high-grade lymphoma in Latin American patients. The neutrophil-to-lymphocyte ratio (NLR) has shown to be prognostic in patients with DLBCL in Asia, Europe, and the United States. We previously reported that NLR ≥4 was an adverse prognostic factor for overall survival (OS) in DLBCL patients treated with chemoimmunotherapy. We aim to assess the prognostic and predictive role of NLR ≥4 in a learning cohort of DLBCL patients from South America and confirm the findings in a validation cohort of DLBCL patients from Mexico.
Methods: The study period was from January 2002 through January 2018, and included patients with de novo DLBCL treated with standard chemoimmunotherapy with a curative intent. A cohort of patients from South America (Peru, Argentina, Venezuela, Chile and Colombia) was the learning cohort, a cohort of patients from Mexico was the validation cohort. Univariate and multivariate logistic regression analysis and Cox proportional-hazard regression models were fitted for complete response (CR) as well as for OS in the learning cohort and the validation cohort, separately. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test.
Results: A total of 597 patients with a diagnosis of DLBCL were included. The learning cohort included 274 patients, and the validation cohort included 323 patients.
In the learning cohort, CR rates for DLBCL patients with NLR ≥4 and NLR <4 were 62% and 78%, respectively (p=0.003). In the multivariate analyses for CR, advanced stage and NLR ≥4 were associated with lower odds of CR (OR 0.39, 95% CI 0.21-0.70, p=0.002; and OR 0.46, 95% CI 0.27-1.63, p=0.006, respectively). NLR ≥4 was independently associated with lower rates of CR when adjusted for the IPI and the NCCN-IPI scores (OR 0.46, 95% CI 0.27-0.79, p=0.005; and OR 0.47,95% CI 0.28-0.81, p=0.006, respectively). The 5-year OS rates for DLBCL patients with NLR ≥4 was 58% versus 70% for patients with NLR <4. In the multivariate analyses for OS, advanced stage (HR 2.47, 95% CI 1.55-3.93; p<0.001) and NLR ≥4 (HR 1.55, 95% CI 1.20-2.36; p=0.04) were statistically significant factors associated with worse OS. NLR ≥4 was an adverse prognostic factor after adjusting for the IPI and the NCCN-IPI scores (HR 1.50, 95% CI 1.01-2.28; p=0.04; and HR 1.47, 95% CI 1.01-2.21; p=0.04, respectively).
In the validation cohort, CR rates for DLBCL patients with NLR ≥4 and NLR <4 were 64% and 81%, respectively (p=0.001). In the multivariate analyses for CR, elevated LDH level and NLR ≥4 were associated with lower odds of CR (OR 0.53, 95% CI 0.29-0.97, p=0.04; and OR 0.49, 95% CI 0.27-0.88, p=0.01, respectively). NLR ≥4 was independently associated with lower rates of CR when adjusted for IPI score and the NCCN-IPI score (OR 0.46,95% CI 0.26-0.82, p=0.008; and OR 0.46, 95% CI 0.25-0.81, p=0.007, respectively). The 5-year OS rates for DLBCL patients with NLR ≥4 was 48% versus 68% for patients with an NLR<4. In the multivariate analysis for OS; ECOG ≥1 (HR 1.85, 95% CI 1.24-2.77; p<0.003), advanced stage (HR 2.04, 95% CI 1.28-3.26, p=0.003) and NLR ≥4 (HR 1.80, 95% CI 1.22-2.65; p=0.03) were independent factors associated with worse OS. NLR ≥4 was an adverse prognostic factor after adjusting for IPI score and NCCN-IPI score (HR 1.81, 95% CI 1.24-2.64; p=0.002; and HR 1.96, 95% CI 1.34-2.86; p=0.001, respectively).
Conclusion: This multi-institutional collaborative study identifies and validates an easy-to-use tool, NLR ≥4, as an independent factor predictive of lower rates of CR and prognostic of worse survival, independent of the IPI and the NCCN-IPI scores, in Latin-American patients with DLBCL treated with standard chemoimmunotherapy.
Disclosures
M: Roche-Mexico: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Merck-Sharp-Dome: Speakers Bureau. Peña:Novartis: Other: Congress inscription and flights; Tecnofarma: Other: Congress inscription and flights; Roche: Other: Congress inscription and flights; Biotoscana: Other: Congress inscription and flights; Janssen: Other: Congress inscription and flights; Pfizer: Membership on an entity's Board of Directors or advisory committees. Rojas:Pfizer: Membership on an entity's Board of Directors or advisory committees; ABBVIE: Membership on an entity's Board of Directors or advisory committees; NOVARTIS: Membership on an entity's Board of Directors or advisory committees; ROCHE: Membership on an entity's Board of Directors or advisory committees. Paredes:Tecnofarma: Honoraria. Ramirez-Ibarguen:Roche-Mexico: Consultancy, Speakers Bureau. Gomez-Almaguer:Amgen: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Teva: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Castillo:Pharmacyclics: Consultancy, Research Funding; Abbvie: Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Janssen: Consultancy, Research Funding.
... The nuclear factor-κB (NF-κB) plays a key role in several cellular functions, e.g., sustenance of proliferative signaling, evasion of growth suppression, resistance to cell death, ability of replicative immortality, and activation of invasion and metastasis in hematological malignancies (1). The inflammatory process has emerged as a useful marker of cancer progression (2,3). NF-κB is also involved in the induction of inflammation (2,3). ...
... The inflammatory process has emerged as a useful marker of cancer progression (2,3). NF-κB is also involved in the induction of inflammation (2,3). Constitutive activation of NF-κB occurs in most malignant lymphomas and plays a major role in lymphomagenesis and clinical aggressiveness (1). ...
Activation of nuclear factor-κB (NF-κB) in Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HL) cells is important in the transformation and development process of these lymphomas. Epstein-Barr virus (EBV) latent membrane protein-1 (LMP-1) and ligand-independent signaling by overexpressed CD30 are known to cause permanent activation of NF-κB in lymphomas. However, hyperactivation of NF-κB triggers cellular senescence and apoptosis. Here, we show that IκB-ζ, an inducible regulator of NF-κB, is constitutively expressed in BL and HL cell lines. In addition, immunohistochemical staining identified nuclear IκB-ζ‑positive BL cells, and Hodgkin and Reed-Sternberg cells in lymph nodes. Expression of LMP-1 and CD30 increased IκB-ζ expression at the transcriptional level. IκB-ζ promoter was regulated by activation of the NF-κB‑inducing kinase (NIK)/IκB kinase/NF-κB pathway via the carboxyl‑terminal tumor necrosis factor (TNF) receptor‑associated factor (TRAF)-interacting regions of LMP-1 and CD30. Interestingly, IκB-ζ inhibited NF-κB activation by LMP-1 and CD30. The results suggest that NF-κB-induced IκB-ζ negatively modulates NF-κB hyperactivation, resulting in a fine balance that ultimately endows a net evolutionary benefit to the survival of BL and HL cells.
... The clinical significance of blood cell ratios as a biomarker has already been accepted for several diseases in humans, and investigations are being conducted on tumors of various origins in dogs. Inflammation plays a fundamental role in lymphomagenesis and tumor progression, and vice versa, and can lead to changes in peripheral blood leukocyte composition (neutrophil, monocyte, and lymphocyte, especially), depending on the severity and extent of inflammation (40,41). PNR was confirmed as an independent prognostic factor in dogs diagnosed with DLBCL, with a cutoff value of 0.032; a higher value increases the risk of tumor progression before 180 days (42). ...
Introduction
Aberrant lymphoma phenotypes are frequently found in dogs, but the clinical implications are sparse.
Methods
Twenty-seven dogs with aberrant lymphoma diagnosed using flow cytometry between 2017 and 2023 were analyzed. Major paraneoplastic syndromes, prognostic factors, and clinical features of lymphoma were compared to their immunophenotypes.
Results
Twenty-seven dogs had aberrant immunophenotypes, with MHCII- (48%) and CD3+/CD21+ (44%) being the most commonly identified aberrancies. In B-cell lymphoma, the most frequent aberrancies were MHC II- (53%), CD3+/CD21+ (41%), CD34+ (24%), and CD79a- (24%). Meanwhile, in T-cell lymphoma, CD3+/CD21+ (63%), CD4-/CD8-(50%), CD5- (50%), and CD45- (50%) were the most common. The platelet–neutrophil ratio was significantly higher in the CD3+/CD21+ group than in the other groups, where either one or both markers were not expressed (55.23 ± 39.64; 18.72 ± 14.95, respectively; p = 0.001). Serum albumin concentration was significantly lower in the MHCII-group (2.59 g/dL, 95% CI 2.31–2.87) than in the MHCII+ group (3.06 g/dL, 95% CI 2.88–3.23; p = 0.009). CD34 expression showed significant correlations with cranial mediastinal mass, WHO clinical substage, and fever (p = 0.028, p = 0.041, and p = 0.047, respectively). MHCII expression was correlated with adverse reactions to chemotherapy, cranial mediastinal masses, and fever (p = 0.009, p = 0.023, and p < 0.001, respectively). No statistically significant differences in the survival period were observed for any of the phenotypic aberrancies.
Conclusion
Aberrant lymphomas are common in dogs. Some clinical prognostic factors that significantly correlate with aberrant immunophenotypes have been identified and can be applied clinically.
... First of all, high RDW de nes a proin ammatory state that can worsen the course of neoplastic diseases. Numerous studies have proved that in ammation plays a crucial role in tumor initiation, growth and progression [42][43]. RDW level correlate with the levels of other in ammatory markers: IL-6, tumor necrosis factor-alpha, hepcidin [15], CRP [44], plasma viscosity, erythrocyte sedimentation rate (ESR), brinogen, leukocyte and neutrophil count [45]. ...
Numerous research proved the prognostic significance of Neutrophil to Lymphocyte Ratio (NLR), Lymphocyte to Monocyte Ratio (LMR), Platelet to Lymphocyte Ratio (PLR) and Red Blood Cell Distribution Width (RDW) in few hematological malignancies. This retrospective cohort study conducted on a group of 204 patients aimed to analyze the role of NLR, LMR, PLR and RDW as markers of prognosis in newly diagnosed acute myeloid leukemia (AML). Initial NLR, RDW-CV were on average higher and LMR, PLR lower within dead patients compared to patients alive at 36 month of observation, MD = 0.29 CI95 [0.01;0.48], p = 0.035; MD = 1.50 CI95 [0.80;2.70], p = 0.001; MD = -0.71 CI95 [-1.69;-0.25], p = 0.001; MD = -16.92 CI95 [-25.25;-3.03], p = 0.004, respectively. Additionally, NLR, RDW-CV and RDW-SD were higher, and LMR lower on average within patients not responding to therapy compared with patients with any response, MD = 0.34 CI95 [0.08;0.49], p = 0.005; MD = 2.00 CI95 [1.10;2.60], p < 0.00; MD = 3.75 CI95 [0.10;6.70], p = 0.043; MD = -0.34 CI95 [-0.91;-0.05], p = 0.015, respectively. Higher NLR, RDW-CV, RDW-SD and lower LMR, PLR are poor prognostic factors, that may help risk-stratify patients with AML.
... Recent research has shown that inflammation is a significant contributor to the initiation and progression of DLBCL. 12,13 Inflammation provides nutrition for tumor cells, stimulates cell growth, and disrupts immune balance. 14 Some combination indices based on the number of circulating inflammatory cells have been developed and proposed as simple measures to assess systemic inflammation, of which the most often utilized were neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR). ...
Background: Systemic inflammatory indicators are clinically significant in guiding diffuse large B-cell lymphoma (DLBCL) prognosis. However, which inflammatory markers are the best predictors of DLBCL prognosis is still unclear. In this study, we aimed to create a nomogram based on the best inflammatory markers and clinical indicators to predict the overall survival of patients with DLBCL. Patients and methods: We analyzed data from 423 DLBCL patients from two institutions and divided them into a training set, an internal validation set, and an external validation set (n = 228, 97, and 98, respectively). The least absolute shrinkage and selection operator and Cox regression analysis were used to develop nomograms. We assessed model fit using the Akaike information criterion and Bayesian information criterion. The concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to assess the nomogram's predictive performance and clinical net benefit and compared with the International Prognostic Index (IPI) and National Comprehensive Cancer Network (NCCN)-IPI. Results: The inclusion variables for the nomogram model were age, Eastern Cooperative Oncology Group performance status, lactate dehydrogenase level, the systemic immune-inflammation index (SII), the prognostic nutritional index (PNI), and β-2 microglobulin (β-2 MG) level. In the training cohort, the nomogram showed better goodness of fit than the IPI and NCCN-IPI. The C-index of the nomogram (0.804, 95% CI: 0.751-0.857) outperformed the IPI (0.690, 95% CI: 0.629-0.751) and NCCN-IPI (0.691, 95% CI: 0.632-0.750). The calibration curve, ROC curve, and DCA curve analysis showed that the nomogram has satisfactory predictive power and clinical utility. Similar results were found in the validation cohort. Conclusion: The nomogram integrated with the clinical characteristics and inflammatory markers is beneficial to predict the prognosis of patients with DLBCL.
... During the last decade, more and more attention has been focused on the relationship between a high NLR (≥7) and infections in various diseases (27)(28)(29). Several current studies have revealed that the inflammatory nature of a tumor microenvironment is an important component of tumor initiation, growth, and progression (30,31). Furthermore, the NLR reflected the balance between the inflammation pathway activity and antiimmune function. ...
Background/aim:
Infection is a common cause of morbidity and mortality in patients treated for diffuse large B-cell lymphoma (DLBCL). However, there is limited information on the impact and risk factors for infection among patients receiving rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone (R-CHOP).
Patients and methods:
A retrospective study evaluating patients with DLBCL receiving R-CHOP and R-COP between 2004 and 2021 was conducted at a medical center. Hospital patients' records for the five-item modified frailty index (mFI-5), sarcopenia, blood-based inflammatory markers, and clinical outcomes were statistically analyzed.
Results:
Patients with frailty, sarcopenia, and high neutrophil-to-lymphocyte ratio (NLR) were associated with a higher risk of infections. The revised International Prognostic Index poor-risk group, high NLR, infections, and treatment modality were risk factors for shorter progression-free and overall survival.
Conclusion:
Pre-treatment high NLR was a predictor of infection and survival outcome in DLBCL patients.
