Hiperplasia linfoide folicular oral: clinicopatológico de uma série de casos

Expression of the Brain Transcription Factor OTX1 Occurs in a Subset of Normal Germinal-Center B Cells and in Aggressive Non-Hodgkin Lymphoma

Follicular lymphoid hyperplasia of the hard palate is a reactive lymphoid proliferation which closely simulates the palatal lymphomas, both clinically and histologically. It is therefore imperative that the pathologist be familiar with the features that separate these two conditions. It reported a case of FLH in a 70-year-old white woman, showing a nodular lesion in right posterior soft palate, reddish, soft, asymptomatic. Histopathological analysis revealed lymphoid aggregates with discrete lobular appearance in the lamina propria of connective tissue showing numerous lymphocytes in the periphery with scanty cytoplasm and homogeneously basophilic nuclei and central areas of germinal centers showing tingible-body macrophages and occasional mitotic figures. In order to distinguish Follicular Lymphoma (FL) from Follicular Hyperplasia (FH), immunohistochemical staining method for bcl-2 was used showing positivity in the mantle zone and absence of immunostaining in the cellular elements within the follicle centres.

Unraveling the Mystery of the Lymphoid Follicle

The authors have observed a unique case of follicular lymphoma in which the central zones of neoplastic nodules were composed predominantly of small cleaved cells (SCC) that were surrounded by small lymphoid cells proliferating in wide mantles as in mantle zone (MZ) lymphoma. The central SCC component displayed a follicular SCC lymphoma-like phenotype (IgD-, CD10+, CD5-, CD68-), whereas the neoplastic cells of the peripheral zones had an MZ lymphoma-like phenotypic profile (IgD+, CD10-, CD5+, CD68+). In extranodal involved tissues, either follicular or diffuse (leukemic-like) patterns of lymphoma infiltration were noted. Flow cytometric analyses showed in the bone marrow or the peripheral blood two leukemic B cell populations, one mimicking the phenotypic profile (IgM+, IgD+, CD5+, CD10-, Leu8-) of small lymphoid cells with MZ-like features, and the other with phenotypic features (IgM+, IgD-, CD5+, CD10+, Leu8+) intermediate between those of MZ-like cells and those of the SCC component (follicular center-like) detected in the lymph node. Immunomagnetic sorting and gene rearrangement studies indicated that both CD10+ and CD10- B lymphocytes and lymph node neoplastic B cells shared the same clonal origin. This unusual follicular lymphoma can be viewed as the result of the proliferation of a single follicular progenitor capable of differentiating toward both a germinal center and an MZ phenotype. The simultaneous presence in the same patient of at least three neoplastic B-cell populations at different maturation stages, encompassing follicular center and MZ phenotypes, and showing the same clonal derivation, indicates a close lineage relationship between follicular SCC and MZ lymphomas.

Immunohistochemical differentiation between follicular lymphoma and nodal marginal zone lymphoma--combined performance of multiple markers.

CTLA-4 haploinsufficiency in a patient with an autoimmune lymphoproliferative disorder

Follicular lymphoid hyperplasia is a very rare though benign reactive process of an unknown pathogenesis that may resemble a follicular lymphoma, clinically and histologically. Oral reactive follicular hyperplasia (RFH) has been described on the hard or soft palate and at the base of the tongue. We describe here the first case of RFH presenting as an aggressive tumor on the right posterior side of the maxilla in a 24-year-old male patient. The lesion had a clinical evolution of 18months and was noticed after the surgical extraction of the right third molar, although we cannot assume a cause-effect relation with that surgical event whatsoever. His medical history was unremarkable. Following an incisional biopsy, histological examination revealed lymphoid follicles comprised by germinal centers surrounded by well-defined mantle zones. The germinal centers were positive for Bcl-6, CD10, CD20, CD21, CD23, CD79a, and Ki-67, while negative for Bcl-2, CD2, CD3, CD5, and CD138. The mantle and interfollicular zones were positive for Bcl-2, CD2, CD3, CD5, CD20, and CD138. Both areas were diffusively positive for kappa and lambda, showing polyclonality. The patient underwent a vigorous curettage of the lesion with no reoccurrences at 36months of follow-up. This case report demonstrates that morphologic and immunohistochemical analyses are crucial to differentiate RFH from follicular lymphoma, leading to proper management.

