The Tumor Microenvironment in Follicular Lymphoma: Its Pro-Malignancy Role with Therapeutic Potential.

In the follicular lymphoma (FL) microenvironment, CXCR5+ICOS+PD1+BCL6+ follicular helper T (Tfh) cells, which closely correlate with FL B cells in neoplastic follicles, play a major role in supporting FL. Interleukin-4 secreted by Tfh cells triggers the upregulation of the lymphocyte chemoattractant CXCL12 in stromal cell precursors, in particular by fibroblastic reticular cells (FRCs). In turn, mesenchymal stem cells (MSCs) can be committed to FRC differentiation in the bone marrow and lymph nodes involved by FL. Noteworthy, MSCs can promote the differentiation of Tfh cells into highly immunosuppressive T-follicular regulatory cells. The tumor suppressor HVEM is highly mutated in FL cells, and its deficiency increases Tfh cell frequency. In contrast, PI3Kδ inhibition impedes the recruitment of Tfh/regulatory T cells and impairs the proliferation of follicular dendritic cells (FDCs) and FDC-induced angiogenesis. Since TIGIT ligands are expressed by FDCs, the immune checkpoint receptor TIGIT plays an important role in tumor-infiltrating T cells. Thus, TIGIT blockade might invigorate cytotoxic T cells in the FL microenvironment. Given their potential to simultaneously reduce the neoplastic B cells, Tfh, and TFR cells could also reinforce the effects of the cytotoxic T cells. This combinatory strategy should be explored as a treatment option to tackle FL.

B Cell Lymphomas of the GI Tract.

PURPOSE OF THE REVIEW: Primary GI lymphomas of B cell origin are a diverse group of lymphomas. In this article, we provide an overview of the diagnosis, pathologic and molecular features, and management of these varied lymphomas. RECENT FINDINGS: The most common primary GI lymphomas are diffuse large B cell lymphoma (DLBCL) and marginal zone lymphomas (MZL), but follicular lymphomas (FL), mantle cell lymphomas (MCL), post-transplant lymphoproliferative disorders (PTLD), and Burkitt lymphoma of the GI tract also occur. Many features of these lymphomas are similar to their nodal counterparts, but certain clinical and biological aspects are unique. Diagnostic and treatment strategies for these lymphomas continue to evolve over time. There are ongoing discoveries about the unique pathophysiology, molecular characteristics, and complications of primary B cell GI lymphomas that are already leading to improvements in management of this histologically diverse set of lymphomas.

Follicular lymphoma.

Follicular lymphoma (FL) is a systemic neoplasm of the lymphoid tissue displaying germinal centre (GC) B cell differentiation. FL represents ~5% of all haematological neoplasms and ~20-25% of all new non-Hodgkin lymphoma diagnoses in western countries. Tumorigenesis starts in precursor B cells and becomes full-blown tumour when the cells reach the GC maturation step. FL is preceded by an asymptomatic preclinical phase in which premalignant B cells carrying a t(14;18) chromosomal translocation accumulate additional genetic alterations, although not all of these cells progress to the tumour phase. FL is an indolent lymphoma with largely favourable outcomes, although a fraction of patients is at risk of disease progression and adverse outcomes. Outcomes for FL in the rituximab era are encouraging, with ~80% of patients having an overall survival of >10 years. Patients with relapsed FL have a wide range of treatment options, including several chemoimmunotherapy regimens, phosphoinositide 3-kinase inhibitors, and lenalidomide plus rituximab. Promising new treatment approaches include epigenetic therapeutics and immune approaches such as chimeric antigen receptor T cell therapy. The identification of patients at high risk who require alternative therapies to the current standard of care is a growing need that will help direct clinical trial research. This Primer discusses the epidemiology of FL, its molecular and cellular pathogenesis and its diagnosis, classification and treatment.

Transformed Follicular Lymphoma (TFL) Predicts Outcome in Advanced Endometrial Cancer.

