Follicular Dendritic Cell Meshworks Research Articles

Analysis of immunophenotypic features in hyaline vascular type Castleman disease

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

T-Cell-Rich Hodgkin Lymphoma With Features of Classic Hodgkin Lymphoma and Nodular Lymphocyte-Predominant Hodgkin Lymphoma: A Borderline Category With Overlapping Morphologic and Immunophenotypic Features.

It is known that a subset of cases of classic Hodgkin lymphoma (CHL) with B-cell-rich nodules (lymphocyte-rich CHL) exhibits morphologic and immunophenotypic features that overlap with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), raising diagnostic difficulties that can be resolved in most cases by performing an adequate battery of immunohistochemical studies. To fully characterize cases of T-cell-rich Hodgkin lymphoma where a specific diagnosis of NLPHL (ie, pattern D) or CHL could not be made even after complete immunophenotypic investigation. The clinical, immunomorphologic, and molecular (when applicable) presentation of 3 cases of T-cell-rich Hodgkin lymphoma was thoroughly investigated. These 3 cases harbored lymphocyte-predominant-like and Hodgkin and Reed-Sternberg-like cells that partially expressed B-cell and CHL markers and were negative for Epstein-Barr virus-encoded small RNA, in a T-cell-rich background with residual follicular dendritic cell meshworks; 1 case had frequent and the other 2 cases scant/absent eosinophils and plasma cells. Two patients with advanced-stage (III or IV) disease presented with axillary and supraclavicular lymphadenopathy, respectively, and without B symptoms. These patients underwent NLPHL-like therapeutic management with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone) chemotherapy; both are in complete remission 7 years posttherapy. One patient presented with stage I disease involving an internal mammary lymph node without B-symptoms and was treated with surgical excision alone; this patient is also in complete remission 1 year later. These cases illustrate overlapping features of T-cell-rich NLPHL and CHL with neoplastic cells expressing both B-cell program and CHL markers. This underrecognized overlap has not been fully illustrated in the literature, although it portrays a therapeutic challenge. These neoplasms may deserve in-depth investigation in the future that may bring up diagnostic or theragnostic implications.

Angioimmunoblastic T-Cell Lymphoma with Concurrent EBV Viremia: A Challenging Case

Abstract Introduction/Objective Angioimmunoblastic T-cell lymphoma (AITL) represents only 1-2% of all non-Hodgkin lymphomas but is one of the most common non-cutaneous T-cell lymphomas. Although typically associated with latent Epstein Barr Virus (EBV) infection, recent studies have demonstrated the presence and prognostic impact of EBV viremia at the time of diagnosis. Here, we present a case of AITL in which the diagnosis was complicated by EBV viremia. Methods/Case Report A 41-year-old male presented to our hospital with generalized abdominal pain, diffuse lymphadenopathy, hepatomegaly, ascites, and diffuse body wall edema. A recent retroperitoneal lymph node biopsy reportedly demonstrated features suggesting an infectious process, and EBV PCR revealed a viral load of 141,050 copies/mL. A left axillary lymph node was excised, which demonstrated vascular proliferation and diffuse architectural effacement by a polymorphous infiltrate including variably sized lymphocytes with moderate to abundant clear cytoplasm, and occasional admixed neutrophils, plasma cells, and eosinophils. Immunohistochemical staining demonstrated an atypical CD4-positive, CD7-negative T-cell population in a vaguely nodular distribution, expressing Bcl-6, PD-1, ICOS, and CXCL13 without definite CD10 expression. CD21 immunostaining demonstrated markedly expanded follicular dendritic cell meshworks in a distribution similar to the atypical T-cell population. No B-cell or cytotoxic T-cell proliferation was seen, and in situ hybridization for EBV-encoded RNA (EBER ISH) demonstrated only scattered EBV- positive cells. Taken together, these findings supported a diagnosis of AITL over an atypical reaction to EBV infection. Next-generation sequencing demonstrated mutations in TET2, IDH2, and RHOA, further confirming the diagnosis. Results (if a Case Study enter NA) NA Conclusion AITL manifests with a diverse range of clinical symptoms and pathological features and may mimic infection. Additionally, acute EBV infection is well-known to mimic various lymphomas and has rarely been reported to mimic AITL. We present this case to raise awareness of the concurrent presentation of AITL with EBV viremia and to highlight features that may be helpful in distinguishing between the two.