Multiparameter Microscopy Analysis of the Follicular Lymphoma Microenvironment and Normal Germinal Centers: In Vivo evidence That Follicular Helper T Cells Form Synapses with Neoplastic B Cells and Are Associated with Proliferation and Expression of Activation Induced Cytidine Deaminase

A majority of B-cell lymphomas, including diffuse large B-cell lymphomas (DLBCLs) and follicular lymphomas (FLs), arise from germinal center (GC) B cells. GC B cells are highly proliferative and manifest genomic instability as a byproduct of immunoglobulin affinity maturation. These characteristics make GC B cells particularly prone to malignant transformation such that DLBCLs and FLs inherit and are dependent on mutations in proteins that are also required for normal GC B cells. For example, the BCL6 transcriptional repressor is required to establish the GC phenotype in both normal B-cell development and GC B-cell malignancy through its effect on silencing expression of plasma cell differentiation and checkpoint genes. GC B cells feature a unique transcriptional program featuring upregulation of genes involved in cell proliferation and other growth pathways. Cell context-specific gene expression is largely mediated through gene enhancers. Hence we hypothesized that transcription factors that activate GC specific gene enhancers would play a critical role in formation of these cells, and would likely be required in turn to maintain the survival of GC-derived lymphoma cells. To address this question we first mapped gene enhancers in primary human resting B cells and purified GC B cells by performing ChIP-seq to map the distribution of H3K27Acetyl, H3K4me1, and H3K4me3. This procedure allowed us to identify several thousand GC-specific enhancers. We next examined these enhancers using bioinformatic approaches to identify transcription factor binding sites and identified a list of fifteen putative GC enhancer regulators. Of these potential GC enhancer regulators, only SOX9 was highly induced in GC B cells as compared to resting B cells, pointing to SOX9 as a candidate master enhancer regulator of the GC transcriptome with potential relevance to lymphomas. Indeed, in addition to the well-known role of SOX9 as a stem cell self-renewal and cell-differentiation regulator during development, SOX9 has also been described as playing a role in colon, breast, and prostate carcinogenesis through inhibition of apoptosis, and promoting proliferation, invasion, and metastasis. We confirmed that SOX9 is highly induced in GC cells using QPCR and Western blots. To determine whether SOX9 would indeed bind to these enhancer sites, we next performed SOX9 ChIP-seq in GC B-cell derived lymphoma cell lines. These experiments validated and showed that SOX9 binds to 1,668 upstream distal enhancer regions (-5 to -100 kb upstream from TSS) associated with 963 genes. These target genes were significantly enriched in cell cycle regulation (CCND2, CDC25B, CDK1), transcription regulation (BCOR, NCOR2), epigenetic regulation (BMI1, DNMT3A, MLL2, SUZ12, TET3), and MAPK signaling (MAP2K3, MAP3K7) and also for B-cell activation and BCL6 repressed pathways (p<0.001). We next wished to determine whether SOX9 was also expressed in GC-derived lymphoma clinical samples. Therefore we next examined RNA-seq gene expression profiles derived from cohorts of FL and DLBCL patients. We found that SOX9 is expressed at higher levels in FL patient samples, but lower levels in most DLBCLs compared to naïve B cells. These data raise the possibility that SOX9 might be differentially relevant to FL more than DLBCLs, perhaps contributing to the biologic distinction between these two GC-derived lymphomas. To determine if SOX9 protein was also expressed in these tumors, we examined protein expression by immunohistochemistry using tissue microarrays (TMAs) containing both FLs and DLBCLs. We found that 88 of the 242 FL TMA samples (36.4%) were positive for SOX9 staining. Eleven of the 114 DLBCL TMA samples (10%) were positive for SOX9 staining, among which 80% (9/11) were GC-type DLBCL and 45% (5/11) had a prior FL history. To determine if any of the currently available GC derived lymphoma cell lines manifest high SOX9 levels, we performed a series of Western blot experiments. These studies show high levels of SOX9 protein in the GC-type DLBCL cell lines HT, Karpas422, DB, and Farage, but not in any of the eight ABC-DLBCLs subtypes. Ongoing studies are assessing the biologic relevance of SOX9 for the GC reaction and possible contribution to lymphomagenesis using gain- and loss-of-function studies in human cells and mouse models. These data will determine whether this apparently key enhancer regulatory protein is a novel lineage factor for follicular lymphoma and potentially suitable as a therapeutic target. Citation Format: Angela A. Fachel, Yanwen Jiang, Wayne Tam, Ashlesha S. Muley, Cem Meydan, Xabier Agirre, Ari M. Melnick, Kristy L. Richards. SOX9 enhancer regulator may play an oncogenic role in B-cell lymphomas [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr 30.