... Activation of humoral immunity plays a key role in pathogenesis. 1 This inflammatory status may precede as well as follow the tumour development. Several autoinflammatory diseases such as rheumatoid arthritis and Sjogren's syndrome are well-known to be related to the development risk of lymphoma. ...
Background: Recent literature involves many cases with lymphoma and ankylosing spondylitis (AS) with or without the use of TNF inhibitors. Herein, we report a patient, a 56-year-old Human Leukocyte Antigen-B27 (HLA-B27) positive man with four years history of AS who was still under treatment with infliximab with clinical remission. He was admitted with a new-onset, 6-week history of bloody diarrhoea with mucus, abdominal pain, fever, and weight loss. An ileocolonoscopy showed linear ileocecal valve ulcers. Histopathological findings of ileocecal valve ulcers revealed peripheral T-cell lymphoma of the small intestine. Infliximab was interrupted because of the possible progression of the lymphoma.
Methods: We aimed to emphasize the underlying potential pathogenic mechanisms and to review the related literature. A literature search was conducted in the PubMed database between January 1980 and November 2020. The keywords including ‘ankylosing spondylitis’ and ‘lymphoma’ were used.
Conclusion: TNFi use, immunosuppression, and chronic inflammation may be related to the development of lymphoma in chronic inflammatory diseases. Ileocecal valve involvement should not be interpreted as inflammatory bowel disease, infection, or vasculitis in the presence of red flags.
... CHOP chemotherapy is the first-line treatment for patients with DLBCL, and multiple variations have been reported with various clinical outcomes, such as immune therapies [45,46] . Also, inflammation is considered as playing a fundamental role in lymphomagenesis and cancer invasion [47] . ...
Objective:
Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. Due to its genetic heterogeneity and abnormal metabolism, many DLBCL patients have a poor prognosis. This study investigated the key metabolism-related genes and potential mechanisms.
Methods:
Differentially expressed genes, differentially expressed transcription factors (TFs), and differentially expressed metabolism-related genes (DEMRGs) of glucose and lipid metabolic processes were identified using the edgeR package. Key DEMRGs were screened by Lasso regression, and a prediction model was constructed. The cell type identification by estimating relative subsets of RNA transcripts algorithm was utilized to assess the fraction of immune cells, and Gene Set Enrichment Analysis was used to determine immune-related pathways. A regulatory network was constructed with significant co-expression interactions among TFs, DEMRGs, immune cells/pathways, and hallmark pathways.
Results:
A total of 1551 DEMRGs were identified. A prognostic model with a high applicability (area under the curve=0.921) was constructed with 13 DEMRGs. Tumorigenesis of DLBCL was highly related to the neutrophil count. Four DEMRGs (PRXL2AB, CCN1, DECR2 and PHOSPHO1) with 32 TF-DEMRG, 36 DEMRG-pathway, 14 DEMRG-immune-cell, 9 DEMRG-immune-gene-set, and 67 DEMRG-protein-chip interactions were used to construct the regulatory network.
Conclusion:
We provided a prognostic prediction model based on 13 DEMRGs for DLBCL. We found that phosphatase, orphan 1 (PHOSPHO1) is positively regulated by regulatory factor X5 (RFX5) and mediates MYC proto-oncogene (MYC) targeting the V2 pathway and neutrophils.
... Lymphoma, as one of the major cancer subtypes involving the lymphatic system, is a severe subgroup of malignancies in human beings [1,2]. The lymphatic system is the center of the circulation immune system, thereby regulating the immune response against external antigens, germs, virus, and even cancers [3]. ...
Lymphoma is a serious malignant tumor that contains more than 70 different types and seriously endangers the body’s lymphatic system. The lymphatic system is the regulatory center of the immune system and is important in the immune response to foreign antigens and tumors. Studies showed that multiple genetic variants are associated with lymphoma but determining the pathogenic mechanisms remains a challenge. In the present study, we first applied the Gene Ontology (GO) and KEGG pathway enrichment analyses of lymphoma-associated and lymphoma-nonassociated genes. Next, the Boruta and max-relevance and min-redundancy feature selection methods were performed to filter and rank features. Then, features preselected and ranked using the incremental feature selection method were applied for the decision tree model to identify the best GO terms and KEGG pathways and extract classification rules. Results indicate that our predicted features, such as B-cell activation, negative regulation of protein processing, negative regulation of mast cell cytokine production, and natural killer cell-mediated cytotoxicity, are associated with the biological process of lymphoma, consistent with those of recent publications. This study provides a new perspective for future research on the molecular mechanisms of lymphoma.
... Recently, mutations such as TP53, SRSF2, IDH2, and ASXL1 were also demonstrated to be valuable in predicting the prognosis of MDS (22)(23)(24). As components of the tumor microenvironment, tumor-associated inflammatory cells play an important role in tumor development (25). In recent years, the importance of patient-related factors has been recognized, particularly those involved in response to systemic inflammation that determines disease outcomes in cancer patients (26). ...
Background
Inflammation appears to have a critical role in carcinogenesis tumor growth according to emerging research. The platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and plasma C-reactive protein (CRP) are considered to reflect the systemic inflammatory response and clinical prognosis. The prognostic value of inflammatory indices in myelodysplastic syndrome (MDS) patients remains unclear.
Methods
A total of 213 MDS patients were enrolled for the study. Univariate and multivariate analyses were performed to determine the prognostic significance of various indicators, including PLR, NLR, and CRP.
Results
MDS patients with higher PLR, NLR, and CRP levels had significantly shorter overall survival (OS). Based on univariate analysis, age (≥60 years), gender (men), lower hemoglobin level (<10 g/dl), higher bone marrow blast percentage (>5%), poorer karyotype, and higher Revised International Prognostic Scoring System (IPSS-R) score were significantly associated with shorter OS. Patients with higher CRP levels had shorter leukemia-free survival (LFS, P = 0.041). However, higher PLR and NLR had no significant influence on LFS (P > 0.05). Multivariate Cox proportional hazards regression analysis indicated that high PLR and CRP were also independent adverse prognostic factors for OS in MDS.
Conclusions
Elevated PLR and CRP predict poor prognosis independent of the IPSS-R and provide a novel evaluation factor for MDS patients.
... In addition, IL-10 gene polymorphisms are linked to elevated risk of NHL development and higher levels of tumor necrosis factor alpha (TNF-α) are associated with developing particular types of NHL [7]. The level and nature of inflammation dysregulation vary between different types of lymphomas [8]. In patients with a compromised immune system due to both malignancy (primary disease) and cancer treatment, the possibility of infections is substantial, which can generate circumstances for VTE complications [9]. ...
Background
Lymphomas are characterized by elevated synthesis of inflammatory soluble mediators that could trigger the development of venous thromboembolism (VTE). However, data on the relationship between specific immune dysregulation and VTE occurrence in patients with lymphoma are scarce. Therefore, this study aimed to assess the association between inflammatory markers and the risk of VTE development in patients with lymphoma.
Methods
The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lactate dehydrogenase (LDH), total protein (TP), and albumin were assessed in 706 patients with newly diagnosed or relapsed lymphoma. Data were collected for all VTE events, while the diagnosis of VTE was established objectively based on radiographic studies. ROC (receiver operating characteristic) curve analysis was performed to define the optimal cutoff values for predicting VTE.
Results
The majority of patients was diagnosed with aggressive non-Hodgkin lymphoma (58.8%) and had advanced stage disease (59.9%). Sixty-nine patients (9.8%) developed VTE. The NLR, PLR, ESR, CRP, and LDH were significantly higher in the patients with lymphoma with VTE, whereas the TP and albumin were significantly lower in those patients. Using the univariate regression analysis, the NLR, PLR, TP, albumin, LDH, and CRP were prognostic factors for VTE development. In the multivariate regression model, the NLR and CRP were independent prognostic factors for VTE development. ROC curve analysis demonstrated acceptable specificity and sensitivity of the parameters: NLR, PLR, and CRP for predicting VTE.
Conclusion
Inflammatory dysregulation plays an important role in VTE development in patients with lymphoma. Widely accessible, simple inflammatory parameters can classify patients with lymphoma at risk of VTE development.
... Anemic condition in our study population was observed naïve to treatments, hence the most possible pathogenesis was due to inflammation [3]. Inflammation has been recognized to play massive role in the development of lymphoma [11]. The pathogenesis of anemia in lymphoma is suggested to be related with inflammation in B cell NHL patients indicated by increased level of inflammatory mediators such as IL-6, TNF-α, IL-1, and gamma interferon [7,8]. ...
Background: The burden of lymphoma is intensified with the presence of anemia. The type of anemia in lymphoma is predominantly anemia of chronic disease. Severe anemia is also often associated with advanced stages leading to poor prognosis and survival as well as a worse quality of life.
Objective: In this study, we aimed to observe the incidence of anemia in lymphoma and to identify any associated clinical and laboratory factors.
Methods: Data from lymphoma patients admitted between 2012 to 2018 with complete hemoglobin (Hb) levels were collected from the medical records in Dr. Sardjito Hospital, Yogyakarta, Indonesia. Clinical and laboratory parameters included were age, sex, nutritional status, Ann Arbor staging, extranodal involvement, number of extranodal sites, Lactate Dehydrogenase (LDH) level, Eastern Cooperative Oncology Group (ECOG) performance status, platelet count, absolute lymphocyte count (ALC), white blood cell count (WBC), and lymphoma prognostic score (Non-Hodgkin Lymphoma/NHL using Index Prognostic International (IPI), Hodgkin’s Lymphoma/HL using International Prognostic Score (IPS)). Statistical analysis was done to observe the difference in any parameters between patients with anemia and non-anemia. Logistic regression was employed to model the relationship between associated or predictive factors and anemia incidence.
Results: Six hundred eleven (611) lymphoma patients were involved in this study, 296 (48.5%) had anemia and 314 (51.5%) did not. Anemia was more prevalent in HL (17/ 33 cases or 51.5%) than in NHL (272/ 564 cases or 48.1%). Patients with anemia frequently presented with mild anemia in 142 (48%), followed by moderate anemia in 139 (46.9%). The incidence of anemia were significantly associated with male sex, advanced Ann Arbor stage (III-IV), underweight, elevated LDH level, abnormal platelet, absolute lymphocyte counts less than 600/mm3, elevated WBC count more than 15,000/mm3, and high total prognostic score (>3). Multivariate analysis demonstrated low or elevated platelet (P=0.044; 95% CI=1.03-8.09) as an independent predictor, meanwhile lymphocytopenia as protective factor (OR=0.05; 95% CI=0.00-0.54; P=0.013).
Conclusion: Anemia commonly occurs in Indonesian lymphoma patients. There is an association and increased risk to develop anemia in male, Ann Arbor stage III-IV, underweight, elevated LDH, abnormal platelet, leukocytosis, and high total prognostic score. Abnormal platelet was an independent predictive factor, and lymphocytopenia is one of the protective factor.
... The level and nature of in ammation dysregulation vary between different types of lymphomas. (7) In patients with a compromised immune system due to both malignancy (primary disease) and cancer treatment, the possibility of infections is substantial, which can generate circumstances for VTE complications.(8) Although the pathways that trigger in ammation are subject to ne modulation and differ based on the type of lymphoma, in ammation has been classically described through white blood cell (WBC) count and standardized acute phase reactants, including C-reactive protein (CRP), sedimentation rate, and brinogen level. ...
Background: Lymphomas are characterized by inflammatory soluble mediators that can trigger the development of venous thromboembolism (VTE). However, data on the relationship between specific immune dysregulation and VTE occurrence in lymphoma are scarce. The study aimed to assess the association between inflammatory markers and the risk of VTE development in lymphoma patients.
Methods: The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lactate dehydrogenase (LDH), total protein (TP), and albumin were assessed in 706 patients with newly diagnosed or relapsed lymphoma. Data were collected for all VTE events, while the diagnosis of VTE was set objectively based on radiographic studies. ROC (receiver operating characteristic) curve analysis was used to define the optimal cutoff values for predicting VTE.
Results: The majority of patients were diagnosed with aggressive non-Hodgkin lymphoma (58.8%) and had advanced disease (59.9%). Sixty-nine patients (9.8%) developed VTE. The NLR, PLR, ESR, CRP, and LDH were significantly higher in lymphoma patients with VTE, whereas the TP and albumin were significantly lower. In the univariate regression analysis, the NLR, PLR, TP, albumin, LDH, and CRP were prognostic factors for VTE development. In the multivariate regression model, the NLR and CRP were independent prognostic factors for VTE development. ROC curve analysis demonstrated acceptable specificity and sensitivity of the NLR, PLR, and CRP for predicting VTE.
Conclusion: Inflammatory dysregulation plays an important role in VTE development in patients with lymphoma. Widely accessible, simple inflammatory parameters can classify lymphoma patients at risk of VTE development.
... Park et al. (13) reported that malnutrition is an adverse prognostic factor in DLBCL patients. Inflammation plays an important role in the pathogenesis and progression of several types of lymphoma, including DLBCL, and there are varying levels of inflammatory infiltrates, including macrophages, and effector and regulatory T cells (14). Due of this association, multiple systemic nutritional and inflammatory biomarkers have been studied in DLBCL patients to predict prognosis. ...
Background:
The international prognostic index (IPI) is widely used as an indicator for evaluating the clinical prognosis of diffuse large B-cell lymphoma (DLBCL). However, more precise prognostic indicators are needed. This study aimed to evaluate the prognostic significance of the advanced lung cancer inflammation index (ALI), prognostic nutritional index (PNI), and systemic immune-inflammation index (SII) in DLBCL.
Methods:
A total of 117 patients with newly diagnosed DLBCL were included in this study. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values for the ALI, PNI, and SII to predict survival, and patients were stratified into high and low groups. Cox regression analysis and the Kaplan-Meier method were used to assess the prognostic ability of these indexes.
Results:
The optimal cut-offs for the ALI, PNI, and SII were 31.26, 36.48, and 486.76, respectively. The ALI had the highest area under the curve (AUC). The high ALI or PNI group had better 5-year overall survival (OS) than the low ALI (73% vs. 53%, P<0.001) or PNI (60% vs. 45%, P<0.001) group, and the low SII group had better 5-year OS than the high SII group (67% vs. 62%, P=0.034). Although all 3 parameters were associated with OS in univariate analyses, only the ALI and PNI were independent factors for OS in multivariate analyses. We found that when DLBCL patients were classified according to IPI combined with ALI, PNI, or SII, respectively, there were more obvious differences in OS among different types.