A Rare Case of Incidental Primary Follicular Lymphoma Co-Existing With Grade Group 5 Prostatic Adenocarcinoma

Abstract Introduction/Objective Primary lymphoma of the prostate is an exceedingly rare entity comprising less than 0.1% of all prostatic cancers with follicular lymphoma making up only 12% of primary prostatic lymphomas. There is very limited literature owing to their rarity and underdiagnosis. To the best of our knowledge, prostatic adenocarcinoma with an incidental follicular lymphoma presenting as a prostate imaging reporting and data system 4 (PI-RADS 4) lesion on multiparametric magnetic resonance imaging (mpMRI) with mildly elevated serum prostate specific antigen (PSA) has not been previously described. Methods/Case Report A 73 year old male presented to Danbury Hospital for follow up on benign prostatic hyperplasia (BPH) diagnosed in 2020. The patient was experiencing nocturia and had a serum PSA of 4.8. Multiparametric MRI revealed an enlarged, 5.5 x 4.1 x 3.3 cm, prostate gland (estimate weight of 45.5 grams) with a 1.2 cm PI-RADS 4 lesion in the right anterior mid gland. There was no evidence of metastatic disease on his most recent body imaging. He was subsequently scheduled for prostate needle biopsy. Histopathology showed a high grade prostatic adenocarcinoma, with a Gleason score 4 + 5=9, along with a focally prominent dense lymphoid infiltrate in four of four cores from the same area of abnormality that was detected on mpMRI. The latter comprised of ill defined follicles and sheets of small cleaved atypical lymphoid cells consistent with centrocytes and very few centroblasts. By immunohistochemical staining, the atypical cells in lymphoid follicles and interfollicular areas were positive for CD20, CD10 and BCL2 and negative for cyclin D1. CD21 stain highlighted the follicular dendritic cell meshwork in the germinal centers with a low Ki67 proliferation index. A final diagnosis of low grade follicular lymphoma (grade1-2) coexisting with the prostatic adenocarcinoma was rendered. The patient is currently undergoing lymphoma staging as the treatment for adenocarcinoma is planned. Results (if a Case Study enter NA) NA Conclusion Primary lymphoma of the prostate usually presents with non specific obstructive voiding symptoms and normal or near normal PSA levels which makes it challenging for physicians to suspect lymphomas. The lymphocytic infiltrate, originally thought to be prostatitis, underwent further evaluation with immunohistochemistry due to its monotonous appearance, which clinched the final diagnosis. Careful evaluation of prostate core needle biopsies is necessary even after spotting carcinoma in order to rule out low grade lymphomas.

Localization of DC-SIGN Expressing Cells in Follicular Lymphoma

The high incidence of unusual mannose-rich glycans on the expressed surface immunoglobulins of follicular lymphoma (FL) suggests a pathogenic role for this modification. While lectin-mediated signaling has been proposed to provide trophic support to FL cells, the localization of the lectins has not been extensively characterized. Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN) is a mannose-selective lectin named for its expression on classic marrow-derived dendritic cells. In vitro, recombinant DC-SIGN induces signaling in primary FL cells. The nodules of Follicular lymphoma (nFL) are the neoplastic counterparts of normal germinal centers (GC). Both GC and nFL contain variable numbers of centrocytic and/or centroblastic B cells, T-cells, and follicular dendritic cells (FDCs), but macrophages are typically found only in GC. Although termed “follicular dendritic cells”, FDCs are thought to be derived from non-blood stem-cells, potentially pericytes. Therefore, nFL lack classic dendritic cells and macrophages so it is unclear what cells in FL could express DC-SIGN. Therefore, we systematically characterized FDC and DC- SIGN localization in sixteen FL and nine Follicular hyperplasia (FH) lymph nodes. Using flow cytometry of disaggregated FL nodes, we were not able to identify a specific cell population expressing DC-SIGN. However, using immunohistochemistry and Immunofluorescence methods, we identified nine cases of FH and five cases of FL (n=5/16) with DC-SIGN and FDC co-localization. Immunohistochemical stains of the FDCs using CD23 and CD21 showed that the follicular dendritic structures were disrupted in almost all the FL cases assessed showing either a peripheral crescentic staining or broken FDC meshwork within the follicle. We identified five cases of FL with an average of more than four well visualized and complete FDC structures staining per low power field (4X) while the remaining cases had an average of less than two complete FDC network staining. There was near complete absence of CD21 positive FDCs meshwork identified in 50% of the FL cases compared to only one case lacking CD23 positive FDCs structure staining. In contrast, FH cases (n=9) showed complete staining of the FDC meshwork within the follicles with both CD21/CD23. For FH, the average number of complete FDC staining with CD23 was 18 while an average of 10 complete FDC meshworks stained with CD21. Furthermore, immunofluorescence imaging analysis showed different pattern of localization of CD23 positive FDC with DC-SIGN with between the two conditions. In FH, DC-SIGN and CD23 colocalization was identified mainly in the light zone. For FL, we observed that DC-SIGN overlap with CD23 localized in the intra-follicular areas and co-localized with CD163 (M2 macrophages) in the inter-follicular zones. Confocal imaging confirmed colocalization of CD23 and DC-SIGN on FDCs with close association to MUM1-positive B cells in both GC and nFL. Additional analysis also showed that 80% (n=5) of the cases which had more than four complete FDC structures staining with CD23 co-localized with DC-SIGN in the intra-follicular areas and the cases with complete FDC network disruption did not. There was no significant relationship identified between the extent of FDC networks and the fraction of non-neoplastic B cells in the FL cases. In summary, our data show that DC-SIGN is expressed on FDCs in FL and FH even though FDCs are not the marrow-derived DCs for which DC-SIGN is named. Furthermore, localization of DC-SIGN to the follicle suggests a potential role for the microenvironment in the pathogenesis of FL and possible therapeutic target.

