Follicular Dendritic Cell Research Articles

A Cytological Review of Follicular Dendritic Cell-Derived Tumors with Emphasis on Follicular Dendritic Cell Sarcoma and Unicentric Castleman Disease.

Follicular dendritic cells (FDCs) are antigen-presenting cells located in the germinal centers of the lymph nodes. Among the few tumors showing FDC differentiation are follicular dendritic cell sarcoma (FDCS) and Castleman disease (CD), more precisely the unicentric hyaline vascular (HV) variant. Both are relatively rare tumors, and the diagnostic cytological experience is limited to descriptions of isolated cases or small series. The purpose of this review is to bring together all the available cytological published information, and our personal experience, in order to obtain a global idea of the cytological features of these peculiar FDC-derived tumors. The different descriptions of FDCS are very similar, reflecting a tumor that shows repetitive and characteristic cytological features. It shows a dimorphic population of mature lymphocytes and large tumoral cells with partial spindle morphology. Most cases of HV variant of CD can be recognized as benign upon cytology, however a precise diagnosis seems more difficult. It is characterized by reactive lymphocytes mixed with vessels and FDCs, either single or forming syncytial aggregates. Both, FDCS and CD are challenging for cytological diagnosis in which a high index of suspicion is necessary for a correct preoperative assessment. Cytology is very useful for follow-up of recurrences and metastases.

Rare variants of histiocytic tumors: peculiarities of diagnosis and choice of treatment (literature review)

Histiocytic tumors are a highly heterogeneous group of diseases, with Langerhans cell histiocytosis occupying the main place among it. Despite the rare frequency of occurrence, long-term analysis of clinical, morpho-immunological and molecular-biological features has allowed the development of effective treatment protocols (especially in the pediatric cohort of patients). In addition to Langerhans cell histiocytosis, the histiocytic tumors group includes rare and casuistic variants, which include histiocytic sarcoma, Langerhans cell sarcoma, indeterminate dendritic cell tumor, interdigitating dendritic cell sarcoma, follicular dendritic cell sarcoma, and fibroblastic reticular cell tumor. The incidence of certain nosological variants is several cases per hundreds of millions of the population. Not surprisingly, the diagnostic criteria for this group of tumors need to be clarified, as do the therapeutic approaches. This review presents current data on rare histiocytic tumors, clinical features as well as morphological and immunobiological characteristics of the tumor substrate. The results of modern surgical and therapeutic treatment approaches are presented.

Imaging features of inflammatory pseudotumor-like follicular dendritic cell sarcoma of the spleen.

Inflammatory pseudotumor (IPT)-like follicular dendritic cell sarcoma (FDCS) is an extremely rare malignant neoplasm. Retrospective analysis of imaging features of splenic IPT-like FDCS, including ultrasonography, computed tomography (CT), and magnetic resonance (MR) and contrast-enhanced imaging were performed. When the masses were small, the ultrasound images showed homogeneous hypoechoic signals, clear boundaries, and complete capsules. Abdominal plain CT scans showed equal density (easy to miss diagnosis), unclear boundaries, and no capsules. Magnetic resonance images (MRI) showed slightly shorter T1, slightly shorter T2, and clear boundaries. When the masses were large, the ultrasound images still showed clear boundaries and complete capsules, but the echoes of the masses were not uniform, and some of the masses showed dendritic hyperechoic centers. Abdominal plain CT scans showed irregular low densities in the center (unclear boundaries) and equal densities in the periphery. MRI showed short T1 and T2, but the central signals were mixed. When the mass was accompanied by extensive necrosis, abdominal plain CT scan showed mostly cystic lesions and slight calcifications in low density lesions. Contrast-enhanced CT showed only moderate enhancement in peripheral and septal areas. MRI showed that T1 and T2 were mainly mixed signals. Contrast-enhanced MR showed moderate enhancement of peripheral areas and septum. This is the first report to describe the IPT manifestations of the spleen (ultrasonography, CT, and MR). The diagnosis of IPT can be made by combining three imaging features.

Evolution of the Tumor Microenvironment throughout Progression and Transformation of EZH2 Mutant Follicular Lymphoma

