Follicular Dendritic Cell Research Articles

T Cell-Derived Lymphotoxin Is Essential for the Anti-Herpes Simplex Virus 1 Humoral Immune Response.

B cell-derived lymphotoxin (LT) is required for the development of follicular dendritic cell clusters for the formation of primary and secondary lymphoid follicles, but the role of T cell-derived LT in antibody response has not been well demonstrated. We observed that lymphotoxin β-receptor (LTβR) signaling is essential for optimal humoral immune response and protection against an acute herpes simplex virus 1 (HSV-1) infection. Blocking the LTβR pathway caused poor maintenance of germinal center B (GC-B) cells and follicular helper T (Tfh) cells. Using bone marrow chimeric mice and adoptive transplantation, we determined that T cell-derived LT played an indispensable role in the humoral immune response to HSV-1. Upregulation of gamma interferon by the LTβR-Ig blockade impairs the sustainability of Tfh-like cells, leading to an impaired humoral immune response. Our findings have identified a novel role of T cell-derived LT in the humoral immune response against HSV-1 infection.IMPORTANCE Immunocompromised people are susceptible to HSV-1 infection and lethal recurrence, which could be inhibited by anti-HSV-1 humoral immune response in the host. This study sought to explore the role of T cell-derived LT in the anti-HSV-1 humoral immune response using LT-LTβR signaling-deficient mice and the LTβR-Ig blockade. The data indicate that the T cell-derived LT may play an essential role in sustaining Tfh-like cells and ensure Tfh-like cells' migration into primary or secondary follicles for further maturation. This study provides insights for vaccine development against infectious diseases.

Altered immune cell follicular dynamics in HIV infection following influenza vaccination.

HIV infection changes the lymph node (LN) tissue architecture, potentially impairing the immunologic response to antigenic challenge. The tissue-resident immune cell dynamics in virologically suppressed HIV+ patients on combination antiretroviral therapy (cART) are not clear. We obtained LN biopsies before and 10 to 14 days after trivalent seasonal influenza immunization from healthy controls (HCs) and HIV+ volunteers on cART to investigate CD4+ T follicular helper (Tfh) and B cell dynamics by flow cytometry and quantitative imaging analysis. Prior to vaccination, compared with those in HCs, HIV+ LNs exhibited an altered follicular architecture, but harbored higher numbers of Tfh cells and increased IgG+ follicular memory B cells. Moreover, Tfh cell numbers were dependent upon preservation of the follicular dendritic cell (FDC) network and were predictive of the magnitude of the vaccine-induced IgG responses. Interestingly, postvaccination LN samples in HIV+ participants had significantly (P = 0.0179) reduced Tfh cell numbers compared with prevaccination samples, without evidence for peripheral Tfh (pTfh) cell reduction. We conclude that influenza vaccination alters the cellularity of draining LNs of HIV+ persons in conjunction with development of antigen-specific humoral responses. The underlying mechanism of Tfh cell decline warrants further investigation, as it could bear implications for the rational design of HIV vaccines.

Clinicopathologic features and prognosis of mantle cell lymphoma: an analysis of 349 cases

Objective: To investigate clinicopathologic features and prognostic factors of mantle cell lymphoma(MCL). Methods: The clinical data of 349 MCL patients diagnosed at Beijing Friendship Hospital from January 2004 to January 2016 were retrospectively collected. Corresponding histological sections were reviewed. Additional studies included immunohistochemical staining using the MaxVision two-step method, IgH/CCND1 fusion gene detection by fluorescent in situ hybridization (FISH), and correlative statistical analysis. Results: Of 349 patients with MCL, the median patient age was 61 years (range: 25-83 years, M∶F=2.7∶1.0) and the age of 243 patients ranged from 51 to 70 years (69.6%). Those with B symptoms accounted for 22.4% (70/313). Most of the patients presented with superficial lymphadenopathy and the clinical stage Ⅲ-Ⅳ accounted for 76.1% (235/309). Extranodal involvement was seen in 47.9% (148/309), among which the gastrointestinal tract accounted for 31.8% (47/148) and splenic involvement accounted for 15.4% (47/305). Three hundred and nine (88.5%) cases were of classical type and 40 (11.5%) cases were of aggressive variant type, and all were composed of proliferating lymphoid cells. All the tumors were positive for CD20 and cyclin D1, and 98.6% (344/349) tumors were weakly positive or positive for CD5. FISH test was positive in 12 cases that were CD5 negative and with cyclin D1 partial expression.Two hundred and forty-three (69.6%) patients had a median follow-up of 26 months (range: 3-108 months). The 3- and 5-year overall survival rates for patients were 63.0% and 34.8%, respectively. Single factor analysis showed that age of >60 years, splenic involvement, aggressive variant type, incompletely overlapping type [Based on the degree of overlap ≥90% and <90% between the follicular dendritic cell (FDC) meshwork and tumor cells, the tumors were divided into the completely overlapped type and incompletely overlapped type] and Ki-67 index >40% had poor prognosis (P<0.05). Multiple factor Cox proportional risk regression analysis after removing the aggressive variant type showed that age, splenic involvement, the degree of overlap between the FDC meshwork and tumor cells and Ki-67 index were independent prognostic factors for overall survival rate of MCL patients (P<0.05). Conclusions: MCL is more commonly found among middle-aged and elderly men. Patient age, splenic involvement, degree of overlap between FDC meshwork and tumor cells and Ki-67 index are the independent prognostic indicators for MCL.