Tissue Eosinophilia in B-cell Lymphoma: An Underrecognized Phenomenon.

Tissue eosinophilia is seldom reported in B-cell lymphoma. It poses diagnostic challenges and frequently leads to the consideration of other diagnoses, particularly T-cell lymphomas. The scarce literature underscores the need for in-depth studies to enhance awareness and understanding of this phenomenon. We investigated 54 cases of B-cell lymphoma with notable tissue eosinophils, analyzing clinical information, hematoxylin and eosin staining, immunohistochemistry, and PCR-based clonality analysis. Nodal marginal zone lymphoma (NMZL) emerged as the most prevalent type (n=26), followed by B-cell lymphoma, not otherwise specified (n=13), diffuse large B-cell lymphoma (n=10), follicular lymphoma (n=2), chronic lymphocytic leukemia/small lymphocytic lymphoma (n=1), extranodal marginal zone lymphoma (n=1), and primary cutaneous marginal zone lymphoma (n=1). Shared features across different lymphoma types, best exemplified by NMZL, included plasmacytic differentiation (57.7%), increased vascularity (84.6%) with a tendency for perivascular distribution of neoplastic cells, and a tumor microenvironment abundant in T cells and histiocytes; some cases showed increased PD-1-positive cells. These features often raise consideration of angioimmunoblastic T-cell lymphoma. Along with clonality analysis, features supporting the diagnosis of B-cell lymphoma included cytological atypia in B cells rather than T cells, and the lack of follicular dendritic cell meshwork expansion. In addition, diffuse large B-cell lymphoma frequently exhibited interfollicular distribution and monocytoid appearance, indicating the possibility of transformed NMZL. Collectively, tissue eosinophilia can occur in diverse B-cell lymphomas but is most prevalent in tumors with a postgerminal stage of differentiation.

MEF2B is the ideal immunohistochemical marker to highlight neoplastic LP cells in nodular lymphocyte-predominant Hodgkin lymphoma.

MEF2B is the ideal immunohistochemical marker to highlight neoplastic LP cells in nodular lymphocyte-predominant Hodgkin lymphoma.

Clinical Research Advances of Duodenal-Type Follicular Lymphoma--Review

Duodenal-type follicular lymphoma (DFL) is a unique subtype of follicular lymphoma (FL), which often involves the second portion of duodenum (descending part of duodenum). Due to its specific pathological features, such as lack of follicular dendritic cells meshwork and disappearance of activation-induced cytidine deaminase expression, DFL presents an inert clinical course and is often confined to the intestinal tract. Inflammation-related biomarkers suggest that the microenvironment may play a likely role in the pathogenesis and favorable prognosis of DFL. Since patients generally have no obvious clinical symptoms and low progression rate, the treatment regimen for DFL is mainly observation and waiting (W&W) strategy. This study will review the latest research progress of epidemiology, diagnosis, treatment and prognosis of DFL in recent years.