The genetic hallmarks of follicular lymphomas include BCL2 translocations and somatic mutations of epigenetic modifier genes such as EZH2. Histologically, FLs typically feature a rich microenvironment, most notably featuring extensive follicular dendritic cell (FDC) networks with dendrites making extensive contact with lymphoma cells. In recent work we showed that the main effect of EZH2 gain-of-function mutations in GC B-cells is to enable them to become less dependent of T-cell help and strengthen their immune synapse formation with FDCs, which induces aberrant proliferation and survival of GC centrocytes and hence formation of a unique lymphoma-permissive immune niche. However, it is still unknown how interactions between EZH2 mutant GC B-cells and other immune cells change throughout the progression of the disease.To evaluate the evolution of the tumor microenvironment (TME) throughout EZH2 mutant lymphoma progression, we developed a genetically engineered mouse model designed for conditional expression of gain-of-function Ezh2 mutant and BCL2 in GC B-cells, Rosa26 LSL.BCL2.IRES.GFP;Ezh2 Y641F;Cγ1Cre (hereafter BCL2/Ezh2 Y641F), in which Cγ1-driven Cre excision of a STOP cassette in the Rosa26 locus leads to overexpression of BCL2 and GFP, and expression of the endogenous Ezh2 mutant Y641F. This mouse model develops low-grade follicular-like lymphoma, characterized by expanded follicles composed largely of centrocyte neoplastic GC B-cells and extensive FDC meshwork, along with presence of CD4 +, TFH and regulatory T cells (FOXP3 +), as depicted by multiparametric in situ imaging and multiparametric flow cytometry. At cytological level, cells are predominantly small with condensed chromatin, irregular nuclei, scant cytoplasm, and inconspicuous nucleoli, without sheets of large cells. Over time, these low grade FLs progress to advanced grade, characterized by disruption of follicle structures, expansion of centroblast-like large tumor cells and reduced CD4 + T cell infiltration and FDC meshwork.Furthermore, we have developed a murine transformed FL cell line by sequential passages of an original BCL2/Ezh2 Y641F low-grade FL into immunodeficient Rag1KO mice. We have transduced this BCL2/Ezh2 Y641F cell line with luciferase, and it successfully engrafted and homed to lymphoid organs when injected i.v. into immunocompetent C57BL6 mice. The cell line consists of high proliferative GC B-cells with multiple and irregular nuclei, open chromatin and prominent nucleoli that resemble DLBCL. The microenvironment of tumors developed in C57BL6 mice is characterized by disruption of follicle structures, severe reduction or absence of FDC meshwork, decreased CD4 +, CD8 + and Tregs, downregulation of MHC-I and MHC-II. Therefore, our mouse model also recapitulates progression and transformation stages.Since MYC translocations are frequent events that occur during histological transformation of FL, we modeled this more aggressive EZB MYC subtype of DLBCL. For that, we further crossed our BCL2/Ezh2 Y641F mice to Rosa26 LSL.MYC.IRES.hCD2. We generated cohorts of transplanted mice by injecting bone marrow cells from BCL2, BCL2/Ezh2 Y641F, BCL2/MYC, and BCL2/Ezh2 Y641F/MYC mice into lethally irradiated C57BL6 recipients. Recipient mice (n=5 per group) were immunized with SRBC to induce formation of GCs and sacrificed 5.5 months post bone marrow transplant. All genotypes showed expansion of FAS +CD38 -BCL2 GFP+ GC B-cells in spleen and lymph nodes; however, the proportion of GC B-cells in Ezh2 Y641F was significantly increased compared with Ezh2 WT, in both presence and absence of MYC. In contrast, FAS -CD38 +BCL2 GFP+ and CD138 +BCL2 GFP+ cells were significantly increased in MYC + mice and decreased in Ezh2 Y641F, suggesting that Ezh2 mutation is required to maintain the GC phenotype. The acquisition of Ezh2 Y641F in BCL2/MYC mice induced a reduction of CD4 + and CD8 + in the TME, and decreased TFH without changes in TFR proportions in GCs. Strikingly, FDC meshwork was significantly shrank in MYC + cases, and partially restored by acquisition of Ezh2 Y641F, indicating that MYC overexpression may contribute to acquire FDC independency for the survival of lymphoma cells.Our results indicate that progression of FL critically affects the TME and acquisition of additional mutations such as MYC alters the interactions between lymphoma cells and tumor supportive immune cells in TME. DisclosuresMelnick: Epizyme: Consultancy; Janssen: Research Funding; KDAC Therapeutics: Current holder of individual stocks in a privately-held company; Celgene Corporation: Consultancy; Constellation Pharmaceuticals: Consultancy; Astra Zeneca: Consultancy; Daiichi Sankyo: Consultancy; Exo Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi US Services: Research Funding.

CHOP but Not Bendamustine Reverses EZH2 Y641 Mutation Induced MHC-I/II Loss in Human Lymphoma Models