Background: Transformed follicular lymphoma (TFL, ZC3H12D) was identified as a candidate tumor suppressor gene that contributes to cell-cycle arrest through regulation of Rb phosphorylation, but the clinical impact of TFL is unknown. The goal of this study was to evaluate the prognostic significance of TFL expression in advanced endometrial cancer.Methods: Tissue samples were obtained from 103 patients with Federation Internationale des Gynaecologistes et Obstetristes stage III-IV endometrial cancer. Associations between TFL expression and outcomes were evaluated using the Kaplan-Meier method and multivariate Cox proportional hazards regression models.Results: There were 24 TFL-low cases (23.3%) and the 10-year progression-free survival (PFS) and overall survival (OS) in these cases were lower than those for patients with normal TFL expression in univariate analysis (PFS, P = 0.003; OS, P = 0.106). In multivariate analysis, TFL status was a significant predictor for PFS [HR = 2.76; 95% confidence interval (CI), 1.45-5.28; P = 0.002] and OS (HR = 1.94; 95% CI, 0.91-4.11; P = 0.085), adjusted for covariates. The TFL gene maps to human chromosome 6q25.1, where estrogen receptor alpha (ERα) gene ESR1 is also located. Lack of ERα expression is a poor prognostic factor in early endometrial cancer. Among 41 ERα-low patients, 10-year PFS was significantly lower in 15 TFL-low cases (univariate analysis, P = 0.055; multivariate analysis, HR = 4.70; 95% CI, 1.68-13.20; P = 0.003).Conclusions: We identified TFL as a strong independent prognostic factor, regardless of ERα status.Impact: An investigation of the mechanism underlying tumor suppression by TFL may lead to new therapies for patients with advanced endometrial cancer. Cancer Epidemiol Biomarkers Prev; 27(8); 963-9. ©2018 AACR.

A Gastric Follicular Lymphoma Presenting as a Submucosal Tumor with a Diagnosis Determined by Endoscopic Resection.

We herein report the case of 74-year-old man with gastric follicular lymphoma resected by endoscopic submucosal dissection (ESD). A submucosal tumor 7 mm in diameter was detected at the gastric middle body. Endoscopic ultrasonography showed a homogenous hypoechoic tumor localized in the submucosa. The tumor was removed by ESD immediately, before further tumor growth would preclude endoscopic resection. The pathological findings indicated follicular lymphoma (FL) with negative horizontal and vertical margins. The clinical stage of FL was confirmed to be stage I by extensive work-up procedures, including contrast-enhanced computed tomography, fluorodeoxyglucose-positron emission tomography, esophagogastroduodenoscopy, and colonoscopy. The patient remains in complete remission without any treatment.

Pathogenesis of follicular lymphoma.

Follicular lymphoma (FL) is presented as a germinal centre B cell lymphoma that is characterized by an indolent clinical course, but remains - paradoxically - largely incurable to date. The last years have seen significant progress in our understanding of FL lymphomagenesis, which is a multi-step process beginning in the bone marrow with the hallmark t(14;18)(q32;q21) translocation. The pathobiology of FL is complex and combines broad somatic changes at the level of both the genome and the epigenome, the latter evidenced by highly recurrent mutations in chromatin-modifying genes such as KMT2D and CREBBP. While the importance of the FL microenvironment has since long been well understood, it has become evident that somatic lesions within tumour cells re-educate normal immune and stromal cells to their advantage. Enhanced understanding of FL pathogenesis is currently leading to refined therapeutic targeting of perturbed biology, paving the way for precision medicine in this lymphoma subtype.

Physical activity, obesity and survival in diffuse large B-cell and follicular lymphoma cases.