Angioimmunoblastic T-cell lymphoma with extensive follicular dendritic cell and fibroblastic reticular cell network proliferation mimicking follicular dendritic cell sarcoma: A case report with pathologic, immunophenotypic, and molecular findings

Angioimmunoblastic T-cell lymphoma (AITL) is a common type of nodal peripheral T-cell lymphoma, which always presents with extensive follicular dendritic cell (FDC) meshwork. Here, we report a case of AITL combined with extensive spindle cell meshwork. Spindle cells occupied were positive for the FDC markers CD21, CD23, and CD35. Furthermore, some cells were positive for desmin and smooth muscle actin (SMA), suggesting the differentiation of fibroblastic reticular cell (FRC). Interestingly, the proliferation of spindle cells was so extensive that was easily misdiagnosed as FDC sarcoma (FDCS). Next-generation sequencing showed that the common mutations reported in AITL, including RHOA, TET2, and IDH2, were also detected in this case, while the genes that are recurrently mutated in FDCS were not detected. Regrettably, the patient died 19 months later. Overall, we highlight the unusual morphologic features in an AITL patient with extensive FDC and FRC network that may be misdiagnosed as FDCS, and careful morphological observation and immunochemical and molecular examinations are crucial for an accurate diagnosis.

Angiomatoid Fibrous Histiocytoma: A Rare Cause of Anemia in a Child

Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue tumor of intermediate potential and is usually found during first two decades of life. It is located mainly in extremities presents as a painless, slow growing mass with extensive blood supply. Embryologically, it arises from a pluripotent mesenchymal cell. Histologically, the tumor has thick pseudo capsule with chronic inflammatory infiltrates and hemorrhagic cystic areas. We present a case of AFH which caused severe anemia in a child with a non-healing ulcer on the medial aspect of left knee. Multiple blood transfusions, incision and drainage and biopsies were done however; only complete surgical resection proved to be fruitful. The biopsy is EMA positive, cytokeratin AE1/AE3 &amp; Desmin are focal positive. CD21 highlights meshwork of follicular dendritic cells. Yearly follow up is advised. Angiomatoid Fibrous Histiocytoma should be kept in the differentials while managing hematoma-like lesions in the extremities. It is often misdiagnosed thus prompt treatment is usually delayed. The prognosis after complete surgical resection is good but chemotherapy should be considered in recurrent cases.

Myeloid nuclear differentiation antigen: an aid in differentiating lymphoplasmacytic lymphoma and splenic marginal zone lymphoma in bone marrow biopsies at presentation

The differential diagnosis between lymphoplasmacytic lymphoma (LPL) and marginal zone B-cell lymphoma, particularly splenic type (SMZL), can be challenging on onset of bone marrow biopsy (BMB) since morphology and phenotype are not specific and clinical features can overlap or be mildly developed at diagnosis. The LPL-specific L265P mutation in the MYD88 gene is not available in all laboratories, and genetic aberrancies identified in SMZL (del7q, mutations of NOTCH2 and KLF2) are seldom searched in routine practice. The study aim is to investigate the potential role of myeloid nuclear differentiation antigen (MNDA) expression in this specific differential diagnosis. We report MNDA reactivity in 559 patients with small B-cell lymphoma including bone marrow biopsies from 90 LPL and 91 SMZL cases. MYD88 p.Leu265Pro mutation status was assessed and confirmed as positive in 24 of 90 LPL cases, which served as the test set. MNDA staining was negative in 23 of 24 LPL cases in the test set (96%). In the 157 remaining cases (66 LPL, 91 SMZL), which served as the validation set, the MYD88 p.Leu265Pro mutation was unavailable and MNDA was more frequently expressed in SMZL (p<0.00001). In addition, immunohistochemical features more consistent with SMZL (i.e., presence of CD23+ follicular dendritic cell meshworks, polytypic plasma cells, DBA44 reactivity) were more often present in MNDA-positive cases (statistically significant for 2 such parameters). On the widest case series so far published focusing on LPL and SMZL immunohistochemical diagnosis at onset of BMB, we demonstrated that MNDA expression significantly support the diagnosis of SMZL. This observation may be of particular help in cases where the MYD88 p.Leu265Pro mutational status and/or SMZL-related genetic aberrations are unavailable.

Pathogenesis of follicular thymic hyperplasia associated with rheumatoid arthritis.