Chemotherapy combined with anti-CD20 antibodies is the standard treatment for patients with symptomatic advanced stage follicular lymphoma (FL). We have previously shown that EZH2 gene mutations were predictive of differential efficacy of the chemotherapy backbone within the GALLIUM trial (NCT01332968; Jurinovic, ASH 2019). Specifically, patients with EZH2 mutant FL had significantly longer progression free survival with CHOP-based immunochemotherapies as compared to patients with EZH2 wild type FL. In contrast, the EZH2 mutation status was not predictive of treatment outcome in patients receiving bendamustine-based regimens. The underlying biology is unclear.Mutations in EZH2, a histone methyltransferase, occur in 25-30% of FL and mostly affect the Y641 residue within the catalytic domain, resulting in more efficient conversion of H3K27me2 to H3K27me3. First, we tested differences in chemosensitivity in lymphoma cell lines that harbor the FL-hallmark translocation t(14;18)[BCL2/IGH] and intrinsic EZH2 mutations (Karpas422, OCI-Ly1, SU-DHL4, DB) or no EZH2 mutation (SU-DHL16, WSU-FSCCL, OCI-Ly8, OCI-Ly19). Treatment with CHOP (4-hydroperoxycyclophosphamide (4-HC), doxorubicin, vincristine, and prednisone), alone or in combination, or bendamustine revealed marked differences in IC50 for cell viability (CellTiter Glo) and apoptosis (Annexin V) between cell lines, but no correlation with EZH2 mutation status. To better control for cell line specific effects, we stably expressed EZH2 Y641N or wild type (WT) in the EZH2 WT cell line SU-DHL16. EZH2 mutant cells indeed showed significantly increased H3K27me3 levels compared to EZH2 WT cells. However, we did not observe differences in global cellular phenotypes, including cell proliferation and cell cycle phases. Furthermore, IC50 for cell viability and apoptosis with CHOP and bendamustine treatment were not significantly different.As we could not identify differences in direct cytotoxic responses, we hypothesized that EZH2 mutations might indirectly affect treatment efficacy, by altering the interaction of FL cells with their tumor microenvironment (TME) in response to chemotherapy. In a mouse model, Ennishi et al. had previously shown that Ezh2 mutant lymphomas have reduced MHC expression and T-cell infiltrates (Cancer Discovery, 2019). Here, we could show that expression of mutant EZH2 in human SU-DHL16 cells also leads to almost complete MHC-I loss by flow cytometry (Fig A). MHC-I loss was fully reversible when cells were treated with increasing doses of tazemetostat, a specific EZH2 inhibitor, or interferon-gamma. Interestingly, treatment with 4-HC, prednisone, doxorubicin and CHOP also resulted in increasing restoration of MHC-I expression in EZH2 mutant cells, while bendamustine (and vincristine alone) had no impact on MHC expression (Fig B,C).Next, we used a fully human B-cell co-culture model (modified from Caeser et al., Nat Comm 2019) for validation and functional studies. Mirroring the TME-dependence of FL, germinal-center (GC) B-cells from human tonsils immortalized by transduction with BCL2 and MYC absolutely require follicular dendritic cell (FDC) support plus IL21 and CD40L for sustained growth. Stable expression of EZH2 Y641N in these GC-B-cells led to increased H3K27me3 levels as compared to EZH2 WT and empty vector (ev) controls, but did not result in FDC+IL21/CD40L independent growth. Again, we observed significantly lower MHC-I/II expression on EZH2 mutant cells (Fig D). Importantly, we show that EZH2 mutation-induced MHC loss resulted in reduced CytoStim-stimulated conjugate formation when cells were co-cultured with autologous CD4 T-cells isolated from the same tonsils (Fig E). Finally, treatment with doxorubicin but not bendamustine resulted in significant upregulation of MHC-I/II on EZH2 mutant GC-B cells (Fig F). Co-culture experiments with autologous CD4 and CD8 T-cells with and without doxorubicin, CHOP and bendamustine treatment are ongoing to analyze the EZH2 mutation-specific chemotherapy effects on T-cell activation, recruitment, and T-cell mediated killing.In conclusion, our data indicates that the particular chemosensitivity of EZH2 mutant FL to CHOP is not the result of differences in direct cytotoxicity, but -unlike bendamustine- is rather mediated by restoring EZH2 mutation-induced MHC-I/II loss, thereby potentially promoting cytotoxic T-cell responses. [Display omitted] DisclosuresHodson: Astra Zeneca: Research Funding. von Bergwelt: Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Astellas: Honoraria, Research Funding, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Miltenyi: Honoraria, Research Funding, Speakers Bureau; Mologen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; MSD Sharpe & Dohme: Honoraria, Research Funding, Speakers Bureau. Subklewe: MorphoSys: Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Roche: Research Funding; Janssen: Consultancy; Klinikum der Universität München: Current Employment; Takeda: Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Miltenyi: Research Funding; Gilead: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Research Funding, Speakers Bureau. Weigert: Janssen: Speakers Bureau; Roche: Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees.

Single-Cell and Spatial Analyses Characterize Distinct Subsets of Malignant T Cells in Angioimmunoblastic T Cell Lymphoma