There is limited information concerning the impact of physical activity and obesity on non-Hodgkin lymphoma (NHL) prognosis. We examined the associations between pre-diagnosis physical activity and body mass index (BMI) with survival in 238 diffuse large B-cell (DLBCL) and 175 follicular lymphoma cases, with follow-up from 2000 to 2015. The most physically active DLBCL cases had 41% lower risk of dying in the follow-up period than the least active [Hazard ratio (HR) = 0·59, 95% confidence interval (CI) = 0·36-0·96], while obese follicular lymphoma cases had a 2·5-fold risk of dying (HR = 2·52, 95% CI = 1·27-5·00) compared with cases with normal BMI. NHL-specific survival results were similar.

Follicular lymphoma in situ in the spleen of a patient with autoimmune hemolytic anemia and carrying HCV was associated with more clonal B-cells than t(14;18) positive B-cells.

Certain autoimmune conditions are associated with an increased risk of lymphoid malignancy. We report a 65-year old patient with autoimmune hemolytic anemia (AIHA) complicated by a follicular lymphoma (FL) in situ and other B-cell clones in the spleen. This diagnosis was made by immunohistochemistry, flow cytometry, and Southern blot analysis of the B-cell receptor. Chromosomal analysis revealed 46,XX,t(14;18)(q32;q21) 2/20, 46,XX,del(7)(q?),del(11)(q?) 2/20, and 46,XX 16/20. It has been speculated that these preneoplastic conditions do not progress to overt FL and other lymphomas without a second lymphomagenic insult. However, AIHA confers a 27.4-fold higher risk of such an insult leading to lymphoma compared with the normal healthy population. Without any therapy after splenectomy, our current study patient remained healthy with no lymphoma development for 28 months. Based on this case, we discuss the pathophysiology of lymphomagenesis in a spleen with AIHA and the roles of a splenectomy for preventing further lymphomagenesis in AIHA patients.

Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study.

BACKGROUND: Follicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories. METHODS AND FINDINGS: Using a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1. CONCLUSIONS: Our results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

Linfoma folicular primario de la conjuntiva simulando conjuntivitis crónica / Primary conjunctival follicular lymphoma mimicking chronic conjunctivitis

CASO CLÍNICO: Paciente varón de 43 años con conjuntivitis folicular crónica resistente a tratamiento local, y serologías para bacterias negativas. Se realizó biopsia incisional que fue compatible con hiperplasia reactiva linfoide. Un año después, una nueva biopsia mostró un linfoma folicular, sin afectación sistémica, que fue tratado con radioterapia local. DISCUSIÓN: Ante una conjuntivitis folicular crónica resistente a tratamiento convencional es esencial realizar una biopsia incisional para el diagnóstico histopatológico, que puede abarcar desde la inflamación crónica y la hiperplasia reactiva linfoide al linfoma. El linfoma folicular es raro entre los linfomas de conjuntiva y la estadificación es indispensable para un correcto abordaje terapéutico

CLINICAL CASE: The case is presented of a 43 year-old male patient with chronic follicular conjunctivitis, negative bacterial serology, and refractory to local treatment. The incisional biopsy performed showed to be consistent with reactive lymphoid hyperplasia. A year later, a new incisional biopsy showed follicular lymphoma, with no systemic involvement, and he was treated with local radiotherapy. DISCUSSION: When a chronic follicular conjunctivitis is refractory to treatment, it is essential to perform an incisional biopsy to establish the histopathological diagnosis that can range from chronic inflammation, reactive lymphoid hyperplasia to lymphoma. Follicular lymphoma is rare among conjunctival lymphomas, and the staging is indispensable for the correct therapeutic approach

High Throughput Sequencing Analysis of the Immunoglobulin Heavy Chain Gene from Flow-Sorted B Cell Sub-Populations Define the Dynamics of Follicular Lymphoma Clonal Evolution.