Lymphoproliferative disorders may occur in patients with rheumatoid arthritis (RA) who are treated with methotrexate. However, follicular thymic hyperplasia (FTH) associated with RA (FTH‐RA) is generally not considered a lymphoproliferative disorder. To investigate the pathogenesis of FTH‐RA, we examined 12 cases of FTH involving thymic enlargement, four of FTH involving RA and eight of FTH involving myasthenia gravis (MG). Increased numbers and larger germinal center (GC) size were observed in FTH‐RA group. The percentage of distorted GCs was 13.3% in FTH‐RA group and 3.25% in FTH associated with MG (FTH‐MG) group. A greater meshwork of follicular dendritic cells was observed in the GCs of FTH‐RA group. Positive indices of CD27+ cells and PD‐1+ cells per GC in FTH‐RA group were significantly higher than those in FTH‐MG group, though positive indices of CD68+ cells and CD163+ cells were similar. Myoid cell proliferation, as evaluated by α‐SMA, tenascin‐C, and l‐caldesmon expression, was significantly increased in the FTH‐RA group compared with the FTH‐MG group. These results suggest that FTH should be considered in patients with RA treated with methotrexate. The pathogenesis of FTH‐RA includes GC expansion and increased numbers of memory B cells, follicular helper T cells, and myoid cells, indicating humoral immunity activation.

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.

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.

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.

Large B-Cell Lymphoma with T-Cell–Rich Background and Nodules Lacking Follicular Dendritic Cell Meshworks: A Case Report with Complete Response to Chemotherapy and a Review of the Literature

In this report, we describe a 38-year-old male with a very rare type of lymphoma, large B cell lymphoma with T cell-rich background and nodules lacking follicular dendritic cell meshworks (THRLBCL). In 2016 the patient presented hot flashes and night sweats (B-symptoms) and peripheral edema. He was treated with R-CHOP (doxorubicin, vincristine, cyclophosphamide, rituximab and Prednisone) chemotherapy, a Positron emission tomography–computed tomography (PET-CT) scan was performed after four cycles of treatment which showed radiologic complete response and blood test (complete blood count (CBC)) results showed normal ranges. As of September, 2020 he patient remains in complete remission. We searched the literature for descriptions of cases spanning the diagnostic spectrum of THRLBCL and we identified only five cases worldwide. The last reported case was in 2014 with distinctive features that were difficult to classify according to the World Health Organization criteria or previously described variants. Our patient is the sixth case of THRLBCL to be reported. He is the youngest of the reported cases and the first from Israel and the Middle East.

Immunopathology of Kikuchi-Fujimoto disease: A reappraisal using novel immunohistochemistry markers.

Kikuchi-Fujimoto disease (KFD) is a self-limited disease characterised by destruction of the lymph node parenchyma. Few studies have assessed the immunohistological features of KFD, and most employed limited antibody panels that lacked many of the novel immunohistochemistry markers currently available. We used immunohistochemistry to reappraise the microanatomical distribution of plasmacytoid dendritic cells (pDCs), follicular helper T cells and cytotoxic T cells, B cells, follicular dendritic cell (FDC) meshworks, and histiocytes in lymph nodes involved by KFD. The study group consisted of 138 KFD patients (89 women; 64.5%) with a median age of 27years (range, 3-50years). Cervical lymph nodes were most commonly involved, in 108 (78.3%) patients. The numbers of pDCs were increased, predominantly around and within apoptotic areas and the paracortex, and tapering off within xanthomatous areas. pDCs formed sizeable tight clusters, most notably around apoptotic/necrotic areas. T cells consisted mostly of CD8-positive cells with predominant expression of T-cell receptor-β. There were notable increases in the numbers of CD8-positive T cells within lymphoid follicles, and their numbers correlated with alterations in FDC meshworks (P<0.001). The number of follicular helper T cells was decreased within distorted FDC meshworks. CD21 highlighted frequent distortion of FDC meshworks, even in lymph node tissue that was distant from apoptotic/necrotic areas. Distorted FDC meshworks spanned all morphological patterns, and FDC meshwork characteristics (intact; distorted; remnant/nearly absent) correlated with morphological patterns (P<0.01). The immunohistological landscape of KFD is complex and characterised by increased numbers of pDCs that frequently cluster around apoptotic/necrotic foci, increased numbers of cytotoxic T cells, and substantial distortion of FDC meshworks.

Good prognosis for follicular lymphoma with estrogen receptor α-positive follicular dendritic cells.