Conclusions:
The ALI and PNI may be easily available markers to predict clinical outcomes in DLBCL patients. SII predicted OS only in univariate analysis.
... NFAT may exert additional effects in different cell types, including stroma cells, by regulating inflammation and inflammation-associated cancer, as previously reported by other reviews on this topic (86,87). To note, inflammation is a hallmark of CLL as well as other lymphoid malignancies where infiltrating immune cells, stroma, and vessels contribute to shape a complex tumor microenvironment (88)(89)(90). With this in mind it is reasonable to hypothesize that inhibition of the NFAT pathway could be effective for the treatment of lymphoproliferative disease since it affects cell function and survival both on and off the tumor. ...
In recent years significant progress has been made in the clinical management of chronic lymphocytic leukemia (CLL) as well as other B-cell malignancies; targeting proximal B-cell receptor signaling molecules such as Bruton Tyrosine Kinase (BTK) and Phosphoinositide 3-kinase (PI3Kδ) has emerged as a successful treatment strategy. Unfortunately, a proportion of patients are still not cured with available therapeutic options, thus efforts devoted to studying and identifying new potential druggable targets are warranted. B-cell receptor stimulation triggers a complex cascade of signaling events that eventually drives the activation of downstream transcription factors including Nuclear Factor of Activated T cells (NFAT). In this review, we summarize the literature on the expression and function of NFAT family members in CLL where NFAT is not only overexpressed but also constitutively activated; NFAT controls B-cell anergy and targeting this molecule using specific inhibitors impacts on CLL cell viability. Next, we extend our analysis on other mature B-cell lymphomas where a distinct pattern of expression and activation of NFAT is reported. We discuss the therapeutic potential of strategies aimed at targeting NFAT in B-cell malignancies not overlooking the fact that NFAT may play additional roles regulating the inflammatory microenvironment.
... These would, in turn, facilitate a dysfunctional tumor microenvironment. It has been theorized that both, neutrophilia and lymphopenia, would synergize to promote lymphoma development [23,24]. The neutrophilia could be explained by the tumors associated neutrophils (TANs), which have dual properties. ...
Data on response and survival outcomes of Latin American patients with diffuse Large B- cell lymphoma (DLBCL) are limited. We describe the clinical, inflammatory and immunohistochemical features of a cohort of DLBCL Peruvian patients treated with chemoimmunotherapy between 2010 and 2015. Logistic models were fitted for complete response (CR), and Cox proportional-hazard regression for progression-free survival (PFS) and overall survival (OS). Seventy-three patients were included in this analysis, 41% had high/high-intermediate IPI and 48% had high/high-intermediate NCCN-IPI scores, 41% had non-germinal center (NGC) profile and 36% were double expressors. CR was attained in 63% of patients, median PFS was 53 months and median OS was 80 months. Both IPI and NCCN-IPI scores were statistically associated with PFS and OS. Neutrophil/lymphocyte ratio (NLR) ≥4 was associated with lower odds of CR (OR 0.19, p = 0.007), worse PFS (HR 2.67, p = 0.02) and worse OS (HR 2.77, p = 0.02). NLR ≥ 4 remained significant after adjusting for the IPI score and had a trend towards significance when adjusted for the NCCN-IPI score. Albumin <3.5 g/dl was associated with worse OS when adjusted for the NCCN-IPI score (HR 2.96, p = 0.04). NGC profile and double expressors were not prognostic. Our study identified NLR ≥ 4 and albumin <3.5 g/dl as potential adverse factors in DLBCL patients and could add to the prognostic value of the IPI or the NCCN-IPI scores.
... I nflammation plays a pivotal role in the pathogenesis of both Hodgkin's and non-Hodgkin's lymphoma. Specifically, it is involved in complex interactions between stromal, lymphoid, and malignant cells in the tumor microenvironment, regulating several stages of tumor progression (1). In Hodgkin's lymphoma in particular, the reactive milieu can form up to 99% of the cellular background (2). ...
Background
There is evidence that metabolic disease burden in lymphoma influences patient outcome. However, the impact of disease severity on the cardiovascular system is unknown.
Objectives
The aim of this study was to examine whether lymphoma is associated with arterial inflammation by investigating the relationship between disease metabolic burden and arterial fluorodeoxyglucose (FDG) uptake.
Methods
Sixty-two chemotherapy-naïve patients with active Hodgkin’s or non-Hodgkin’s lymphoma were matched (2:1) to individual control groups of lymphoma patients previously treated and free of active disease. All groups underwent ¹⁸F-FDG position emission tomography–computed tomography imaging. Disease severity was quantified by metabolic tumor volume (MTV) and total lesion glycolysis corresponding to standardized uptake values (SUVs) ≥41% or ≥2.5 of the maximum SUV within lymphoma regions, and aortic FDG uptake was quantified through the target-to-background ratio (TBR). Inflammatory and disease severity biomarkers were also measured.
Results
MTV and total lesion glycolysis measurements were significantly correlated with inflammatory and disease biomarkers. Aortic TBR was higher in patients with active non-Hodgkin’s lymphoma compared with control subjects (median difference 0.51; 95% confidence interval [CI]: 0.28 to 0.78; p < 0.001). Similarly, patients with active Hodgkin’s lymphoma had higher values of aortic TBR compared with control subjects (median difference 0.31; 95% CI: 0.15 to 0.49; p < 0.001). In addition, aortic TBR was modestly increased in patients with stage III to IV disease compared with those with stage I to II disease (median aortic TBR: 2.23 [interquartile range: 2.01 to 2.54] vs. 2.06 [interquartile range: 1.83 to 2.27; p = 0.050). In multivariable analysis, aortic FDG uptake and MTV≥2.5 values were independently associated (β = 0.425; 95% CI: 0.189 to 0.662; p = 0.001; R² = 0.208), as were aortic FDG uptake and MTV≥41% (β = 0.407; 95% CI: 0.167 to 0.649, p = 0.001; R² = 0.191).
Conclusions
Aortic wall FDG uptake is related with disease severity indicative of a possible vascular effect of lymphoma. This work highlights a new potential role of molecular imaging in cardio-oncology for evaluating disease severity and its consequences on the vasculature.
... It is known that an inflammatory microenvironment has a causal role in the development of B-cell lymphomas. 56 Various genetically engineered mouse models have been developed to understand how B-cell lymphomas arise. 57 Some of the genetically engineered mouse models reproduced the inflammatory context of B-cell lymphoma development, but others do not. ...
Hepatocellular carcinoma (HCC) is the most common form of liver tumors. Although HCC is associated with chronic viral infections, alcoholic cirrhosis, and non-alcoholic fat liver disease, genetic factors that contribute to the HCC risk remain unknown. The BRCA2 DNA repair associated (BRCA2) and cyclin dependent kinase inhibitor 1A (CDKN1A) interacting protein, known as BCCIP, are essential for cell viability and maintenance of genomic stability. In this study, we established a new genetically engineered mouse model with Bccip deficiency. Mosaic or heterozygous Bccip deletion conferred an increased risk of spontaneous liver tumorigenesis and B-cell lymphoma development at old age. These abnormalities are accompanied with chronic inflammation, histology of nonalcoholic steatohepatitis, keratin and ubiquitin aggregates within cytoplasmic Mallory-Denk bodies, and changes of the intra-cellular distribution of high mobility group box 1 protein. Our study suggests BCCIP dysregulation as a risk factor for HCC, and it offers a novel mouse model for future investigations of non-viral or non-alcoholic causes of HCC development.
... Biologically, the NLR can serve as a reflection of two separate but interrelated underlying processes in lymphomas. Specifically, the absolute neutrophil count might serve as a marker of systemic inflammation, which can provide a permissive environment for the development of lymphoma (Carbone et al, 2014). On the other hand, the absolute lymphocyte count might be reflective of immunosuppression, which has also been associated not only with development of lymphoma but also with a worse outcome in a number of solid and haematological malignancies (Castillo et al, 2010;Wei et al, 2015). ...
Introduction: Peripheral T-cell lymphoma (PTCL) encompasses a group of rare and aggressive lymphomas. PTCL, unspecified (PTCLU) is the most common subtype of PTCL, and carries a poor prognosis. The International Prognostic Index (IPI) and the Prognostic Index for PTCLU (PIT) scoring systems are powerful risk-stratification tools in patients with PTCL. The neutrophil-to-lymphocyte ratio (NLR) has shown to be prognostic in patients with advanced stage PTCLU (Beltran Leuk Lymphoma 2016). The aim of this study was to evaluate whether the NLR is a prognostic factor in patients with early stage PTCLU.
Methods: We included patients with a pathological diagnosis of PTCLU who were diagnosed and treated at our institution between 2001-2016. We excluded cases with stage 3 or 4 disease. IRB approval was obtained prior to research. Pathological samples were reviewed by hematopathologists to confirm the diagnosis. Pertinent clinicopathological data were collected through chart review, and are presented using descriptive statistics. The NLR was calculated by dividing the neutrophil by the lymphocyte count, and dichotomized in NLR>=4 and NLR<4. Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate Cox models were fitted to evaluate hazard ratios (HR) for overall survival (OS).
Results: 48 patients with a diagnosis of early stage PTCL were included in this analysis. Histologically, 40 patients (83%) were PTCL, unspecified, 7 (15%) were anaplastic large cell lymphoma, and 1 (2%) was enteropathy-associated T-cell lymphoma. The median age at diagnosis was 60 years (range 18-83 years) with a slight male predominance (82%). Clinically, 49% of patients were 60 or older, 34% presented with ECOG>1, 36% with elevated LDH, and 65% with extranodal disease; 44% had stage II and 56% had stage I disease. No patient had bone marrow involvement. 30% of patients presented with high/high-intermediate IPI score and 34% with high/high-intermediate PIT score. 27% of patients had a NLR >=4. There were no differences in age, LDH levels, extranodal involvement and stage between NLR>=4 and NLR<4. There was a trend towards worse ECOG performance status in NLR>=4 patients (p=0.06). The 3- and 5-year OS rates were 67% (95% CI 50-80%) and 52% (95% CI 29-71%), respectively. High/high-intermediate IPI score was associated with a worse outcome (HR 4.9, 95% CI 1.7-14.2; p=0.004), as well as high-high-intermediate PIT score (HR 3.9, 95% CI 1.2-12.7; p=0.03). According to NLR, NLR>=4 patients had a higher risk of death (HR 9.9, 95% CO 3.2-30.1; p<0.001). In a multivariate analysis adjusting for IPI and PIT scores, NLR>=4 was the only independent factor associated with a worse survival (HR 6.2, 95% CI 1.9-20.9; p=0.003).
Conclusion: The NLR appears as a novel and easy to use prognostic factor for OS in previously untreated patients with early-stage PTCL. Our findings support the need for validation of the NLR in larger retrospective or prospective studies in patients with PTCL.
Disclosures
Castillo: Otsuka: Consultancy; Pharmacyclics: Honoraria; Abbvie: Research Funding; Millennium: Research Funding; Janssen: Honoraria; Biogen: Consultancy.
... To date, studies of the MPO/PON ratio have only been investigated in relation to cardiovascular diseases, such as researching the function of HDL and the assessment of Coronary artery disease risk. But, conditions such as inflammation, oxidative stress, and dyslipidemia which may cause the dysfunction of HDL are also related to many diseases besides cardiovascular diseases (3,4,6,7,20,26,27). To our knowledge, this is the first study in the literature to evaluate MPO/PON ratio in lymphoma patients. ...
Background: The aim of this study is to investigate the myeloperoxidase/paraoxonase ratio which indicates dysfunction of high-density lipoprotein in various types of lymphoma characterized by abnormal lipid metabolism, oxidative stress, and inflammation. Methods: Thirty lymphoma patients and 30 healthy subjects were enrolled in this study. Serum myeloperoxidase, paraoxonase, arylesterase, lipid hydroperoxide and routine biochemistry tests levels were measured on an automated analyzer. The diagnosis of lymphoma patients was made according to the histological examination of the biopsy material. Results: Compared with healthy control group; the albumin, arylesterase, high-density lipoprotein, thiol, and Hemoglobin levels were significantly lower while myeloperoxidase / paraoxonase, myeloperoxidase/arylesterase, and lipid hydroperoxide levels were significantly higher, in patients with lymphoma. Also, lipid hydroperoxide level was significantly correlated with myeloperoxidase / paraoxonase and myeloperoxidase / arylesterase (r= 0.330, p=0.046; r= 0.588, p< 0.001, respectively). Conclusions: We think that dysfunctional high-density lipoprotein is an important factor in the inflammatory process, atherosclerosis, oxidative stress, and impaired lipid metabolism that can be observed in patients with lymphoma. We believe that in the future the myeloperoxidase/paraoxonase ratio can be used as a treatment criterion to prevent diseases that cause dysfunctional high-density lipoprotein.
... Mounting evidence supports a systemic inflammatory response in cancer, and also in lymphoma, as "protumoral." [19][20][21] Different laboratory parameters, such as the neutrophil/lymphocyte ratio, the lymphocyte/monocyte ratio, the lymphocyte/platelet index, Creactive protein, or fibrinogen levels, have been identified as prognostic parameters in cancer that could be a reflection of a deranged systemic inflammatory response promoting genetic instability, among other carcinogenetic processes. 22 In a previous study, we evaluated the prognostic value of the neutrophil/lymphocyte ratio in patients with DLBCL treated with chemoimmunotherapy, as well as in patients with peripheral T-cell lymphoma, not otherwise specified, treated with anthracycline-containing regimens. ...
Introduction:
The red blood cell distribution width (RDW) is an easy-to-obtain laboratory value that has emerged as a potential prognostic factor in solid and hematologic malignancies.
Patients and methods:
We evaluated 121 patients with de novo diffuse large B-cell lymphoma (DLBCL) treated with standard chemoimmunotherapy at our institution between 2010 and 2012. We categorized patients with high RDW (> 14.6%) and normal RDW (11.6%-14.6%). We fitted multivariate regression models for complete response (CR) and overall survival (OS).