Understanding the dynamics of evolution of Follicular Lymphoma (FL) clones during disease progression is important for monitoring and targeting this tumor effectively. Genetic profiling of serial FL biopsies and examples of FL transmission following bone marrow transplant suggest that this disease may evolve by divergent evolution from a common ancestor cell. However where this ancestor cell resides and how it evolves is still unclear. The analysis of the pattern of somatic hypermutation of the immunoglobulin gene (Ig) is traditionally used for tracking the physiological clonal evolution of B cells within the germinal center and allows to discriminate those cells that have just entered the germinal center and display features of ancestor cells from those B cells that keep re-circulating across different lymphoid organs. Here we investigated the pattern of somatic hypermutation of the heavy chain of the immunoglobulin gene (IgH-VH) in 4 flow-sorted B cells subpopulations belonging to different stages of differentiation, from sequential lymph node biopsies of cases displaying diverse patterns of evolution, using the GS-FLX Titanium sequencing platform. We observed an unexpectedly high level of clonality, with hundreds of distinct tumor subclones in the different subpopulations from the same sample, the majority detected at a frequency <10-2. By using a lineage trees analysis we observed in all our FL and t-FL cases that the oligoclonal FL population was trapped in a narrow intermediate stage of maturation that maintains the capacity to undergo SHM, but was unable to further differentiate. The presence of such a complex architecture highlights challenges currently encountered in finding a cure for this disease.

Follicular lymphoma presenting with hypercalcaemia: an unusual mechanism of hypercalcaemia.

Hypercalcaemia is a frequent finding in patients with cancer. In up to 30% of malignancies, the disease course is complicated with hypercalcaemia. For hospitalized patients, cancer is the most common cause of hypercalcaemia. In normal physiological circumstances, the ionized calcium is kept in check by the influence of two important hormones, parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D (1,25(OH)2D). However, cancer can misbalance the calcium homeostasis by generating certain humoural mediators. Overproduction of parathyroid hormone-related peptide (PTH-rp), intact PTH, 1,25(OH)2D, and cytokines all cause hypercalcaemia. Hypercalcaemia is frequent in certain haematological cancers such as multiple myeloma and aggressive lymphomas. But hypercalcaemia is rare in patients with indolent lymphomas such follicular lymphoma. This case illustrates as a first to our knowledge the involvement of cytokines and chemokines in the pathophysiology of lymphoma-related hypercalcaemia. A pathophysiological mechanism is offered based upon the current understanding of cytokines and chemokines related to follicular lymphoma.

PET-CT and diagnostic CT: the synergy of metabolic and morphological data in onco-haematology.

PURPOSE: Our goal was to determine how interpreting diagnostic CT together with PET-CT could improve the assessment of morphology in onco-haematology. PATIENTS AND METHODS: Fifty-nine patients with aggressive lymphoma were retrospectively included. The diagnostic CT scan was interpreted by two radiologists, followed by a combined analysis of the CT and the PET-CT carried out by two specialists in metabolic and morphological imaging. The diagnostic performances were assessed in terms of sensitivity and specificity, then concordance and discordance rates (kappa) were studied. RESULTS: A combined interpretation of CT and PET-CT showed better diagnostic performances than those of interpretations of CT only in the assessment of nodal sites (826 sites, sensitivity of 99% versus 85%, P<0.05), extranodal sites (649 sites, sensitivity of 88% versus 78%) and bone sites (one analysed per patient, sensitivity of 50% versus 27%). The combined interpretation also improved inter-observer agreement and led to an upgraded Ann Arbor staging in 15% of patients, with a change of treatment in 10%. CONCLUSION: Interpretation of diagnostic CT in onco-haematology can be improved by combining it with an assessment of PET-CT. The synergy between metabolic and morphological information leads to improved diagnostic capabilities and renders interpretations more reproducible.

Integrated genomic analysis identifies recurrent mutations and evolution patterns driving the initiation and progression of follicular lymphoma.