Follicular lymphoma (FL) has a meshwork of follicular dendritic cells (FDCs). We previously demonstrated the presence of estrogen receptor alpha (ERα)+CD23+ FDCs in grades 1‐2 FL. The significance of FDCs as a prognostic factor in FL remains unknown. The current study aimed to compare clinicopathological features, including prognosis, between FL with and without ERα+ FDCs. This study evaluated the clinicopathological significance of ERα expression in 70 FL patients by immunostaining. The presence of ERα mRNA on FDCs from 5 FL patients was confirmed by CD21/ERα double staining (immunohistochemistry and in situ hybridization). We defined patients with frequent ERα expression as the ERαhigh group and those with infrequent ERα expression as the ERαlow group. Thirty‐two patients were assigned to the ERαhigh group (45.7%), and 38 patients were assigned to the ERαlow group (54.3%). Both overall survival (OS) and progression‐free survival (PFS) were significantly better in the ERαhigh group than in the ERαlow group (OS, log‐rank, P = .0465; PFS, log‐rank, P = .0336). Moreover, high ERα expression on FDCs was an independent prognostic factor for OS in both the univariate ([hazard ratio] HR, 0.163; P = .0260) and multivariate (HR, 0.050; P = .0188) analyses and for PFS in both the univariate (HR, 0.232; P = .0213) and multivariate (HR, 0.084; P = .0243) analyses. ERα mRNA expression was detected in CD21+ FDCs within the neoplastic follicles of FL patients. In conclusion, a neoplastic follicular microenvironment with ERα‐positive FDCs might affect the grade and presence of the follicular pattern of FL and improve patient prognosis.

Angioimmunoblastic T-cell lymphoma-like lymphadenopathy in mice transgenic for human RHOA with p.Gly17Val mutation

ABSTRACT A missense mutation in RHOA encoding p.Gly17 Val has been reported to occur frequently in angioimmunoblastic T-cell lymphoma (AITL). Here, we describe a murine model which expresses the human RHOA mutant gene product in a T-cell specific manner and develops AITL-like symptoms. Most transgenic mice feature with latency one or two enlarged lymph nodes characterized by aberrant lymph node architecture, extensive lymphocytic infiltration, extrafollicular meshwork of follicular dendritic cells (FDC) and arborized endothelial venules. Importantly, we provide evidence for expansion of PD-1+ follicular helper T (Tfh) cells which are the neoplastic cells of AITL. In addition, we saw proliferation of B-cells leading to hypergammaglobulinemia and the presence of dominant T cell clonal populations. Transplantation of lymph node cells to immunocompromised mice partly recreated lymphadenopathy after a long latency and with low penetrance suggesting that cells have undergone partial transformation to a premalignant state. Transcriptomic profiling revealed that the gene expression pattern within affected lymph nodes of the mice closely resembles that of AITL patients with the identical RHOA p.Gly17 Val mutation. The murine model should, therefore, be useful in dissecting pathogenesis of AITL at the molecular level particularly for the cases with the RHOA p.Gly17Val mutation.

Primary Dural Lymphoma Masquerading as a Meningioma: A Rare Clinical Entity

Abstract Primary dura mater–based lymphomas are extremely uncommon and when detected are often clinically and radiologically misidentified. As per literature search, they account for &lt;0.1% of all non-Hodgkin lymphomas; however, a precise incidence is unknown since only a few cases have been described in the literature. Here we report a case of a 64-year-old female who presented for evaluation of a newly diagnosed left tentorial tumor, diagnosed as “consistent with meningioma” on imaging studies with significant mass effect on the left occipital lobe and left cerebellum with effacement of the fourth ventricle. She had been experiencing disabling headaches, balance dysfunction, and reduced vision. On examination, the patient had right visual field defect with wide-based gait. No evidence of systemic lymphoma or clinically suspicious lymphadenopathy was documented. An intraoperative consultation revealed sheets of lymphocytes, rather highly concerning for lymphoma. H&amp;E sections showed dense fibroconnective tissue heavily infiltrated by mature small- to intermediate-sized lymphocytes with irregular nuclei and condensed chromatin without a discernible architecture. Only sparse and scattered larger lymphocytes were seen. Flow cytometry identified a subset of B cells with lambda-restricted immunophenotype expressing CD19+, CD20+, CD10+, CD5–, and CD23–. On tissue sections, Ki-67 showed an overall proliferation index of 10% to 20%. However, no residual follicular dendritic cell meshwork was detected by CD21 or CD23. PCR analysis detected clonal B-cell IgH and IgKappa gene rearrangements. A diagnosis of low-grade CD10-positive B-cell lymphoma (likely follicle center-cell origin) was made and the patient was discharged after 3 days of surgery for outpatient follow-up and treatment. In conclusion, low-grade dural-based lymphomas are extremely rare and often misdiagnosed as meningiomas clinically and radiologically. Additionally, it is important distinguish lymphomas of the dura mater, which are excluded from the definition of primary CNS lymphomas and may have a different clinical management and outcome.