Results:
Patients with high RDW were less likely to achieve CR to chemoimmunotherapy than patients with normal RDW (48% vs. 83%; P < .001). The 5-year OS rate for patients with high RDW was lower than in patients with normal RDW (51% vs. 79%; P = .001). In multivariate regression models, high RDW was independently associated with lower odds of achieving CR (odds ratio, 0.32; 95% confidence interval [CI], 0.12-0.83; P = .02) and with higher risk of death from any cause (hazard ratio [HR], 2.04; 95% CI, 1.03-4.02; P = .04) than normal RDW in patients with DLBCL treated with chemoimmunotherapy. High RDW remained an independent adverse factor for OS after adjustment for the International Prognostic Index and the National Comprehensive Cancer Network-International Prognostic Index scores with HR 2.20 (95% CI, 1.12-4.31; P = .02) and HR 2.67 (95% CI 1.28-5.59; P = .009), respectively.
Conclusion:
High RDW appears to be an adverse predictive and prognostic factor in patients with de novo DLBCL treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone).
... 37 In contrast, lymphocytes in the tumor tissue could accelerate cancer cell apoptosis by way of direct or indirect anticancer immune responses. 38 Thus, the NLR could be a useful biomarker representing the link between inflammation and tumor progression, which was also confirmed in bladder cancer. ...
Objective:
An elevated neutrophil-to-lymphocyte ratio (NLR) is significantly associated with poor outcomes in many types of malignancies, including bladder cancer. However, the prognostic value of NLR in patients with nonmuscle-invasive bladder cancer (NMIBC) treated with GreenLight photoselective vaporization of bladder tumor (PVBT) has not been well studied. In this study, we aimed to explore the association between NLR and survival outcomes in patients with NMIBC who underwent PVBT.
Materials and methods:
We retrospectively investigated 463 patients with NMIBC who underwent PVBT in Tianjin Union Medical center from January 2012 to January 2017. The patients were divided into two groups based on the NLR value (NLR ≥2.5 and NLR <2.5). Overall survival (OS), cancer-specific survival (CSS), and recurrence-free survival (RFS) were determined using Kaplan-Meier analysis and the log-rank test.
Results:
Among 463 patients, age, tumor size, tumor focality, tumor grade, or tumor stage in the two groups did not differ significantly. The median follow-up was 40 months (range, 15-60). Thirty-eight patients (8.2%) died of any cause; 24 (5.2%) patients died of bladder cancer. In addition, 88 (19.0%) patients experienced disease recurrence. Elevated NLR was significantly associated with poor OS (χ2 = 7.457, p = 0.002), CSS (χ2 = 6.242, p = 0.012), and RFS (χ2 = 5.372, p = 0.020) in patients with NMIBC who underwent PVBT.
Conclusions:
Elevated preoperative NLR was significantly associated with poor OS, CSS, and RFS, and it could be considered as an effective and convenient prognostic biomarker for patients with NMIBC who were treated with PVBT.
... Because OS and PFS/EFS are correlated with each other, the 3-level random-effect meta-analysis model is applied to assess the prognostic role of NLR in DLBCL patients. Several recent studies have demonstrated that the inflammatory nature of a tumor's microenvironment is a critical component of tumor initiation, growth, and progression [33,34]. Furthermore, a variety of systemic inflammatory biomarkers have been identified and studied in patients with DLBCL, such as NLR [35], serum LDH [36], serum C-reactive protein (CRP) [37], serum albumin [38], etc. NLR has the advantage of low economic cost and wide availability, thereby drawing increasing attention. ...
Background
The neutrophil-to-lymphocyte ratio (NLR), a biomarker for systematic inflammation, has been recently identified as a prognostic factor for various types of both solid and hematologic malignancies. Here we conducted an updated dose–response meta-analysis to investigate whether NLR can be served as a prognostic biomarker in diffuse large B cell lymphoma (DLBCL).
Methods
We systematically searched PubMed, Embase, ISI Web of Science and CNKI for relevant studies. Odds ratios or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) were pooled to estimate the association between NLR and clinicopathological parameters or survival of cancer patients.
Results
Eleven trials with 2515 DLBCL patients were included in the meta-analysis. The results revealed that elevated pretreatment NLR was significantly associated with elder age, advanced Ann Arbor stage, higher incidence rate of B symptoms and bone marrow involvement, and higher lactate dehydrogenase level, etc. Moreover, increased NLR also predicted poorer overall survival (HR 1.826, 95% CI 1.238–2.692) and progression-free survival/event-free survival (PFS/EFS) (HR 1.591, 95% CI 1.124–2.252). And two-stage dose–response meta-analysis revealed non-linear association between increased NLR and risk of mortality in DLBCL patients.
Conclusion
DLBCL patients with higher NLR are more likely to have poorer prognosis than those with lower NLR.
Electronic supplementary material
The online version of this article (10.1186/s12935-018-0609-9) contains supplementary material, which is available to authorized users.
... Biologically, the NLR can serve as a reflection of two separate but interrelated underlying processes in lymphomas. Specifically, the absolute neutrophil count might serve as a marker of systemic inflammation, which can provide a permissive environment for the (Carbone et al, 2014). On the other hand, the absolute lymphocyte count might be reflective of immunosuppression, which has also been associated not only with development of lymphoma but also with a worse outcome in a number of solid and haematological malignancies (Castillo et al, 2010;Wei et al, 2015). ...
... Biologically, the NLR can serve as an easy-to-measure-and-use tool reflecting on two distinct but otherwise intertwined processes in DLBCL: a systemic inflammatory response and lymphopenia. Previous studies have shown that a systemic inflammatory response is protumoral [14]. An increase in number of neutrophils mediated by the inflammatory response favors tumor angiogenesis and may negatively influence the activity of specific subtypes of T-lymphocytes [15,16]. ...
The neutrophil:lymphocyte ratio (NLR) has emerged as prognostic in patients with hematological malignancies. We aimed at evaluating the NLR as predictive for complete response (CR) and prognostic for progression-free (PFS) and overall survival (OS) in a study cohort of 121 Peruvian patients with diffuse large B-cell lymphoma (DLCBL) treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Patients with an NLR ≥6 (n = 28) were more likely to have a performance status ECOG ≥2 (74% vs. 23%; p < 0.001). NLR ≥6 was associated with lower CR rate to R-CHOP (46% vs. 74%; p = 0.02) and there was a trend towards significance in multivariate regression analyses (OR 0.36, 95% CI 0.11-1.00; p = 0.05). Patients with NLR ≥6 had lower 5-year PFS rate (39% vs. 72%; p < 0.001) and lower 5-year OS rate (46% vs. 75%; p = 0.001) than patients with NLR <6 and was an independent adverse factor for PFS (HR 2.43, 95% CI 1.21-4.87; p = 0.01) and OS (HR 2.68, 95% CI 1.31-5.47; p = 0.007) in multivariate Cox regression analyses. NLR ≥6 was prognostic of PFS and OS after adjusting for the International Prognostic Index and the NCCN-IPI scores. In conclusion, the NLR could add predictive and prognostic value to well established prognostic tools in DLBCL.
... Human lymphomas develop in tissue microenvironments characterized by stromal and lymphoid cells that interact with malignant cells. 25 A gene expression study identified three subsets of DLBCL: 'oxidative phosphorylation', 'B-cell receptor/ proliferation' and 'host response' (HR), that were characterized by the high content of microenvironmental cells. 26 Relevant immune cells in this microenvironment are FOXP3 + regulatory T lymphocytes (Tregs), CD8 + cytotoxic T lymphocytes and alternatively activated type 2 tumour-associated macrophages (M2-like TAMs). ...
Aims and methods:
We aimed to define the clinicopathological characteristics of 29 primary sinonasal diffuse large B-cell lymphoma (DLBCL(sn) ) in a series of 240 DLBCL(all NOS) including DLBCL(sn) training set (n=11) and validation set (n=18), and DLBCL(non-sn) (n=211).
Results:
In the training set 82% had non-GCB phenotype and 18% were EBER(+) . The genomic profile showed gains(+) of 1q21.3q31.2 (55%), 10q24.1 (46%), 11q14.1 (46%) and 18q12.1q23 (46%); losses(-) of 6q26q27 (55%) and 9p21.3 (64%); and copy-number neutral LOH at 6p25.3p21.31 (36%). This profile is comparable to DLBCL NOS (GSE11318, n=203.) and closer to non-GCB/ABC subtype. Nevertheless, +1q31, -9p21.3 and -10q11.1q26.2 were more characteristic of DLBCL(sn) (P<0.001). Array results were successfully verified by FISH on +1q21.3 (CKS1B), -6q26 (PARK2), +8q24.21 (MYC), -9p21.3 (MTAP, CDKN2A/B), -17p13.1 (TP53) and +18q21.33 (BCL2) with 82%-91% agreement. MCRs included biologically relevant genes of MNDA (+1q23.1), RGS1/RGS13 (+1q31.2), FOXP1 (+3p13), PRDM1 and PARK2 (-6q21-q26), MYC (+8q24.21), CDKN2A (-9p21.3), PTEN (-10q23.31), MDM2 (+12q15), TP53 (-17p13.1), and BCL2 (+18q21.33). Correlation between DNA-copy-number and protein-immunohistochemistry was confirmed for RGS1, RGS13, FOXP1, PARK2 and BCL2. The microenvironment had high infiltration of M2-TAMs, and CD8+ Tc that associated with higher genomic instability. The DLBCL(sn) validation set confirmed the clinicopathological characteristics, all FISH loci and IHC for RGS1. RGS1, one of the most frequently altered genes, was analyzed by immunohistochemistry in DLBCL(all) and high RGS1 expression associated to non-GCB, EBER+ and unfavorable overall survival (Hazard ratio=1.794; P=0.016).
Conclusions:
DLBCL(sn) has a characteristic genomic profile. High RGS1 IHC expression associates with poor overall survival in DLBCL(all NOS).
... Chronic inflammation in the autoimmune setting is considered a risk factor for HL. [31][32][33] Also, Epstein-Barr virus (EBV) infection and history of infectious mononucleosis is known to play an aetiological role in HL, at least for a subset (approximately 20-30%) of HL cases. [34] EBV has been found in tissue from appendectomised patients [35] and case reports have indicated an increased risk of appendicitis in teenagers with active infectious mononucleosis. ...
Objective:
Appendectomy remains one of the most common surgical procedures, but possible long-term consequences for health and disease are incompletely investigated. The appendix forms part of the secondary lymphoid system and appendectomy has been associated with increased risks of hematolymphoproliferative malignancies in some studies.
Materials and methods:
We examined the risk of lymphoid neoplasms in a large cohort of 337,437 appendectomised patients <60 years of age in Sweden 1975-2009. We estimated relative risks of non-Hodgkin lymphoma (NHL) and major subtypes, Hodgkin lymphoma (HL), chronic lymphocytic leukaemia (CLL), myeloma, and acute lymphoblastic leukaemia (ALL) versus the general population using standardised incidence ratios (SIRs) with 95% confidence intervals (CIs).
Results:
There was no increased risk of NHL (SIR = 0.97, 95%CI 0.88-1.06), major NHL subtypes, CLL (SIR = 0.87, 95%CI 0.70-1.06), myeloma (SIR = 1.14, 95%CI 0.96-1.33) or ALL (SIR = 1.10, 95%CI 0.80-1.47) following appendectomy. An increased risk of HL was observed among patients diagnosed with appendicitis (SIR = 1.29, 95%CI 1.07-1.54, p=0.007), especially individuals aged <20 years at surgery (SIR = 1.43, 95%CI 1.11-1.82), and for the nodular sclerosis subtype of HL (SIR = 1.55, 95%CI 1.01-2.27). A marginally increased risk of myeloma was noted among men, but the association was limited to the first few years of follow-up.
Conclusion:
Appendectomy is not associated with any notable increase in risk of lymphoid neoplasms. A small increased risk of HL following appendicitis (rather than appendectomy per se) could reflect a true association, or shared susceptibility to infection/inflammation among individuals prone to develop HL. The association observed for myeloma may be explained by chance or surveillance bias.
... Very recently, the so-called enhanced IPI, an updated version of the IPI for patients with DLBCL treated in the rituximab era, has been proposed [94]. Table 4 highlights highly aggressive DLBCL subgrouped according to adverse prognostic factors: lack of CD20 expression, special phenotypes linked to cell of origin and CD5 expression, EBV infection, and complex karyotypes [95,96]. ...
Diffuse large B cell lymphoma (DLBCL) comprises specific subtypes, disease entities, and other not otherwise specified (NOS) lymphomas. This review will focus on DLBCL NOS because of their prevalence and their heterogeneity with respect to morphology, clinical presentation, biology, and response to treatment. Gene expression profiling of DLBCL NOS has identified molecular subgroups that correlate with prognosis and may have relevance for treatment based on signaling pathways. New technologies have revealed that the "activated B cell" subgroup is linked to activation of the nuclear factor kB (NF-kB) pathway, with mutations found in CD79A/B, CARD11, and MYD88, and loss of function mutations in TNFAIP3. The "germinal center B cell-like" subgroup is linked to mutational changes in EZH2 and CREBBP. Biomarkers that are related to pathways promoting tumor cell growth and survival in DLBCL have been recognized, although their predictive role requires clinical validation. Immunohistochemistry for detecting the expression of these biomarkers is a practical technique that could provide a rational for clinical trial design.
Background & aims:
Earlier studies have provided varying risk estimates for lymphoma in patients with inflammatory bowel disease (IBD) but have often been limited by detection biases, (especially during the first year of follow-up), misclassification, and small sample size; and rarely reflect modern-day management of IBD.
Methods:
Binational register-based cohort study (Sweden and Denmark) during 1969-2019. We compared 164,716 patients with IBD to 1,639,027 matched general population reference individuals. Cox regression estimated hazard ratios (HRs) for incident lymphoma by lymphoma subtype, excluding the first year of follow-up.
Results:
During 1969-2019, 258 patients with Crohn's Disease (CD), 479 patients with ulcerative colitis (UC), and 6675 matched reference individuals developed lymphoma. This corresponded to incidence rates of 35(CD) and 34(UC)/100,000 person-years [PY] in IBD patients, compared to 28 and 33/100,000 PY in their matched reference individuals. While both CD (HR=1.32; 95%CI=1.16-1.50) and UC (HR=1.09; 95%CI=1.00-1.20) were associated with an increase in lymphoma, the 10-year cumulative incidence difference was low even in CD patients (0.08%; 95%CI=0.02 to 0.13])). HRs increased the past two decades, corresponding to increasing use of immunomodulators and biologics during the same time-period. HRs were increased for aggressive B-cell NHL in CD and UC patients, and for T-cell NHL in CD patients. Although the highest HRs were observed in patients exposed to combination therapy (immunomodulators and biologics) or second line biologics, we also found increased HRs in patients naïve to such drugs.