FilGAP, a Rho GTPase-activating protein (GAP), acts as a mediator of Rho/ROCK (Rho-associated protein kinase)-dependent amoeboid movement, and its knockdown results in Rac-driven mesenchymal morphology. Herein, we focus on the possible roles of FilGAP expression in normal and malignant lymphocytes. Eighty-three cases of follicular lymphoma (FL), 84 of diffuse large B-cell lymphoma (DLBCL), and 25 of peripheral T-cell lymphoma (PTCL), as well as 10 of normal lymph nodes, were immunohistochemically investigated. In normal lymph nodes, FilGAP immunoreactivity was significantly higher in lymphocytes in the mantle zone as compared to those in the germinal center and paracortical areas. In contrast, the expression levels of both cytoplasmic and perinuclear Rac1 were significantly lower in the germinal center as compared to paracortical regions, suggesting that changes in the FilGAP/Rac axis may occur in B-cell lineages. In malignant lymphomas, FilGAP expression was significantly higher in B-cell lymphomas than PTCL, and the immunohistochemical scores were positively correlated with cytoplasmic Rac1 scores in FL and DLBCL, but not in PTCL. Patients with FL and germinal center B-cell-like (GCB)-type DLBCL showing high FilGAP scores had poor overall survival rates as compared to the low-score patients. Moreover, multivariate Cox regression analysis showed that a high FilGAP score was a significant and independent unfavorable prognostic factor in FL, but not in DLBCL. In conclusion, FilGAP may contribute to change in cell motility of B-lymphocytes. In addition, its expression appears to be useful for predicting the behavior of B-cell lymphoma, in particular FL.

The Premalignant Ancestor Cell of t(14;18)+ Lymphoma

Introduction/Objective Genes involved in histone methylation are frequently mutated in non-Hodgkin’s lymphomas. For instance, frequent mutations in genes encoding histone methytransferases MML2 and EZH2 are present in diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). The aim of this study was to characterize the immunohistochemical expression of H3K4Me3 in benign/reactive lymph nodes (LNs) with comparison to follicular lymphoma (FL). Methods/Case Report Immunohistochemical staining with an anti-H3K4Me3 antibody was performed on FFPE whole slide section from patients with benign/reactive LNs (n=21), low grade (grade 1-2) FL (n=21). H3K4Me3 reactivity was scored for staining intensity and percentage of lymphocytes showing reactivity. Results (if a Case Study enter NA) The majority of the reactive LN sections (15 out of 21 cases) showed a distinct distribution of H3K4Me3 staining, with the majority of cells in the mantle zone and the interfollicular zones showing moderate-strong staining, whereas reactive germinal centers (GCs) showed significantly decreased or close to negative staining. Neoplastic follicles in all the FL cases contained positive cells with significantly stronger staining compared to that in the germinal centers in benign lymph nodes. The interfollicular zones, while diminished in FL due to expanded neoplastic follicles, showed retained H3K4Me3 staining. The difference in staining intensity between follicles and mantle/interfollicular zones became indistinct in FL. Conclusion H3K4Me3 expression in benign/reactive LNs is characterized by positive expression in lymphocytes in interfollicular and mantle zones and significantly decreased in GCs. However, the expression pattern is different in FL, which showed significantly increased expression in the follicles compared to that in reactive GCs. In FL, the expression in GCs is similar to that in the interfollicular and mantle zone lymphocytes. It is reported that about 90% of FL have MLL2 mutation and MLL2 is the enzyme responsible for the methylation of H3K4. So far, it is unclear whether the mutation of MLL2 in FL affects the overall methylation activity of the enzyme. In our study, there is increased methylation of H3K4 in the follicles of FL, which raises the possibility that MLL2 mutation somehow increases H3K4 methylation.

Immunolocalization of the ICE/Ced-3–Family Protease, CPP32 (Caspase-3), in Non-Hodgkin's Lymphomas, Chronic Lymphocytic Leukemias, and Reactive Lymph Nodes

Immunolocalization of the ICE/Ced-3–Family Protease, CPP32 (Caspase-3), in Non-Hodgkin's Lymphomas, Chronic Lymphocytic Leukemias, and Reactive Lymph Nodes

Molecular genetics of aggressive B-cell lymphoma.