Follicular lymphoma is an incurable malignancy, with transformation to an aggressive subtype representing a critical event during disease progression. Here we performed whole-genome or whole-exome sequencing on 10 follicular lymphoma-transformed follicular lymphoma pairs followed by deep sequencing of 28 genes in an extension cohort, and we report the key events and evolutionary processes governing tumor initiation and transformation. Tumor evolution occurred through either a 'rich' or 'sparse' ancestral common progenitor clone (CPC). We identified recurrent mutations in linker histone, JAK-STAT signaling, NF-κB signaling and B cell developmental genes. Longitudinal analyses identified early driver mutations in chromatin regulator genes (CREBBP, EZH2 and KMT2D (MLL2)), whereas mutations in EBF1 and regulators of NF-κB signaling (MYD88 and TNFAIP3) were gained at transformation. Collectively, this study provides new insights into the genetic basis of follicular lymphoma and the clonal dynamics of transformation and suggests that personalizing therapies to target key genetic alterations in the CPC represents an attractive therapeutic strategy.

Changes in angiogenesis and hypoxia-inducible factor-1α protein expression in relapsed/refractory indolent non-Hodgkin lymphomas.

Angiogenesis is involved in the pathogenesis and progression of non-Hodgkin lymphomas (NHL), and hypoxia-inducible factor-1α (HIF-1α, also termed HIF1A) might contribute to this process. Currently, there is no direct evidence that the clinical progression of indolent NHL is associated with angiogenesis, and the expression of HIF-1α at recurrence is unknown. Matched lymph node biopsies at diagnosis and recurrence of relapsed/refractory indolent NHL patients were analysed by immunohistochemical and morphometric analysis. We observed an increased vascular network and HIF-1α protein expression in the second biopsy, providing direct evidence that angiogenesis is an essential process for disease progression.

Follicular non-Hodgkin's lymphoma: correlation between histology, pathophysiology, cytogenetic, prognostic factors, treatment, survival.

BACKGROUND: Folicullar lymphoma (FL) is one of the most common types of all non-Hodgkin's lymphomas (25-40%), characterized by a slowly progressive enlargement of lymph nodes, impairment of hematopoiesis, increased risk to infections, a relatively good prognosis, but usually incurable. Histopathologically, FL has been graded according to the proportion of centroblasts and stratified into grades 1-3: FL grade 1-2 (low-grade), which include cases with few centroblasts, and FL grade 3, divided into grades 3a and 3b, based on the absence of centrocytes in the latter category. Several studies have identified some differences between grade 3a and grade 3b of FL, with most cases of FL grade 3b being more closely related to diffuse large B-cell lymphoma (DLBCL) at molecular level. Several multicenter prospective randomized trials demonstrated an improved outcome when Rituximab (R) was added to chemotherapy for the treatment of follicular non-Hodgkin's lymphomas and a beneficial effect in the quality of life after Rituximab maintenance therapy at these patients. AIM OF STUDY: To establish some correlation between histology, prognostic factors, treatment and evaluate whether maintenance therapy with anti-CD20+ monoclonal antibodies prolonged progression free survival compared to observation only at the patients with follicular lymphomas treated with R-chemotherapy regimens. PATIENTS AND METHODS: We studied nineteen patients with follicular non-Hodgkin's lymphomas (grades 1-3) treated with R-CHOP/R-miniCHOP regimens hospitalized in the Clinic of Hematology from Craiova (Romania), between 2008-2011. After these treatments, nine patients with stage III/IV follicular lymphomas were treated with Rituximab maintenance therapy (eight cycles Rituximab 375 mg/m(2), i.v., once every three months for two years) vs. observation only at 10 patients. RESULTS: In our study, low-grade FL was correlated with a good prognosis at patients with FLIPI score 0-2; the statistical analysis revealed that the progression free survival (PFS) was prolonged at the patients with stage III/IV follicular lymphomas who received Rituximab maintenance therapy compared to the ones with observation only with 1.9 years. CONCLUSIONS: Low-grade (1-2) FL was correlated with a good prognosis in patients with FLIPI score 0-2; Rituximab maintenance therapy compared with observation only is safe and prolonged progression free survival at patients with follicular lymphomas treated with R-chemotherapy as first line therapy.