Conclusions:
During the past 20 years, HRs for lymphomas have increased in CD, but not in UC, and were driven mainly by T-cell lymphomas and aggressive B-cell lymphomas.
In this study, pre-chemotherapy hematological values of 14 dogs diagnosed with diffuse B-cell small lymphocytic lymphoma were compared with the hematological data of 26 healthy dogs. Neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), platelet/lymphocyte ratio (PLR) and platelet/neutrophil ratio (PNR) were evaluated between two groups. Anemia and an increased total leukocyte count were observed in dogs with lymphoma compared to healthy ones. The PNR value was found to be significantly lower in dogs with lymphoma, It was concluded that more comprehensive studies studies are needed to clearly understand the diagnostic and prognostic importance of hematological parameters in B-cell small lymphocytic lymphoma of dogs.
Diffuse large B‐cell lymphoma (DLBCL) is the most common haematopoietic tumour in dogs and recognized as clinical model for its human counterpart. Recently, neutrophil‐to‐lymphocyte (NLR) and lymphocyte‐to‐monocyte (LMR) ratios have been shown to predict time‐to‐progression (TTP) and lymphoma‐specific survival (LSS) in dogs with DLBCL treated with CHOP‐based chemotherapy. We retrospectively evaluated in 59 dogs diagnosed with DLBCL the prognostic value of haematological parameters and derived ratios: NLR, LMR, platelet‐to‐lymphocyte (PLR) and platelet‐to‐neutrophil (PNR) ratios for TTP, LSS and associated secondary end‐points (time‐to‐progression‐rate [TTPR] and lymphoma‐specific survival‐rate [LSSR]) as rates at 180 and 365 days. PNR is an independent prognostic marker (p ≤ .001) for TTPR/180 and 365 days, dogs with a PNR above 0.032 were more likely to progress before 180 days (sensitivity 46.5%, specificity 87.5%, p = .004). On univariate analysis, NLR showed a prognostic significance for LSSR/180 (p = .006) and LSSR/365 (p = .009). A baseline NLR value below 7.45 was positively associated with survival at 180 days (sensitivity 52%, specificity 85.3%, p = .025). The presence of substage b, was associated with early progression and decreased survival at 180 days (p = .031). Anaemia significantly reduced LSSR at 365 days (p = .028). This is the first study evaluating PLR and PNR in canine DLBCL and demonstrates that PNR could be a predictor of early lymphoma progression. Since peripheral blood cell composition can be affected by several non‐oncological causes, the development of larger multicenter studies with homogeneous inclusion criteria could help to better determine the true predictive values of blood cell ratios in dogs' DLBCL treated with CHOP chemotherapy.
Peripheral T-cell lymphoma (PTCL) is a rare and highly heterogeneous non-Hodgkin lymphoma (NHL). Although a few prognostic models have been put forward to predict the prognosis of PTCL, some patients with poor prognosis remain unidentified. Therefore, we conducted a retrospective study of 213 adult PTCL patients and assessed the prognostic role of platelet-lymphocyte ratio (PLR) and neutrophil-lymphocyte ratio (NLR) in the complete response (CR) and survival of PTCL patients. Patients with PLR ≥ 232.5 achieved a lower CR rate than patients with PLR < 232.5 (18.5% vs. 56.6%, p < .001). Moreover, there was a statistical significance in CR rate between patients with NLR ≥ 3.7 and < 3.7 (31.7% vs. 60.7%, p < .001). The univariable analysis indicated that both PLR and NLR were related with worse OS. However, only PLR remained an independent prognostic indicator of OS (p = .002) by multivariable analysis.
Chronic inflammation, including that driven by autoimmunity, is associated with the development of B-cell lymphomas. IL1R8 is a regulatory receptor belonging to the IL1R family, which negatively regulates NF-κB activation following stimulation of IL1R or Toll-like receptor family members. IL1R8 deficiency is associated with the development of severe autoimmune lupus-like disease in lpr mice. We herein investigated whether concomitant exacerbated inflammation and autoimmunity caused by the deficiency of IL1R8 could recapitulate autoimmunity-associated lymphomagenesis. We thus monitored B-cell lymphoma development during the aging of IL1R8-deficient lpr mice, observing an increased lymphoid cell expansion that evolved to diffuse large B-cell lymphoma (DLBCL). Molecular and gene-expression analyses showed that the NF-κB pathway was constitutively activated in Il1r8 -/-/lpr B splenocytes. In human DLBCL, IL1R8 had reduced expression compared with normal B cells, and higher IL1R8 expression was associated with a better outcome. Thus, IL1R8 silencing is associated with increased lymphoproliferation and transformation in the pathogenesis of B-cell lymphomas associated with autoimmunity.
Background:
The Advanced Lung Cancer Inflammation Index (ALI, body mass index × albumin/neutrophil-to-lymphocyte ratio) has been demonstrated to be a prognostic factor of survival in some solid cancers. We retrospectively investigated the usefulness of the ALI to predict chemotherapy response and survival in 212 patients with diffuse large B cell lymphoma (DLBCL) treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy.
Methods:
Patients were allocated to a low ALI group (n = 82, 38.7%) or a high ALI group (n = 130, 61.3%) according to an optimal pretreatment ALI cut-off value of 15.5 as determined by receiver operating curve analysis.
Results:
The low ALI group displayed more adverse clinical characteristics, lower rates of complete remission (54.9 vs. 75.4%, p = 0.008), and poorer 5-year progression-free (PFS, 58.1 vs. 77.3%, p = 0.006) and overall (OS, 64.2 vs. 80.2%, p = 0.008) survival. Multivariate analysis showed that low ALI was found to independently predict shorter PFS and OS. Interestingly, a low ALI reverted to a high ALI during treatment in 58 patients (27.4%), and the 5-year OS of these patients was better than that of patients whose ALI remained low (n = 24, 72.5 vs. 24%, p < 0.001).
Conclusions:
ALI might be an easily available marker for predicting clinical outcomes in DLBCL patients treated with R-CHOP chemotherapy.
There is ample epidemiologic evidence for an association of chronic hepatitis C virus (HCV) infection with B-cell non-Hodgkin Lymphoma (B-NHL). B-NHL subtypes most frequently associated with HCV are marginal zone lymphoma and diffuse large B-cell lymphoma. The most convincing evidence for a causal relationship between HCV infection and lymphoma development is the observation of B-NHL regression after HCV eradication by antiviral therapy (AVT). In fact, for indolent HCV-associated B-NHL, first-line AVT instead of standard immune-chemotherapy might be considered. Molecular mechanisms of HCV-NHL development are still poorly understood. Three general theories have emerged to understand the HCV-induced lymphomagenesis: 1. Continous external stimulation of lymphocyte receptors by viral antigens and consecutive proliferation; 2. HCV replication in B-cells with oncogenic effect mediated by intracellular viral proteins; 3. Permanent B-cell damage, e.g. mutation of tumor suppressor genes, caused by a transiently intracellular virus ("hit and run" theory). This review systematically summarizes the data on epidemiology, interventional studies and molecular mechanisms of HCV-associated B-NHL.
PURPOSEOur aim was to reliably identify patients with advanced-stage classical Hodgkin lymphoma (cHL) at increased risk of death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available formalin-fixed paraffin-embedded tissue (FFPET). METHODS
Expression levels of 259 genes, including those previously reported to be associated with outcome in cHL, were determined by digital expression profiling of pretreatment FFPET biopsies from 290 patients enrolled onto the E2496 Intergroup trial comparing doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and Stanford V regimens in locally extensive and advanced-stage cHL. A model for OS separating patients into low- and high-risk groups was produced using penalized Cox regression. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. Weighted analysis methods generated unbiased estimates of predictor performance in the population-based registry.ResultsA 23-gene outcome predictor was generated. The model identified a population at increased risk of death in the validation cohort. There was a 29% absolute difference in 5-year OS between the high- and low-risk groups (63% v 92%, respectively; log-rank P < .001; hazard ratio, 6.7; 95% CI, 2.6 to 17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses. CONCLUSIONA gene expression-based predictor, developed in and applicable to routinely available FFPET biopsies, identifies patients with advanced-stage cHL at increased risk of death when treated with standard-intensity up-front regimens.
Hepatitis C Virus (HCV) is a major health problem, infecting about 3 % of people worldwide and leading to liver as well as extrahepatic diseases. This justifies the definition of HCV infection as a systemic disease. Based on available data, the link between the virus and some of these extrahepatic disorders is certain, whereas for some others needs further confirmation. HCV-related lymphoproliferative disorders, ranging from benign, but pre-lymphomatous conditions, like mixed cryoglobulinemia, to frank lymphomas, represent the extrahepatic manifestations most closely related to HCV. The primary involvement of the liver and lymphatic system corresponds to the double viral tropism, being HCV able to infect both hepatic and lymphatic cells. Other HCV-associated disorders include renal, endocrine, dermatological, cardiovascular, rheumatologic and central nervous system diseases. On the whole, the HCV disease appears a very important, mainly hidden, public health problem leading to heavy direct and indirect costs. The possibility that HCV may be eradicated following antiviral therapy is important for both the therapeutic and preventive points of view, making the HCV disease an ideal model for pathogenetic studies.
Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis.
B-cell non-Hodgkin's lymphoma comprises biologically and clinically distinct diseases the pathogenesis of which is associated with genetic lesions affecting oncogenes and tumour-suppressor genes. We report here that the two most common types--follicular lymphoma and diffuse large B-cell lymphoma--harbour frequent structural alterations inactivating CREBBP and, more rarely, EP300, two highly related histone and non-histone acetyltransferases (HATs) that act as transcriptional co-activators in multiple signalling pathways. Overall, about 39% of diffuse large B-cell lymphoma and 41% of follicular lymphoma cases display genomic deletions and/or somatic mutations that remove or inactivate the HAT coding domain of these two genes. These lesions usually affect one allele, suggesting that reduction in HAT dosage is important for lymphomagenesis. We demonstrate specific defects in acetylation-mediated inactivation of the BCL6 oncoprotein and activation of the p53 tumour suppressor. These results identify CREBBP/EP300 mutations as a major pathogenetic mechanism shared by common forms of B-cell non-Hodgkin's lymphoma, with direct implications for the use of drugs targeting acetylation/deacetylation mechanisms.
Lenalidomide is an immunomodulatory agent with antitumor activity in B-cell malignancies. This phase II trial aimed to demonstrate the safety and efficacy of lenalidomide in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular grade 3 lymphoma (FL-III), or transformed lymphoma (TL).
Patients received oral lenalidomide 25 mg on days 1-21 every 28 days as tolerated or until progression. The primary end point was overall response rate (ORR).
Two hundred and seventeen patients enrolled and received lenalidomide. The ORR was 35% (77/217), with 13% (29/217) complete remission (CR), 22% (48/217) partial remission, and 21% (45/217) with stable disease. The ORR for DLBCL was 28% (30/108), 42% (24/57) for MCL, 42% (8/19) for FL-III, and 45% (15/33) for TL. Median progression-free survival for all 217 patients was 3.7 months [95% confidence interval (CI) 2.7-5.1]. For 77 responders, the median response duration lasted 10.6 months (95% CI 7.0-NR). Median response duration was not reached in 29 patients who achieved a CR and in responding patients with FL-III or MCL. The most common adverse event was myelosuppression with grade 4 neutropenia and thrombocytopenia in 17% and 6%, respectively.
Lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive non-Hodgkin's lymphoma.
Follicular lymphoma patients display heterogeneous overall survival and variable risk of transformation. Recent studies have highlighted the role of the microenvironment. The contribution of microvessel density to follicular lymphoma survival remains controversial. We used a quantitative tumor mapping approach to determine whether the degree of vascularization correlated with outcome in a uniformly treated cohort. Whole-tissue sections of diagnostic biopsies from 84 cases were stained for CD34 and tumor-to-vessel-distance that encompassed 90% of the tumor (TVD(90)) was determined using image analysis. Twenty-one cases with lower TVD(90) showed inferior overall survival (P=0.0001) and high risk of transformation (P=0.01). These cases significantly correlated with increased Lymphoma-Associated Macrophages (χ(2)=0.025). In multivariate analysis macrophages content, IPI and TVD(90) were independent predictors of overall survival (P=0.05, P=0.001 and P=0.01, respectively) and IPI and TVD(90) predicted risk of transformation (P=0.008 and P=0.08, respectively). Increased angiogenesis is an independent marker of inferior survival and may promote transformation.
Despite advances in treatments for Hodgkin's lymphoma, about 20% of patients still die from progressive disease. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on the International Prognostic Score.
Using gene-expression profiling, we analyzed 130 frozen samples obtained from patients with classic Hodgkin's lymphoma during diagnostic lymph-node biopsy to determine which cellular signatures were correlated with treatment outcome. We confirmed our findings in an independent cohort of 166 patients, using immunohistochemical analysis.
Gene-expression profiling identified a gene signature of tumor-associated macrophages that was significantly associated with primary treatment failure (P=0.02). In an independent cohort of patients, we found that an increased number of CD68+ macrophages was correlated with a shortened progression-free survival (P=0.03) and with an increased likelihood of relapse after autologous hematopoietic stem-cell transplantation (P=0.008), resulting in shortened disease-specific survival (P=0.003). In multivariate analysis, this adverse prognostic factor outperformed the International Prognostic Score for disease-specific survival (P=0.003 vs. P=0.03). The absence of an elevated number of CD68+ cells in patients with limited-stage disease defined a subgroup of patients with a long-term disease-specific survival of 100% with the use of current treatment strategies.
An increased number of tumor-associated macrophages was strongly associated with shortened survival in patients with classic Hodgkin's lymphoma and provides a new biomarker for risk stratification.