IntroductionAngioimmunoblastic T-cell lymphoma (AITL) is the most frequent of nodal peripheral T-cell lymphomas. AITL results from the transformation of T follicular helper (T FH) cells and is characterized by chemo-resistance and poor survival (5-year OS around 30%). Recent data from prospective clinical trials suggest that disease outcome may be impacted by factors other than genomic features, such as the tumor microenvironment (TME) and overall intra-tumoral heterogeneity. Our understanding of AITL intra-tumoral genetic, transcriptional and functional heterogeneity is limited because most molecular data generated so far have come from bulk analyses. Single-cell RNA sequencing (scRNA-seq) enables fine characterization of cell types and functional cell states. When focused on T or B cells, 5'-end scRNA-seq also yields the TCR or BCR sequences that allow tracking clonally related cells. Here we studied the intra-tumor heterogeneity of AITL tumors using integrative scRNA-seq.MethodsWe analyzed lymph node live cell suspensions from AITL patients (n=10) using droplet-based 10x Genomics 5'-end scRNA-seq. Malignant T cells from 4 AITL samples were also analyzed by FACS index sorting and plate-based 5'-end scRNA-seq to link cell surface phenotype and gene expression profile. We identified malignant T cell clones by intersecting the gene expression and TCR sequencing data, and performed separate focused analyses of TME subsets and malignant T cells. We compared subsets of malignant T cells from all patients using marker gene-based metaclustering to identify AITL T cell states conserved across patients. We explored the genetic heterogeneity of malignant T cells by mapping RHOA G17V mutations and inferring copy number variation (CNV) subclones from scRNA-seq data. In select cases, we performed in situ analysis by immunohistochemistry (IHC) or spatial transcriptomics to characterize the spatial distribution of malignant T cell subsets identified by scRNA-seq.ResultsBased on gene expression, malignant T cells grouped in patient-specific clusters, while non-malignant T, B and myeloid TME cells from all patients clustered by cell type or cell state. Among TME cells, we identified 7 subsets of B cells (including activated B cells, plasma cells, and one patient-specific monoclonal B cell proliferation), 6 subsets of myeloid cells (including macrophages, conventional and plasmacytoid dendritic cells), and 8 subsets of non-malignant T cells (including activated cytotoxic T lymphocytes (CTL) with clonal expansions). Patient-specific malignant T cells were heterogeneous and divided into several gene-expression based clusters. Metaclustering of malignant T cell subsets identified T central memory (T CM)-like and T FH-like states in 10/10 samples. We also identified in 3/10 samples clusters of CTL-like malignant T cells expressing characteristic marker genes (including NKG7, GNLY, GZMK, PRF1). We observed an intra-sample continuum of gene expression states from quiescent T CM-like to proliferating T FH-like states. T FH-like cells were larger in size and expressed higher levels of surface PD1 and ICOS than T CM-like and CTL-like subsets. We detected the RHOA G17V mutation in malignant T cells of 4/4 mutated cases, with no evidence of subclonal heterogeneity for that mutation. We detected clonal and subclonal CNV in most AITL malignant T cells. CTL-like states were enriched in specific CNV subclones, but the T CM-like to T FH-like continuum was observed in all CNV subclones, suggesting that functional plasticity and subclonal genetic evolution may occur independently. In situ staining of markers for T FH-like (PD1, ICOS, CD200) and CTL-like (GZMK, GZMA) cells showed that T FH-like and CTL-like cells occupied distinct tissue niches within the tumor. In spatial transcriptomics analysis, T FH-like cells mapped to follicular dendritic cell (FDC)-rich areas, while T CM-like cells were associated with T-zone reticular cells.ConclusionsOur analyses recapitulate known characteristics of AITL TME, and uncover previously unrecognized heterogeneity among malignant T cells across multiple patients. The distinct gene expression programs, phenotypes, genetics, and locations of T FH-like, T CM-like and CTL-like states suggest that AITL malignant T cells undergo significant functional plasticity and genetic divergence, which could influence response to therapy and overall clinical course. [Display omitted] DisclosuresLemonnier: Institut Roche: Research Funding; Gilead: Other: travel grant. Gaulard: Gilead: Consultancy; Innate Pharma: Research Funding; Sanofi: Research Funding; Alderaan: Research Funding; Takeda: Consultancy, Honoraria. Milpied: Institut Roche: Research Funding; Innate Pharma: Research Funding; Bristol Myers Squibb: Research Funding.

A Challenging and Rare Case of Metastatic Follicular Dendritic Cell Sarcoma Originating from a Tonsil

Abstract Introduction/Objective Follicular dendritic cell sarcoma (FDCS) is a rare malignant tumor of follicular dendritic cells. Most cases of FDCS are described in lymph nodes, but it can involve extra-nodal locations such as the tonsil. Methods/Case Report We report a case of a 55-year-old male with a 6-month history of a slow growing left neck mass. The patient had a poorly differentiated carcinoma of the left tonsil diagnosed based on morphologic features eight years ago, followed by chemoradiation, and subsequent left tonsillectomy without tumor identified. Imaging reported a 4.0 cm mass in the left neck level III lymph node location. Biopsy of the mass revealed a spindle cell neoplasm. It was difficult to reach a definitive diagnosis despite an extensive work-up. Review of the previous left tonsil biopsy showed a pleomorphic epithelioid cell proliferation. On the radical resection specimen of the left neck mass, a 4.5 cm, tan-gray, fleshy, necrotic mass was present. Microscopically, it demonstrated a neoplasm with spindle cell and epithelioid cell proliferation, with extensive necrosis. A wide panel of immunostains was performed; the tumor cells showed positivity for CD21, CD23, CD35, and focally weak positivity for cytokeratin OSCAR and Synaptophysin. Squamous cell markers were negative. These findings are consistent with FDCS. Further work-up on the original tonsil tumor displayed immunostaining profile of FDCS. This case was consulted with the National Institute of Health (NIH) for confirmation of the diagnosis. Results (if a Case Study enter NA) NA Conclusion Morphologically, FDCS can present with various histologic patterns, which can lead to diagnostic pitfalls, and common confusion with poorly differentiated carcinoma or soft tissue tumors, especially in needle biopsies. Generally, patients present with a prolonged clinical course, with a 50% and 25% chance of recurrence and metastasis respectively, hence the awareness and accurate diagnosis of this entity is important in biopsies of lymph nodes or of extranodal locations such as a tonsil.