Follicular lymphoma (FL) and the GCB subtype of diffuse large B-cell lymphoma (DLBCL) derive from germinal center B cells. Targeted resequencing studies have revealed mutations in various genes encoding proteins in the NF-kappaB pathway that contribute to the activated B-cell (ABC) DLBCL subtype, but thus far few GCB-specific mutations have been identified. Here we report recurrent somatic mutations affecting the polycomb-group oncogene EZH2, which encodes a histone methyltransferase responsible for trimethylating Lys27 of histone H3 (H3K27). After the recent discovery of mutations in KDM6A (UTX), which encodes the histone H3K27me3 demethylase UTX, in several cancer types, EZH2 is the second histone methyltransferase gene found to be mutated in cancer. These mutations, which result in the replacement of a single tyrosine in the SET domain of the EZH2 protein (Tyr641), occur in 21.7% of GCB DLBCLs and 7.2% of FLs and are absent from ABC DLBCLs. Our data are consistent with the notion that EZH2 proteins with mutant Tyr641 have reduced enzymatic activity in vitro.
Peripheral T-cell lymphoma (PTCL) is often challenging to diagnose and classify. Gene expression profiling was performed on 144 cases of PTCL and natural killer cell lymphoma and robust molecular classifiers were constructed for angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-positive (ALK(+)) anaplastic large-cell lymphoma (ALCL), and adult T-cell leukemia/lymphoma. PTCL-unclassifiable was molecularly heterogeneous, but we were able to identify a molecular subgroup with features of cytotoxic T lymphocytes and a poor survival compared with the remaining PTCL-not otherwise specified cases. Many of the pathologic features and substantial components of the molecular signature of AITL are contributed by the follicular dendritic cells, B-cell, and other stromal components. The expression of Th17-associated molecules in ALK(+) ALCL was noted and may represent aberrant activation of Th17-cell differentiation by abnormal cytokine secretion. Adult T-cell leukemia/lymphoma has a homogeneous molecular signature demonstrating high expression of human T-lymphotropic virus type 1-induced genes. These classifiers reflect the biology of the tumor cells as well as their microenvironment. We also constructed a molecular prognosticator for AITL that appears to be largely related to the microenvironmental signature, and the high expression of 2 immunosuppressive signatures are associated with poor outcome. Oncogenic pathways and tumor-host interactions also were identified, and these findings may lead to better therapies and outcome in the future.
Tumor microenvironment influences the behavior of follicular lymphoma (FL), although the specific cell subsets involved are not well known. The aim of this study was to determine the impact of programmed cell death 1 (PD-1) -positive inhibitory immunoregulatory lymphoid cells in the clinicobiologic features and outcome of patients with FL.
We examined samples from 100 patients (53 men and 47 women; median age, 54 years) at diagnosis, as well as in 32 patients at first relapse, with a recently generated monoclonal antibody against PD-1. The cells were quantified using computerized image analysis. Additional analysis consisted of double immunofluorescence and flow cytometry.
PD-1 expression was alternative to FOXP3 in lymphoid cells from both reactive tonsils and FL. At diagnosis, the median percentage of PD-1-positive cells was 14% (range, 0.1% to 74%). Patients with grade 3 FL, poor performance status, and high serum lactate dehydrogenase showed lower numbers of PD-1-positive cells. After a median follow-up of 6.2 years, patients with PD-1-positive cells <or= 5% (n = 25), 6% to 33% (n = 50), and more than 33% (n = 25) had a 5-year progression-free survival rate of 20%, 46%, and 48% (P = .038) and overall survival (OS) of 50%, 77%, and 95% (P = .004), respectively. PD-1 and FL International Prognostic Index maintained prognostic value for OS in multivariate analysis. Patients with PD-1-positive cells <or= 5% showed a higher risk of histologic transformation. At that time, transformed diffuse large B-cell lymphomas had lower percentage of PD-1-positive cells than FL.
A high content of PD-1-positive cells predicted favorable outcome of FL patients, whereas a marked reduction is observed in transformation.
The addition of rituximab to combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP), or R-CHOP, has significantly improved the survival of patients with diffuse large-B-cell lymphoma. Whether gene-expression signatures correlate with survival after treatment of diffuse large-B-cell lymphoma is unclear.
We profiled gene expression in pretreatment biopsy specimens from 181 patients with diffuse large-B-cell lymphoma who received CHOP and 233 patients with this disease who received R-CHOP. A multivariate gene-expression-based survival-predictor model derived from a training group was tested in a validation group.
A multivariate model created from three gene-expression signatures--termed "germinal-center B-cell," "stromal-1," and "stromal-2"--predicted survival both in patients who received CHOP and patients who received R-CHOP. The prognostically favorable stromal-1 signature reflected extracellular-matrix deposition and histiocytic infiltration. By contrast, the prognostically unfavorable stromal-2 signature reflected tumor blood-vessel density.
Survival after treatment of diffuse large-B-cell lymphoma is influenced by differences in immune cells, fibrosis, and angiogenesis in the tumor microenvironment.
The lymphocytes surrounding Reed-Sternberg cells may play an important role in the pathogenesis of Hodgkin's disease. In this study, T cells in different subtypes of Hodgkin's disease were analyzed in situ by an immunoperoxidase method employing a panel of antibodies, including several paraffin tissue-reactive monoclonal antibodies. The T cells in Hodgkin's disease-involved tissues were found to be activated CD4-positive T cells that are UCHL1+ and CD45R-. This immunophenotype is compatible with an activated helper-inducer memory T cell population. The T cells in the nodular lymphocyte predominance subtype were found to have additional positivity for Leu 7, indicating a subpopulation of CD4+ T cells, normally confined to the light zone of germinal centers of secondary follicles.
8538
Background: Follicular lymphoma (FL) is a heterogeneous disease with a variable prognosis. Transformation to an aggressive lymphoma is associated with a poor prognosis. Previous studies have identified tumor microenvironment cells such as CD68+ macrophages, PD-1+ and FOXP3+ cells as prognostic in FL. However, results have been conflicting and infrequently address the risk of transformation. In this study we analyzed various components of the microenvironment and their association with transformation. Methods: Patients with FL that later transformed were identified through Mayo Clinic lymphoma database. Tissue specimens at diagnosis were stained with CD68, CD11c, CD21, CXCL13, FOXP3, PD-1 and CD14 and characterized by pattern of location and semi-quantitative cell content. Time to transformation (TTT) and overall survival (OS) were assessed by Kaplan-Meir analysis. Significant variables were further analyzed by cox proportional hazards model. Results: 58 patients were included with a median TTT of 4.7 years (range, 0.4-20). Presence of CD14+ cells vs absence and their location (follicular vs non-follicular) were associated with shorter TTT (4.5 vs 6.2 yrs., p=0.037 and 3.8 vs 5.9 yrs. p= 0.027, respectively). The quantity of PD-1+ cell content was not associated with TTT or OS. However, localization of PD-1 to the follicle compared to diffuse was associated with a longer TTT (6.1 vs 3.6 yrs. p=0.033) and superior OS (9.7 vs 4.6 yrs. p=0.009). On multivariate analysis, the pattern of CD14 and PD-1 staining remained significantly associated with shorter TTT (Table). Conclusions: In follicular lymphoma, a diffuse pattern of PD-1+ cells is associated with inferior TTT and OS. CD14+ cells localized to the follicle is associated with a shorter TTT. After accounting for FLIPI score, both these factors remained significant. These results identify two independent predictors of the rate of transformation in follicular lymphoma and suggest it is location rather than quantity of CD14+ or PD-1+ cells that influence outcomes. [Table: see text]
Gene expression profiling has been used to distinguish two major subtypes of diffuse large B cell lymphoma (DLBCL), termed germinal center B cell-like (GCB) DLBCL and activated B cell-like (ABC) DLBCL. Following CHOP-like chemotherapy, GCB and ABC DLBCLs had distinct 5-year survival rates of ∼60% and ∼30%, respectively. Prognostic gene expression signatures in CHOP-treated DLBCL include the lymph node signature, which reflects a non-malignant host response, the MHC class II signature, both favorable when expressed and the proliferation signature which is adverse when expressed. The addition of rituximab to CHOP chemotherapy (R-CHOP) has significantly improved the outcome for DLBCL patients. We therefore investigated, if gene expression signatures that predicted survival among DLBCL patients treated with CHOP remained predictive for DLBCL patients treated with R-CHOP. Gene expression profiling was performed on 156 samples from previously untreated patients with DLBCL using Affymetrix U133 plus arrays. All patients received rituximab and CHOP-like chemotherapy. Samples were classified as GCB DLBCL, ABC DLBCL, or unclassified, and were assessed for expression of the lymph node and proliferation signatures. A Cox-proportional hazards model was used to determine the association of these gene expression features with overall survival (OS). 71 DLBCL samples were classified as GCB DLBCL, 63 as ABC DLBCL, and 22 were unclassified. The addition of rituximab improved OS for both GCB and ABC DLBCL compared to historical controls treated with CHOP-like chemotherapy alone. After a median follow-up of 2.3 years, GCB DLBCL had a more favorable OS than ABC DLBCL, with 3-year OS rates of 86% vs. 68% (p = 0.014). The 3-year OS rate of unclassified DLBCLs was 69%. The lymph node signature was associated with favorable OS (p = 0.023) and the proliferation signature with inferior OS (p = 0.009), whereas the MHC class II signature was not associated with OS (p = 0.44). In summary, addition of rituximab to CHOP-like chemotherapy improved OS for both GCB and ABC DLBCL but ABC DLBCL remained inferior to GCB DLBCL. The prognostic value of the lymph node and proliferation signatures were maintained in the context of R-CHOP therapy. An understanding of the biological attributes of DLBCL tumors that are reflected in these gene expression signatures remains critical to our ability to improve survival of these patients.
Hepatocyte growth factor (HGF )/scatter factor (SF ) is the ligand for a tyrosine kinase cell surface receptor encoded by the MET protooncogene (c-MET). HGF/SF can induce proliferation and motility in epithelial cells and promotes invasion of carcinoma cells and NIH3T3 fibroblasts transfected with both HGF/SF and c-MET genes. Our results show that HGF/SF and c-MET also play a role in adhesion and invasion of human lymphoma cells. c-MET mRNA is expressed in hemopoietic cells, such as hemopoietic progenitor cells (CD34+ cells) in bone marrow (BM) and mobilized peripheral blood, immature B cells in cord blood and BM, and germinal center B-centroblasts. In normal peripheral blood B cells, which are c-MET−, c-MET expression was induced by PMA, ConA, HGF/SF, and Epstein-Barr virus (EBV) infection. Using immunohistochemistry, we detected c-MET on the cell surface of large activated centroblasts in lymph nodes from patients with B-non–Hodgkin's lymphoma and Hodgkin's disease. In the latter group, c-MET expression correlated well with the presence of EBV. Because HGF/SF and c-MET promote metastasis of carcinoma cells, we studied the effects of c-MET stimulation by HGF/SF of B-lymphoma cells on properties relevant for metastasis, ie, adhesion, migration, and invasion. HGF/SF stimulated adhesion of the c-MET+ B-cell lines to the extracellular matrix molecules fibronectin (FN) and collagen (CN) in a dose dependent manner. However, adhesion to laminin was not affected by HGF/SF. Adhesion to FN was mediated by β1-integrins α4β1 (VLA4) and α5β1 (VLA5) since blocking antibodies against β1- (CD29), α4- (CD49d), or α5- (CD49e) integrin subunits, completely reversed the effect of HGF/SF. Furthermore, HGF/SF induced adhesion was abrogated by addition of genistein, which blocks protein tyrosine kinases, including c-MET. Addition of HGF/SF resulted in a sixfold increase in migration of c-MET B-lymphoma cells through Matrigel, compared to medium alone. In rat fibroblast cultures, HGF/SF doubled the number of c-MET+ B-lymphoma cells that invaded the fibroblast monolayer. In these adhesion, migration and invasion assays HGF/SF had no effect on c-MET− cell lines. In conclusion, c-MET is expressed or can be induced on immature, activated, and certain malignant B cells. HGF/SF increased adhesion of c-MET+ B-lymphoma cells to FN and CN, mediated via β1-integrins α4β1 and α5β1 , and furthermore promoted migration and invasion.
Germinal centers develop in the B cell follicles of secondary lymphoid tissues during T cell-dependent (TD) antibody responses. The B cells that give rise to germinal centers initially have to be activated outside follicles, in the T cell-rich zones in association with interdigitating cells and T cell help. After immunization with a single dose of protein-based antigen, the germinal centers formed are oligoclonal; on average three B blasts colonize each follicle. These blasts undergo massive clonal expansion and activate a site-directed hypermutation mechanism that acts on their immunoglobulin-variable (Ig-v)-region genes. Mature germinal centers are divided into dark and light zones. The proliferating blasts, centroblasts, occupy the dark zone and give rise to centrocytes that are not in cell cycle and fill the light zone. The light zone contains a rich network of follicular dendritic cells (FDC) that have the capacity to take up antigen and hold this on their surface for periods of more than a year. The antigen is held as an immune complex in a native unprocessed form; but the antigen may be taken up from FDC by B cells, which can process this and present it to T cells. Centrocytes appear to be selected by their ability to interact with antigen held on FDC. There is a high death rate among centrocytes in vivo, and when these cells are isolated in vitro, they undergo apoptosis within hours on culture. The onset of apoptosis can be delayed by crosslinking centrocytes' surface Ig, and long-term survival is achieved by signalling through their surface CD40. After activation through CD40 the centrocytes increase their surface Ig and acquire characteristics of memory B cells. These observations suggest centrocyte selection involves uptake and processing of antigen held on FDC and its presentation to T cells that can be induced to express CD40 ligand at the point of cognate interaction. Other signals that induce a proportion of germinal center cells to become plasma cells have also been described. Germinal centers persist for about 3 weeks following immunization, but after this, memory B blasts continue to proliferate in follicles throughout the months of T cell-dependent antibody responses. These cells are probably the source of plasma cells and memory cells required to maintain long-term antibody production and memory after the first 3 weeks of T cell-dependent antibody responses.