Mimics of carcinoma: pancytokeratin positive follicular dendritic cell sarcoma

Abstract Introduction/Objective Follicular dendritic cell sarcoma (FDC-S) is a malignant neoplasm of follicular dendritic cells that can present with variable morphology including epithelioid and spindle cell components. Given its morphological diversity, FDC-S can mimic neoplasms including poorly differentiated carcinomas. Here we present a rare case of FDC-S in which immunohistochemical staining for pancytokeratin was focally positive, potentially leading to an erroneous diagnosis if a full spectrum of immunohistochemical stains was not considered. Methods/Case Report A 34-year-old man presented with an enlarging left neck mass, night sweats and fatigue that began approximately three months ago. CT scan showed a 5.6 x 4.2 x 3.7 cm necrotic mass in the left upper lateral carotid space. Histologic examination of the incisional biopsy specimen demonstrated portions of soft tissue comprised of pleomorphic and plump spindle cells forming whorls with no discernable node architecture (Panels A-B). The tumor cells are large with oval nuclei, vesicular chromatin, distinct nucleoli, and a moderate amount of eosinophilic cytoplasm. Occasional binucleated and multinucleated tumor cells, rare tumor cells with nuclear pseudoinclusions and atypical mitotic figures, and focal necrosis are identified. Scattered small mature lymphocytes are present. By immunohistochemistry, tumor cells are positive for pancytokeratin (focal) (Panel C), CD21 (panel D), CD23 (panel E), D2-40 (panel F), CD35 and clusterin, and negative for CD3, CD20, CD30, CD45, ALK-1, EMA, PAX5, PDL1 and S100 stains. The overall morphology and immunostaining pattern are compatible with follicular dendritic cell (FDC) sarcoma. Results (if a Case Study enter NA) NA Conclusion FDC sarcoma rarely occurs as the solitary mass in the head and neck region. The unusual focal positivity for pancytokeratin highlights the importance of comprehensive immunohistochemistry stains to confirm the diagnosis of FDC sarcoma since this case is focally positive for pancytokeratin, mimicking other neoplasms such as poorly differentiated carcinomas

A Rare Lymphoproliferative Disease: Castleman Disease

Castleman disease is a rare lymphoproliferative disease also known as angiofollicular lymph node hyperplasia. It is classified as hyaline vascular and plasmacytic variants histologically but characteristics of both types can coexist. Most unicentric cases of the disease are hyaline vascular while most multicentric cases are of the plasmacytic type. Although the pathogenesis is not completely understood, the role of interleukin (IL)-6 in unicentric disease and the roles of IL-6 and human herpes virus-8 in multicentric disease are well defined. Unicentric disease is typically localized and symptoms are minimal and treated locally. Multicentric disease is systemic and clinically characterized by generalized lymphadenopathy, splenomegaly, anemia, and systemic inflammatory symptoms. Systemic therapies are primarily given. Several malignant diseases including lymphomas, POEMS syndrome, follicular dendritic cell sarcomas, paraneoplastic pemphigus, Kaposi sarcoma, and amyloidosis can be associated with Castleman disease. In this paper, recent information about Castleman disease, which is a rare disease, is summarized.

Mechanism of a COVID-19 nanoparticle vaccine candidate that elicits a broadly neutralizing antibody response to SARS-CoV-2 variants.

Vaccines that induce potent neutralizing antibody (NAb) responses against emerging variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential for combating the coronavirus disease 2019 (COVID-19) pandemic. We demonstrated that mouse plasma induced by self-assembling protein nanoparticles (SApNPs) that present 20 rationally designed S2GΔHR2 spikes of the ancestral Wuhan-Hu-1 strain can neutralize the B.1.1.7, B.1.351, P.1, and B.1.617 variants with comparable potency. The adjuvant effect on vaccine-induced immunity was investigated by testing 16 formulations for the multilayered I3-01v9 SApNP. Using single-cell sorting, monoclonal antibodies (mAbs) with diverse neutralization breadth and potency were isolated from mice immunized with the receptor binding domain (RBD), S2GΔHR2 spike, and SApNP vaccines. The mechanism of vaccine-induced immunity was examined in the mouse model. Compared with the soluble spike, the I3-01v9 SApNP showed sixfold longer retention, fourfold greater presentation on follicular dendritic cell dendrites, and fivefold stronger germinal center reactions in lymph node follicles.

Development of follicular dendritic cells in lymph nodes depends on retinoic acid-mediated signaling.