Distinction of lymphocyte predominance Hodgkin's disease (LPHD) from other forms of lymphoma often requires immunohistochemistry (IHC). Most previously published recommended panels include markers to define the large neoplastic cells (for example, CD20, J chain, CD45) as well as the non-neoplastic background cells (CD21, CD45RO, CD57, TiA1). In the present study we examine the practical use of a double IHC method designed to look simultaneously at two germinal center specific cell types:bcl6+ cells and [bcl6+, CD57+] co-positive cells. All 10 nodular LPHD had bcl6+ large cells and numerous CD57+ small background cells, including [bcl6+ CD57+] cells in rosettes. One case of LPHD with large cell transformation contained numerous bcl6+ large cells both singly (in areas of typical LPHD) and in sheets (in foci of large cell transformation), many CD57+ small cells but few [bcl6+ CD57+] co-positive cells and no rosettes. In none of the five cases of florid progressive transformation of germinal centers were true rosettes seen, although all contained variable numbers of bcl6+ large cells and CD57+ cells. Lymphocyte-rich classic Hodgkin's disease LRCHD cases were notable for bcl6 reactivity in Reed-Sternberg cells in all cases, numerous background small bcl6+ lymphocytes, and rare CD57+ cells. Two phenotypic profiles were associated with the 10 cases of T cell-rich B cell large cell lymphoma (TCRBCL). In the first, group “A,” six of six cases had bcl6− large cells and few CD57+ small cells, and none had significant numbers of [bcl6+, CD57+] co-positive cells. In the second, group “B,” four of four cases had bcl6+ large cells with numerous CD57+ and [bcl6+, CD57+] co-positive cells. These findings not only show that LPHD can be distinguished from its morphologic mimics through identification of specific germinal center cell types, but also identifies a second group of TCRBCL (group “B”) whose phenotype suggests it might be an architectural variant of nodular LPHD. Nodular lymphocyte predominance Hodgkin's disease (N-LPHD) is an indolent germinal center B cell malignancy composed of a minor population of large cells distributed among a predominant population of small mature-appearing B cells. The nodularity, which is created by loose aggregates of follicular dendritic cells (FDCs), is a defining feature of this disorder and is of central importance in distinguishing it from typically diffuse processes such as T cell-rich B cell lymphoma (TCRBCL) and lymphocyte-rich forms of classic Hodgkin's disease (LRCHD). When the FDC network breaks down, however, diffuse areas arise and in such circumstances LPHD may be more difficult to diagnose. Distinction from florid progressive transformation of germinal centers (PTGC) may also be difficult because this benign disorder shares with LPHD the nodular motif of disrupted germinal centers with dispersed centroblasts that may mimic the neoplastic “L&H” cells of LPHD both cytologically and by the presence of T cell rosettes. 26 Recent studies 25,35 have examined the morphologic and immunophenotypic features of both the large cell and small cell components of these entities, but none has proven to be an absolute discriminator. The present study examines the use of double antibody immunostaining with CD57 and bcl6, two markers that together highlight the extent to which a proliferation recapitulates specific aspects of the germinal center milieu, in the diagnosis and differential diagnosis of LPHD, a malignancy of germinal center B cells. Bcl6 is a 95 kD transcriptional regulator that, when present in lymphocytes, is detected only in germinal center B cells and in a small fraction of T-helper cells in the germinal center. 2,11 Both natural killer (NK) and NK-like T cells express the glycoprotein CD57, and previous studies have shown that a small but distinctive subset of CD57+ T-helper cells found within the germinal center will co-express bcl6. 7
There is widespread interest in macrophages as a therapeutic target in cancer. Here, we demonstrate that trabectedin, a recently approved chemotherapeutic agent, induces rapid apoptosis exclusively in mononuclear phagocytes. In four mouse tumor models, trabectedin caused selective depletion of monocytes/macrophages in blood, spleens, and tumors, with an associated reduction of angiogenesis. By using trabectedin-resistant tumor cells and myeloid cell transfer or depletion experiments, we demonstrate that cytotoxicity on mononuclear phagocytes is a key component of its antitumor activity. Monocyte depletion, including tumor-associated macrophages, was observed in treated tumor patients. Trabectedin activates caspase-8-dependent apoptosis; selectivity for monocytes versus neutrophils and lymphocytes is due to differential expression of signaling and decoy TRAIL receptors. This unexpected property may be exploited in different therapeutic strategies.
The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.
Follicular dendritic reticulum cells (DRCs) are known to be normally present in primary follicles and both follicular centres and mantle zones of secondary follicles of peripheral lymphoid tissue. Involved frozen biopsy tissue specimens from eight cases of intermediate lymphocytic lymphoma/mantle zone lymphoma (ILL/MZL); eight cases of follicular centre cell lymphomas (FCCL) of the centroblastic/ centrocytic type; and seven cases of well-differentiated lymphocytic lymphoma (WDLL) consistent with chronic lymphocytic leukaemia (CLL) were analysed immunohistologically with R4/23 (DRC-1) monoclonal antibody reactive with ‘bystander’ DRCs. As opposed to FCCL and most WDLL/CLL cases, the DRCs consistently formed a loose, ill-defined meshwork with a radiating or blurred outline in all MZL cases and one ILL. On the basis of the observed findings as well as from those reported in literature, the hypothesis is proposed that ILL/MZL originates from the follicular mantle zone and represents a distinct lymphoma entity owing to its peculiar immunostaining pattern of DRCs that allows it to be separated from both FCCL and WDLL/CLL. Moreover, the absence of DRCs in the microenvironment of other B-cell malignancies such as prolymphocytic leukaemia and hairy cell leukaemia, analogously with most CLL cases, would speak in favour of their different—possibly extrafollicular— compartment of origin within lymphoid tissue.
The interaction between lymphoid tumor cells and their tissue microenvironment is thought to promote dissemination and progression of lymphoma. Those type of interactions consists of at least three cornerstones, among them mesenchymal- or bone marrow-derived stromal cells, cells of the innate or adaptive immune response, and the lymphoma cells themselves. The molecular pathways of crosstalk between the lymphoma cells and their nursing stroma are not well understood and their dissection is challenging because of (1) the complexity of stroma cell subpopulations, (2) kinetic and developmental transitions/switches of stroma composition, and (3) inherent technical difficulties to isolate and analyze defined stroma cell subsets. However, recent studies of bone marrow stroma interaction with leukemia or lymphoma cells have revealed therapeutic targets involved in regulating tumor cell mobilization. Release of tumor cells from their supportive niches could be effectuated by inhibition of homing and retention signals. The present review focuses on the effects of homing receptors and cytokines attributed to lymphoid tissue formation in tumor-stroma interactions within secondary lymphoid tissues. We discuss possible cellular and molecular mechanisms of lymphoma-stroma crosstalk and highlight novel therapeutic strategies based on the disruption of tumor-stroma interaction in secondary lymphoid organs.
Little is known about the dynamics of cancer cell death in response to therapy in the tumor microenvironment. Intravital microscopy of chemotherapy-treated mouse mammary carcinomas allowed us to follow drug distribution, cell death, and tumor-stroma interactions. We observed associations between vascular leakage and response to doxorubicin, including improved response in matrix metalloproteinase-9 null mice that had increased vascular leakage. Furthermore, we observed CCR2-dependent infiltration of myeloid cells after treatment and that Ccr2 null host mice responded better to treatment with doxorubicin or cisplatin. These data show that the microenvironment contributes critically to drug response via regulation of vascular permeability and innate immune cell infiltration. Thus, live imaging can be used to gain insights into drug responses in situ.
Twenty-five reactive lymph nodes, 10 palatine tonsils, and 72 B-cell non-Hodgkin's lymphomas (NHLs) of supposed follicular origin were investigated in an immunohistologic study of fixed, paraffin-embedded tissues using a panel of monoclonal antibodies reactive with antigens resistant against fixation and paraffin-embedding techniques together with polyclonal antibodies. The results concerning the microenvironmental organization of reactive lymphoid follicles confirmed that the distribution of CD21+ and CD23+ dendritic reticulum cells, vimentin+ fibroblastic reticulum cells, and CD68+ tingible-body macrophages is heterogeneous with reference to their immunostaining patterns and topographic localization within the germinal center and mantle zone. Moreover, a close microenvironmental similarity between the follicular lymphomas of supposed germinal center or mantle zone origin and their normal counterparts was noted. The study of the microenvironment of the B-zone small lymphocytic lymphoma cases, showing the same distribution patterns for the nonlymphoid cells as seen in mantle zone lymphomas, corroborated the supposed follicular origin of this unusual variant of small lymphocytic lymphoma. In conclusion, this study shows that monoclonal antibodies recognizing CD21, CD23, and CD68 antigens may be valuable additions to vimentin, S-100 protein, laminin, and type IV collagen antibodies for investigating the microenvironmental organization of lymphoid tissues in both normal and neoplastic conditions.
We analyzed the distribution of fibroblastic reticulum cells (FRCs), stationary cells of lymphoid tissues, as visualized by the anti-vimentin (V9) monoclonal antibody in human reactive and neoplastic lymphoid follicles, by using immunoenzymatic and immunofluorescence methods on fixed and paraffin-embedded tissue sections from 37 lymphoid specimens with reactive disorders and 10 specimens with nodular/follicular non-Hodgkin's lymphomas (NHLs). The pattern of distribution of the vimentin-positive (VIM+) FRCs was compared with that of follicular dendritic reticulum cells (DRCs) as visualized by anti-S-100 protein antibody. Elongate VIM+ FRCs intimately attached to reticulum fibers were randomly distributed in the paracortical and interfollicular areas of lymph nodes, whereas they were recognized specifically in the mantle zones of the secondary follicles, mostly in the outer margins. Germinal centers were consistently devoid of VIM+ FRCs. Comparative analysis on serial sections as well as paired immunoperoxidase and double immunofluorescence studies demonstrated that there was a sharp difference between the patterns of intrafollicular distribution of VIM+ FRCs and S-100 protein-positive (S-100+) DRCs without juxtaposition, the FRCs being confined to the mantle zones. In the 10 nodular/follicular NHLs VIM+ FRCs could be observed in the thinned mantles of neoplastic nodules displaying a corona-like pattern that accentuated the boundaries of the nodules. The results of this study support the view that the intrafollicular distribution of VIM+ FRCs is specific for the mantle zone. The different microenvironmental organization within the follicles of VIM+ FRCs and S-100+ DRCs suggests that FRCs or at least VIM+ FRCs are stationary cells strictly related to the mantle zone microenvironment, where they may play a role in supposed sustentacular and immunologic functions similar to that of DRCs in the germinal center microenvironment.
Both patients with cutaneous T-cell lymphoma (CTCL) and those with atopic dermatitis (AD) have pruritus, T(H)2-biased T cells, and a tendency to have bacterial infections, suggesting a common pathologic basis for these two diseases. Recently, interleukin (IL)-22-producing T cells were reported in skin of patients with AD. In this study, we investigated expression levels of T(H)22- and T(H)17-related molecules in lesional skin and sera isolated from patients with CTCL.
Skin biopsies and sera were collected from patients with CTCL or psoriasis and from healthy volunteers. Protein and mRNA expression levels of IL-22, IL-17A, IL-17F, IL-23p19, IL-10, IL-4, CCL20, CCR6, IL-8, and IL-20 were examined in lesional tissue and a subset of these molecules in sera. Phosphorylation of STAT3 was also assessed in lesional skin of CTCL and psoriasis by immunohistochemistry.
IL-22, IL-10, IL-4, CCL20, and CCR6 mRNA and protein levels, but not IL-17A, IL-17F, IL-23p19, IL-8, or IL-20, were significantly elevated in lesional skin of CTCL. Phosphorylation of STAT3 was detected in epidermis of CTCL skin. Moreover, serum IL-22, IL-10, and CCL20 levels were increased in CTCL and correlated with disease severity.
Our results suggest that IL-22 is important in establishing the tumor microenvironment for CTCL. Enhanced expression of CCL20 may explain epidermal hyperplasia and migration of CCR6(+) cells, such as Langerhans cells, into lesional skin. Relatively low expression of IL-17 may explain the lack of neutrophils in lesions of CTCL, which correlates with bacterial infections that commonly occur in skin affected by CTCL.
The mediators and cellular effectors of inflammation are important constituents of the local environment of tumours. In some types of cancer, inflammatory conditions are present before a malignant change occurs. Conversely, in other types of cancer, an oncogenic change induces an inflammatory microenvironment that promotes the development of tumours. Regardless of its origin, 'smouldering' inflammation in the tumour microenvironment has many tumour-promoting effects. It aids in the proliferation and survival of malignant cells, promotes angiogenesis and metastasis, subverts adaptive immune responses, and alters responses to hormones and chemotherapeutic agents. The molecular pathways of this cancer-related inflammation are now being unravelled, resulting in the identification of new target molecules that could lead to improved diagnosis and treatment.
Lymphomatoid granulomatosis (LG) exhibits many similarities both clinically and pathologically to angiocentric T/NK cell lymphoma and was until recently considered to be part of the same disease spectrum. However, recent data indicate that LG is an EBV positive B cell proliferation associated with an exuberant T cell reaction. LG presents in extranodal sites, most commonly the lung (Katzenstein and Peiper, 1990). Other frequent sites of involvement include kidney, skin, central nervous system and liver. The pattern of necrosis in both LG and T/NK cell lymphoma is very similar, emphasizing the probable importance of EBV in mediating the vascular damage. Recent studies implicate the chemokines IP-10 and Mig in the pathogenesis of the vascular damage. Although the predominant infiltrating cells are T cells, the T cell receptor genes are not clonally rearranged. However, by VDJ polymerase chain reaction, approximately 60% of cases contain clonal rearrangements. EBV sequences can be localized to B cells and are clonal in most cases. Most patients with LG when carefully evaluated clinically have defects in cytotoxic T cell function and reduced levels of CD8+ T cells. LG is also common in many immunodeficiency states, such as AIDS, Wiskott-Aldrich syndrome and post-transplantation immunodeficiency. Thus, in many respects, LG resembles an EBV driven lymphoproliferative disorder. Some cases of LG regress spontaneously, but most patients require therapy. Treatment approaches have included cyclophosphamide and prednisone, aggressive combination chemotherapy and interferon alpha 2b, because of its antiviral, antiproliferative and immunomodulatory effects.
It has become increasingly clear that proliferation and survival in FL is not only driven by genetic changes, but also and possibly even predominantly by the close interaction with the immune microenvironment and stromal cells. Based on in vitro studies and experimental models and supported by immunohistochemical studies in biopsy specimens of FL patients, classes of CD4+ T-cell populations including follicular helper T cells and regulatory T cells are now identified as major players to regulate the delicate balance of effector populations into a supportive microenvironment. These insights may thoroughly change the therapeutic approaches in FL and translate into programs that combine direct cytotoxic and indirect immunomodulatory aspects.
The understanding of the molecular pathogenesis of non-Hodgkin's lymphomas (NHL) has significantly improved in recent years. Advances in molecular biology and genetics lead to the identification and characterization of several oncogenic pathways involved in lymphomagenesis. This knowledge will ultimately lead to improved diagnostic and therapeutic strategies for patients with NHL. This review summarizes current concepts of the molecular pathogenesis of the most common NHL subtypes, with a special emphasis on diffuse large B-cell lymphoma, the most common lymphoma subtype.