Specialized stromal cells occupy and help define B- and T-cell domains, which are crucial for proper functioning of our immune system. Signaling through lymphotoxin and TNF receptors is crucial for the development of different stromal subsets, which are thought to arise from a common precursor. However, mechanisms that control the selective generation of the different stromal phenotypes are not known. Using in vitro cultures of embryonic mouse stromal cells, we show that retinoic acid-mediated signaling is important for the differentiation of precursors towards the Cxcl13pos follicular dendritic cell (FDC) lineage, and also blocks lymphotoxin-mediated Ccl19pos fibroblastic reticular cell lineage differentiation. Accordingly, at the day of birth we observe the presence of Cxcl13posCcl19neg/low and Cxcl13neg/lowCcl19pos cells within neonatal lymph nodes. Furthermore, ablation of retinoic acid receptor signaling in stromal precursors early after birth reduces Cxcl13 expression, and complete blockade of retinoic acid signaling prevents the formation of FDC networks in lymph nodes.

Tre-P-28 - Primary cutaneous B-cell lymphoma leg-type related to an anti-TNF-alpha therapy

<h3>Introduction:</h3> Drug-induced primary cutaneous B-cell lymphomas are rare. <h3>Observation:</h3> A 63 year old woman was referred for a lumbar cutaneous lesion which had been rapidly growing for 1 month. Her past medical history included multiple allergies and a rheumatoid arthritis which was treated with oral methotrexate 10 mg per week and adalimumab. Methotrexate had been taken for 8 years, while adalimumab had been initiated 6 months earlier. Physical examination revealed a solitary thick, violaceous plaque of 6 X 4 cm in diameters, without enlarged lymph nodes. No fatigue, fever or pruritus were present. The first clinical hypothesis was a cutaneous B-cell lymphoma. The histological examination of a skin biopsy specimen showed a monomorphous dermal proliferation of large centroblast-like cells with large round, sometimes irregular, nuclei. Only rare reactive small cells were present. The infiltrate spared the epidermis, with a Grenz zone. The tumor cells were positive for CD45, CD20, bcl2, bcl6, MUM1, highly proliferating (Ki67 95%), and negative for CD3, CD30, CD10 and EBV/EBER. No CD21 or CD23 positive follicular dendritic cell network was identified. Fluorescence in situ hybridization showed no BCL2, BCL6 or CMYC rearrangement, while high resolution melting identified the MYD88 L265P mutation. A B-cell rearrangement was detected in the lesion. Whole body FDG-PET/CT showed a single hypermetabolic activity corresponding to the cutaneous lombar lesion, without distant tumours. Although the Borrelia burgdorferi serology was negative, a 15 days course of doxycyline 200 mg daily was given. Once the diagnosis of primary cutaneous large B-cell lymphoma, leg type (PCLBCL-LT) was made, adamimumab (but not methotrexate) was discontinued. The tumor completely disappeared within 4 months. No other TNF inhibitors were later given. No recurrence was observed after a follow-up time of 4 years. <h3>Discussion:</h3> PCDLBCL-LT are aggressive B-cell lymphomas mainly (but not exclusively) located on the leg, characterized by a monomorphous proliferation of large CD20+, Bcl2+, Mum1+, CD10 - B cells, frequently exhibiting the MYD88 L265P mutation, as observed in our patient. In contrast with indolent subtypes of primary cutaneous B-cell lymphomas, spontaneous regressions in PCLBCL-LT are exceptional, and constantly followed by recurrences. Progression of undiagnosed cutaneous lymphomas after anti-TNF-alpha therapy (mainly cutaneous T-cell lymphomas misdiagnosed as psoriasis or eczema) have been reported [1]. However, the role of anti-TNF-alpha in the occurrence of new lymphoproliferative disorders remains controversial [2,3]. To our knowledge, no PCLBCL-LT related to TNF-alpha inhibitors has been reported to date. Although methotrexate may play a role as a cofactor for the development of this B-cell malignancy, the negative EBV staining and the long-term complete remission after adalimumab withdrawal while methotrexate was continued, strongly argue for a predominant role of the anti-TNF-alpha in the occurrence of this lymphoma.

Follicular dendritic cell sarcoma.

SummaryFollicular dendritic cells (FDC) are mesenchymal-derived dendritic cells located in B-follicles where they play a pivotal role in triggering and maintaining B-cell adaptive immune response. In 1986 Dr. Juan Rosai first reported a series of neoplasms showing features of FDC and defined it as Follicular Dendritic Cell Tumor, subsequently renamed as “sarcoma” (FDCS). In its seminal and subsequent articles Rosai and colleagues highlighted the heterogeneous microscopic appearance of FDCS and its immunohistochemical and ultrastructural features.FDCS mostly occurs in extranodal sites (79.4% of cases) and lymph nodes (15.1%); in about 7%-10% of cases it is associated with hyaline-vascular Castleman disease. Given its significant growth pattern and cytological variability, FDCS can be confused with various neoplasms and even inflammatory processes. The diagnosis requires the use of a broad spectrum of FDC markers (e.g. CD21, CD23, CD35, clusterin, CXCL13, podoplanin), particularly considering that tumor antigen-loss is frequent. The inflammatory-pseudotumor-like (IPT-like) variant of FDCS, in addition to its peculiar histopathological and clinical features, is characterized by positivity of tumor cells for Epstein-Barr virus, representing a diagnostic requisite.No distinctive genetic and molecular anomalies have been identified in FDCS. It often carries an aberrant clonal karyotype and chromosomal structural alterations, frequently involving onco-suppressor genes. Direct or next generation sequencing showed alterations on genes belonging to the NF-κB regulatory pathway and cell-cycle regulators. In contrast to hematopoietic-derived histiocytic and dendritic cells tumors, FDCS typically lacks mutations in genes related to the MAPK pathway.FDCS recurs locally in 28% and metastasizes in 27% of cases. Extent of the disease, surgical resectability and histopathological features are significantly associated with the outcome. IPT-like FDCS behaves as an indolent tumor, even if it often recurs locally over years.Complete surgical excision is the gold standard of treatment. Data on targeted therapies (e.g.: tyrosine kinase inhibitors) or immune checkpoint inhibitors are very limited and responses are variable. A better understanding of the molecular drivers of this tumor may lead to potential new therapeutic strategies.