Hodgkin's lymphoma (HL) represents the most common subtype of malignant lymphoma in young people in the Western world. Most patients can be cured with modern treatment strategies, although approximately 20% will die after relapse or progressive disease. The histologic hallmark of the disease is the presence of the characteristic Hodgkin Reed-Sternberg (HRS) cells in classical HL and so-called lymphocyte-predominant (LP) cells in nodular lymphocyte-predominant HL. HL is unique among all cancers because malignant cells are greatly outnumbered by reactive cells in the tumor microenvironment and make up only approximately 1% of the tumor. Expression of a variety of cytokines and chemokines by the HRS and LP cells is believed to be the driving force for an abnormal immune response, perpetuated by additional factors secreted by reactive cells in the microenvironment that help maintain the inflammatory milieu. The malignant HRS and LP cells manipulate the microenvironment, permitting them to develop their malignant phenotype fully and evade host immune attack. Gene expression signatures derived from non-neoplastic cells correlate well with response to initial and subsequent therapies, reflecting their functional relevance. Recent biomarker studies have added texture to clinical outcome predictors, and their incorporation into prognostic models may improve our understanding of the biologic correlates of treatment failure. Moreover, recent preclinical and clinical studies have demonstrated that the tumor microenvironment represents a promising therapeutic target, raising hope that novel treatment strategies focused on the interface between malignant and reactive cells will soon emerge.
Coupland S E (2011) Histopathology 58, 69–80 The challenge of the microenvironment in B-cell lymphomas
B-cell non-Hodgkin lymphomas (B-NHL) represent the most common malignant lymphoid neoplasms, with the majority of these arising from germinal centre or post-germinal centre B cells, due to (at least) a disruption of the different phases of normal B-cell development. The most common B-cell lymphoma subtypes include follicular lymphoma, diffuse large B-cell lymphoma, marginal zone lymphoma and mantle cell lymphoma.
As with other malignancies, it has been demonstrated that the development and progression of B-cell lymphomas involves complex interactions between the neoplastic B-cells and the surrounding microenvironment, including stromal cells, the intratumoral vasculature, the various types of macrophages, as well as T-cells, including regulatory T-cells (also termed T-regs). The complex communications between the cell populations involves interplay between chemokines, chemokine receptors and adhesion molecules, and the balance between these determines whether there is a tumour cell growth promotion or inhibition. The demonstration of the importance of the microenvironment in B-NHL has been shown recently using methodologies such as gene expression profiling, and has been validated in some B-NHL lymphoma subtypes using other techniques, such as immunohistochemistry. This is particularly in the case of follicular lymphomas, in which both T-regs and macrophages have been demonstrated to have prognostic value.
As such, the microenvironment of B-cell lymphomas represents a challenge to the development of therapeutic agents, requiring re-direction and inclusion of these non-neoplastic supportive cells into future treatment strategies.
Interferon regulatory factor 4 (IRF4) expression is detected in many lymphoid and myeloid malignancies, and may be a promising therapeutic target. IRF4 is strongly expressed in classical Hodgkin lymphoma (cHL) and its expression is up-regulated by CD40L and down-regulated by both anti-proliferative and pro-apoptotic stimuli. This study analysed the effects of IRF4 silencing in a panel of HL-derived cell lines. We demonstrated that IRF4 down-modulation determined a remarkable decrease of both cell number and clonogenic growth in L-1236, L-428, KM-H2 and HDLM-2 cells, but not in IRF4-negative L-540 cells. IRF4 silencing induced apoptosis, as evaluated by caspase-3 activation and Annexin-V staining and up-regulation of the pro-apoptotic molecule Bax. CD40 engagement by both soluble and membrane bound-CD40L almost totally reduced IRF4 down-modulation and growth inhibition by IRF4 silencing in both L-1236 and L-428 cells. Finally, IRF4 silencing decreased CCL5 secretion in all HL cell lines tested and CCL17 in KM-H2 cells. Taken together, our results demonstrated that IRF4 down-modulation by IRF4 silencing was reversed by CD40 engagement, inhibited HL cells proliferation, induced apoptosis and decreased CCL5 secretion, thus suggesting that IRF4 may be involved in HL pathobiology.
Several novel targeted therapies have recently emerged as active in the treatment of non-Hodgkin lymphoma, including small molecules that inhibit critical signaling pathways, promote apoptotic mechanisms, or modulate the tumor microenvironment. Other new agents target novel cell surface receptors or promote DNA damage. Although most of these drugs have single-agent activity, none have sufficient activity to be used alone. This article reviews the utility and potential role of these new agents in the treatment of non-Hodgkin lymphoma with a specific focus on data that highlight how these agents may be incorporated into current standard treatment approaches.
Tumor-infiltrating CD8(+) T cells are strongly associated with patient survival in a wide variety of human cancers. Less is known about tumor-infiltrating CD20(+) B cells, which often colocalize with T cells, sometimes forming organized lymphoid structures. In autoimmunity and organ transplantation, T cells and B cells collaborate to generate potent, unrelenting immune responses that can result in extensive tissue damage and organ rejection. In these settings, B cells enhance T cell responses by producing Abs, stimulatory cytokines, and chemokines, serving as local APCs, and organizing the formation of tertiary lymphoid structures that sustain long-term immunity. Thus, B cells are an important component of immunological circuits associated with persistent, rampant tissue destruction. Engagement of tumor-reactive B cells may be an important condition for generating potent, long-term T cell responses against cancer.
Clinical correlative studies have linked 1p36 deletions with worse prognosis in follicular lymphoma (FL). In this study, we sought to identify the critical gene(s) in this region that is responsible for conferring inferior prognosis. BAC array technology applied to 141 FL specimens detected a minimum region of deletion (MRD) of ∼97 kb within 1p36.32 in 20% of these cases. Frequent single-nucleotide polymorphism-detected copy-neutral loss of heterozygosity was also found in this region. Analysis of promoter CpGs in the MRD did not reveal differential patterns of DNA methylation in samples that differed in 1p36 status. Exon sequencing of MRD genes identified somatic alterations in the TNFRSF14 gene in 3 of 11 selected cases with matching normal DNA. An expanded cohort consisting of 251 specimens identified 46 cases (18.3%) with nonsynonymous mutations affecting TNFRSF14. Overall survival (OS) and disease-specific survival (DSS) were associated with the presence of TNFRSF14 mutation in patients whose overall treatment included rituximab. We further showed that inferior OS and DSS were most pronounced in patients whose lymphomas contained both TNFRSF14 mutations and 1p36 deletions after adjustment for the International Prognostic Index [hazard ratios of 3.65 (95% confidence interval, 1.35-9.878, P=0.011) and 3.19 (95% confidence interval, 1.06-9.57, P=0.039), respectively]. Our findings identify TNFRSF14 as a candidate gene associated with a subset of FL, based on frequent occurrence of acquired mutations and their correlation with inferior clinical outcomes.
Reports focusing on the immunological microenvironment of peripheral T-cell lymphomas (PTCL) are rare. Here we studied the reciprocal contribution of regulatory (Treg) and interleukin-17-producing (Th17) T-cells to the composition of the lymphoma-associated microenvironment of angioimmunoblastic T-cell lymphoma (AITL) and PTCL not otherwise specified on tissue microarrays from 30 PTCLs not otherwise specified and 37 AITLs. We found that Th17 but not Treg cells were differently represented in the two lymphomas and correlated with the amount of mast cells (MCs) and granulocytes, which preferentially occurred in the cellular milieu of AITL cases. We observed that MCs directly synthesized interleukin-6 and thus contribute to the establishment of a pro-inflammatory, Th17 permissive environment in AITL. We further hypothesized that the AITL clone itself could be responsible for the preferential accumulation of MCs at sites of infiltration through the synthesis of CXCL-13 and its interaction with the CXCR3 and CXCR5 receptors expressed on MCs. Consistent with this hypothesis, we observed MCs efficiently migrating in response to CXCL-13. On these bases, we conclude that MCs have a role in molding the immunological microenvironment of AITL toward the maintenance of pro-inflammatory conditions prone to Th17 generation and autoimmunity.
It has become clear that cancer is not merely a growth of autonomously proliferating cells, but that other non-malignant cell types are a functional part of the disease. Immune cells, fibroblasts, specialized mesenchymal cells and microvasculature together make up the tumour microenvironment and have functional interactions with tumour cells. Classical Hodgkin's lymphoma (cHL) is characterized by only a few malignant cells and an abundance of inflammatory cells. Hodgkin and Reed-Sternberg (HRS) cells are surrounded by T and B cells admixed with plasma cells, macrophages, eosinophils and mast cells. A constitutive activity of NF-kappaB and an altered JAK-STAT signalling pathway are part of the biological background associated with the increased expression of cytokines and cytokine receptors seen in HRS cells. Over-expression of the members of the TNF receptor family, especially CD30 and CD40, is a hallmark of HRS cells. cHL is a tumour where aberrant cytokine production contributes not only to the proliferation of HRS cells but also to the maintenance of an appropriate environment for the tumour cells. In addition, several chemokines contribute to the composition of the inflammatory background in cHL. This review summarizes updated information on the complex interactions between the HRS cells and their tissue microenvironment and highlights the development of newer therapeutic strategies aimed at targeting the non-malignant inflammatory/immune cellular components of HL that are involved in cancer cell growth and/or immune escape.
Despite major therapeutic advances, most mature B-cell malignancies remain incurable. Compelling evidence suggests that crosstalk with accessory stromal cells in specialized tissue microenvironments, such as the bone marrow and secondary lymphoid organs, favors disease progression by promoting malignant B-cell growth and drug resistance. Therefore, disrupting the crosstalk between malignant B cells and their milieu is an attractive novel strategy for treating selected mature B-cell malignancies. Here we summarize the current knowledge about the cellular and molecular interactions between neoplastic B lymphocytes and accessory cells that shape a supportive microenvironment, and the potential therapeutic targets that are emerging, together with the new problems they raise. We discuss clinically relevant aspects and provide an outlook into future biologically oriented therapeutic strategies. We anticipate a paradigm shift in the treatment of selected B-cell malignancies, moving from targeting primarily the malignant cells toward combining cytotoxic drugs with agents that interfere with the microenvironment's proactive role. Such approaches hopefully will help eliminating residual disease, thereby improving our current therapeutic efforts.
Hodgkin and Reed-Sternberg (HRS) cells in classical Hodgkin lymphoma (HL) and lymphocytic and histiocytic (L&H) cells in nodular lymphocyte-predominant HL (NLPHL) are derived from germinal-center B cells. HRS cells have, however, largely lost their B cell phenotype and aberrantly express markers and transcriptional regulators of other hematolymphoid cell types. Deregulation of multiple signaling pathways and downstream transcription factors, including receptor tyrosine kinases, nuclear factor-kappa B (NF-kappaB), and Janus kinase/signal transducer and activator of transcription (JAK/STAT), is a further hallmark of HRS cells. These cells harbor genetic lesions that contribute to or cause increases in the activity of transcription factors of the NF-kappaB and STAT families. HRS cells are found within a mixed reactive cellular infiltrate and interact with these nonmalignant cells in a complex fashion that appears to be essential for HRS cell survival and proliferation. Less is known about the pathogenesis of L&H cells in NLPHL, but increases in the activity of receptor tyrosine kinases, NF-kappaB, and JAK/STAT have also been detected.
The human lymph node is a complex tissue resulting from the microenvironmental organisation of different cell populations linked by topographical and/or functional relationships. Germinal centres (GCs) of lymphoid follicles contain a meshwork of follicular dendritic cells in addition to B-cells and some CD4(+) T cells. Moreover, there is a sharp demarcation around the whole follicle centre, which is highlighted by fibroblastic reticulum cells. On the whole, GC exerts a role in B cell physiology and malignancy. In GC-derived lymphomas, gene expression profiling studies have raised the possibility that survival of the affected patients may be associated with signatures preferentially expressed in non-malignant T cells and macrophages and/or dendritic cells. Immunohistological analyses in lymphoma biopsy samples have confirmed that the biological behaviour and tumour progression may be influenced by the tumour microenvironment. This review will examine GC-derived lymphomas, including follicular lymphomas, Hodgkin lymphomas and angioimmunoblastic T-cell lymphoma, through their integrated cellular microenvironment, highlighting those findings which may serve as a useful surrogate marker for tumour diagnosis or tumour progression, together with key molecules involved in tumour development.
Hodgkin's lymphoma was first described in 1832. The aetiology of this lymphoma, however, remained enigmatic for a long time. Only within the past 10 years has the B-cell nature of the pathognomonic Hodgkin and Reed-Sternberg (HRS) cells been revealed, along with several recurrent genetic lesions. The pathogenetic role for Epstein-Barr virus infection has also been substantiated. HRS cells in classical Hodgkin's lymphoma have several characteristics that are unusual for lymphoid tumour cells, and the Hodgkin's lymphoma microenvironment is dominated by an extensive mixed, potentially inflammatory cellular infiltrate. Understanding the contribution of all of these changes to the pathogenesis of this disease is essential for the development of novel therapies.
Classical Hodgkin Lymphoma (cHL) is morphologically characterized by a small number of tumour cells, Hodgkin and Reed-Sternberg (HRS) cells, surrounded by numerous tumour-infiltrating lymphocytes (TIL). The functional role of these TIL is still controversial. While generally considered to represent an anti-tumour immune response, TIL in cHL might result from the profoundly deregulated immunity of cHL patients. Eighty-seven cases of cHL were available to evaluate the prognostical significance of tumour-infiltrating cytotoxic T lymphocytes (CTL), T helper 1 (Th1) cells, T helper 2 (Th2) cells and regulatory T cells (Treg). We confirm that in cHL the microenvironment is dominated by Th2 cells and Treg and show that large numbers of Th2 cells are associated with significantly improved disease-free survival (p = 0.021) and event-free survival (p = 0.012). Furthermore, a high ratio of Treg over Th2 cells resulted in a significantly shortened disease-free survival (p = 0.025). These observations suggest that Treg may exert inhibitory effects on anti-tumour immune responses mediated through Th2 cells and that Th2 cells may be more important for effective anti-tumour immunity than anticipated.