Geographic Variability of Nodular Lymphocyte-Predominant Hodgkin Lymphoma.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) differs from classic Hodgkin lymphoma (CHL) in terms of clinicopathologic features, including Epstein-Barr virus (EBV) association. CHL geographic variability is well known, with higher frequencies of mixed-cellularity subtype and EBV positivity in low/middle-income countries (LMICs), but there are few well-characterized series of NLPHL from LMICs. We detail clinicopathologic findings of 21 NLPHL cases received in consultation from Kenya and summarize reports of NLPHL with EBV testing published since 2000. Median age of consultation cases was 36 years, and male/female ratio was 3.2. All cases involved peripheral lymph nodes and showed at least some B-cell-rich nodular immunoarchitecture, with prominent extranodular lymphocyte-predominant (LP) cells and T-cell-rich variant patterns most commonly seen. LP cells expressed pan-B-cell markers, including strong OCT2; lacked CD30 and CD15 expression in most cases; and were in a background of expanded/disrupted follicular dendritic cell meshworks and increased T-follicular helper cells. LP cells were EBV negative in 18 cases. Historical cases showed a low rate of EBV positivity with no significant difference between LMICs and high-income countries. Unlike CHL, NLPHL shows few geographic differences in terms of clinicopathologic features and EBV association. These findings have implications for diagnosis, prognostication, and treatment of patients with NLPHL in LMICs.

Mediastinal and neck follicular dendritic cell sarcoma treated with definitive radiation therapy using the volumetric modulated arc therapy technique: a case report

AbstractFollicular dendritic cell sarcoma (FDCS) is a rare malignancy that affects the nodal and extranodal tissues. The mediastinum is a rare site for this tumor, with few published reports and series. Although surgery is the mainstay of treatment for this disease entity, in this report we present a case of mediastinal FDCS treated with definitive radiation therapy (RT) with a near‐total radiological response. A 28‐year‐old woman presented with chest tightness and neck swelling. Radiological findings were suggestive of a conglomerated nodal mass involving the mediastinum and extending superiorly into the anterior neck. Biopsy results led to a diagnosis of FDCS. The tumor was deemed unresectable, and definitive RT was planned as the treatment. The patient was treated with volumetric modulated arc therapy to a total dose of 54 Gy in 30 fractions over 6 weeks. Her symptoms had completely resolved at the first follow‐up visit, 3 months after RT completion, with a near‐total radiological response on a contrast‐enhanced computed tomography scan. Although surgery is the standard of care in FDCS, based on the favorable response of FDCS to RT, as in this case, the role of definitive RT needs to be studied in more patients to determine its efficacy in long‐term tumor control as an alternative to surgery.

Canine Non-Angiogenic, Non-Myogenic Splenic Stromal Sarcoma: a Retrospective Clinicopathological Analysis and Investigation of Podoplanin as a Marker of Tumour Histogenesis

Splenic stromal sarcomas are rarely reported tumours that were previously grouped as non-angiomatous, non-lymphomatous mesenchymal neoplasms of the canine spleen. Highly variable survival times have been reported probably due to their heterogeneous nature. The purpose of this study was to assess the outcome and prognostic factors in dogs with splenic stromal sarcoma after treatment by splenectomy. Clinical data were collected retrospectively and histopathology was reviewed for 47 patients. Histological classification, based on morphology in haematoxylin and eosin-stained sections, in conjunction with immunolabelling of macrophage scavenger receptor-A (CD204), desmin, factor VIII-related antigen and smooth muscle actin ,yielded diagnoses of undifferentiated stromal sarcoma (n=22), complex nodular hyperplasia (CNH, n=9), sarcoma arising from benign complex nodular hyperplasia (n=3), histiocytic sarcoma (n=3), haemangiosarcoma (n=1) and leiomyosarcoma (n=1). Four samples were excluded from analysis due to extensive necrosis. An anti-podoplanin (PDPN) antibody was validated on canine tissue and used to assess expression of this protein as a potential indicator of the tissue of origin of the neoplasms (28/42 tumours were positive). There was a statistically significant difference in survival time between patients with stromal sarcoma (sarcoma from benign CNH and undifferentiated stromal sarcoma) and CNH (178d versus 637d, respectively; P=0.027). Dogs with stromal sarcomas and high mitotic count (≥9 per 10 high-power fields) had a significantly shorter survival time (67d versus 439d; P=0.01). Clinical diagnosis of splenic tumours should include evaluation for the presence of benign nodular hyperplasia morphology and immunohistochemistry to exclude more aggressive malignancies where adjuvant therapy is recommended. As in humans, PDPN may be an effective marker for stromal sarcomas of the canine spleen and immunopositivity suggests a fibroblastic reticular or follicular dendritic cell origin.

Incidence and clinicopathological features of Follicular T-cell lymphoma in Finland: a population-based immunohistochemical study

Follicular T-cell lymphoma (FTCL) is a rare subtype of mature T-cell lymphoma. It was recently recognized as a separate lymphoma entity in the 2017 revised fourth edition of the World Health Organization classification. The main goals of the present study were to gain better knowledge of the incidence and histopathological and clinical features of FTCL in Finland. In this study, we reviewed all angioimmunoblastic T-cell (AITL) and peripheral T-cell lymphomas, not otherwise specified, from the patient records in three hospital districts in Finland over a 10-year period, to identify FTCL cases and estimate its incidence. Five patients rediagnosed with FTCL and 34 with AITL were analyzed. Hodgkin/Reed-Sternberg (HRS)-like cells were observed in 24 of the 34 AITL cases and four of the five FTCL cases. We found that the main features that differentiated FTCL from AITL were rosetting of T-cells around HRS-like cells, the absence of clear cells, follicular dendritic cell meshwork and T-cell monoclonality. Our estimated incidence of FTCL is 0.20 per 100,000 people in Finland.

Emerging roles for IL-6 family cytokines as positive and negative regulators of ectopic lymphoid structures

IL-6 family cytokines display broad effects in haematopoietic and non-haematopoietic cells that regulate immune homeostasis, host defence, haematopoiesis, development, reproduction and wound healing. Dysregulation of these activities places this cytokine family as important mediators of autoimmunity, chronic inflammation and cancer. In this regard, ectopic lymphoid structures (ELS) are a pathological hallmark of many tissues affected by chronic disease. These inducible lymphoid aggregates form compartmentalised T cell and B cell zones, germinal centres, follicular dendritic cell networks and high endothelial venules, which are defining qualities of peripheral lymphoid organs. Accordingly, ELS can support local antigen-specific responses to self-antigens, alloantigens, pathogens and tumours. ELS often correlate with severe disease progression in autoimmune conditions, while tumour-associated ELS are associated with enhanced anti-tumour immunity and a favourable prognosis in cancer. Here, we discuss emerging roles for IL-6 family cytokines as regulators of ELS development, maintenance and activity and consider how modulation of these activities has the potential to aid the successful treatment of autoimmune conditions and cancers where ELS feature.

Primary Follicular Dendritic Cell Sarcoma of Urinary Bladder.

Follicular dendritic cell sarcoma is a rare malignant mesenchymal neoplasm composed of follicular dendritic cells. A subset of cases can be found at extranodal sites. Only 2 follicular dendritic cell sarcomas were previously reported in the urinary bladder. We report a follicular dendritic cell sarcoma that involved the urinary bladder of an 81-year-old woman, who presented with painless gross hematuria. The neoplasm was composed of large epithelioid cells with atypical nuclei, admixed with inflammatory cells. On immunohistochemistry, the neoplastic cells were reactive only for CD21, CD35, and vimentin. The tumor was considered unresectable due to its large size and proximity to the iliac vessels and the patient was treated with bortezomib, cyclophosphamide, and dexamethasone. Although a full course of chemotherapy was not completed due to adverse side effects, the tumor was reduced in size. A subsequent involved-field radiotherapy was performed. Three years postdiagnosis and 2 years after the radiotherapy treatment, a recurrent tumor was identified on imaging in the left posterolateral bladder wall. However, at that time the patient was found to have a newly developed advanced colonic adenocarcinoma. Three and a half months later she developed a bowel perforation and died.

Hepatic inflammatory pseudotumor-like follicular dendritic cell tumor: a case report

BackgroundInflammatory pseudotumor-like follicular dendritic cell sarcoma is a rare histological variant of follicular dendritic cell sarcoma involving typically the spleen and the liver, often linked to the presence of Epstein–Barr virus infection. Definite diagnosis of this type of sarcoma is difficult to make owing to nonspecific clinical and imaging findings and is based on histopathological features. Inflammatory pseudotumor-like follicular dendritic cell sarcoma is described as a low-aggressivity tumor with a favorable prognosis.Case presentationWe report the case of a 34-year-old Caucasian woman, Epstein–Barr virus positive, diagnosed with hepatic inflammatory pseudotumor-like follicular dendritic cell sarcoma and surgically treated in November 2014, who developed 6 years later a recurrence for which she underwent once again surgical treatment. As far as we know, fewer than 30 reports of inflammatory pseudotumor-like follicular dendritic cell liver tumors have been reported in the English literature.ConclusionsAlthough it is an uncommon tumor, inflammatory pseudotumor-like sarcoma is a diagnostic worth being taken in consideration, and surveillance is recommended owing to the possibility of recurrence.