Effectiveness of rituximab-containing treatment regimens in idiopathic multicentric Castleman disease.

Human herpes virus type 8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disease often involving constitutional symptoms, cytopenias, and multiple organ system dysfunction. In China, the majority of MCD cases are HHV-8 negative. Given that siltuximab, the only FDA-approved treatment for iMCD is not available in China; rituximab- and cyclophosphamide-containing regimens are often used in the treatment of Chinese iMCD patients. To evaluate the efficacy of rituximab in this rare and heterogeneous disease, clinical and pathological data from 27 cases of iMCD were retrospectively analyzed from two large medical centers in China. The novel diagnostic criteria for iMCD were applied, and POEMS syndrome, IgG4-related diseases, and follicular dendritic cell sarcomas cases were excluded from analyses. Total response rate of rituximab- and cyclophosphamide-containing regimens was 55.5%, with 33.3% (9/27) of the cases reaching CR and 22.2% (6/27) PR. In the 14 cases of R-R iMCD, total response rate was only 42.9% (CR 14.3% [2/14], PR 28.6% [4/14]). The 5-year OS of these 27 iMCD cases was 81% (95% CI 64-98; 27 total patients, 4 events, 23 censored) after receiving these regimens, but the 5-year PFS was 43% (95% CI 19-66; 25 total patients, 11 events, 14 censored). Thus, rituximab-based regimens should be considered for the treatment of iMCD patients when siltuximab is not available and potentially in siltuximab-refractory cases.

Inflammatory Pseudotumor of the Spleen in a Patient with Idiopathic Thrombocytopenic Purpura

Inflammatory pseudotumor tumors (IPTs) of the spleen are uncommon lesions of uncertain pathogenesis. A definitive clinical diagnosis is challenging because radiological, as well as gross pathologic features may suggest a lymphoma, an inflammatory myofibroblastic tumor (IMT), or an IPT-like follicular dendritic cell tumor (IPT-FDC). Herein, we report a case of an IPT of the spleen in a 48-year-old woman who presented with idiopathic thrombocytopenic purpura (ITP) symptoms. The results of abdominal ultrasonography revealed the presence of a splenic mass that continued to enlarge after the recovery from ITP, leading to the suspicion of lymphoma. A splenectomy was performed for diagnostic and curative purposes. The lesion was a non-encapsulated yellowish mass (largest diameter: 4,4 cm). The presence of spindle cells expressing smooth muscle actin, vimentin, and focal CD68 admixed with polymorphous lymphoid infiltrate supported the IPT diagnosis. The negative expression of CD21, CD23, CD35, and ALK excluded inflammatory myofibroblastic and follicular dendritic cell tumors. Any evidence of the recurrence of either ITP or IPTs was not noted 60 months after the operation. The present case and the review revealed that splenic IPT tends to occur in middle-aged females and diagnosis is challenging due to the absence of specific symptoms or the characteristic hematological or radiological findings. Surgery is the most frequently performed treatment. Although multiple factors have been suggested in the etiology and pathogenesis, previous bleeding may also play a role in the presence of IPTs in patients with ITP. The rare occurrence of splenic IPT and the lack of diagnostic clinical signs and symptoms do not exclude their consideration in the differential diagnosis of spleen tumors, especially in patients with imaging features that cannot rule out malignancy.

Inflammatory Pseudotumor-Like Follicular Dendritic Cell Sarcoma of the Spleen: Computed Tomography Imaging Characteristics in 5 Patients.

The purpose of this study was to retrospectively review the computed tomography (CT) and clinicopathological characteristics of inflammatory pseudotumor (IPT)-like follicular dendritic cell sarcoma (FDCS) of the spleen in 5 patients. Clinical, pathologic, and CT imaging findings of 5 patients with IPT-like FDCS of the spleen were reviewed and analyzed. Computed tomography imaging and pathologic features were compared. Abdominal unenhanced CT revealed a well-defined hypodense mass in the spleen with complex internal architecture with focal necrosis and/or speckle-strip calcification. On postcontrast CT, slightly delayed enhancement was observed in 5 cases. Four patients had a normalized spleen. The fourth patient had lung metastasis. The fifth patient had 2 relatively small lesions as well as metastases to the spine. Computed tomography imaging features of IPT-like FDCS of the spleen are distinctly different from other hypovascular splenic neoplasm; however, the definitive diagnosis requires further confirmation with needle biopsy or surgery. Inflammatory pseudotumor-like FDCS of the spleen should be suggested by using the CT imaging features of the splenic mass with evidence of metastatic disease.

The Feasibility of Thoracoscopic Left Pneumonectomy.

In this study, we describe our experience with video-assisted thoracoscopic surgery (VATS) left pneumonectomy as a treatment for advanced malignant and benign diseases. Patients who underwent VATS left pneumonectomy in our clinic between October 2013 and August 2017 were retrospectively evaluated. VATS pneumonectomy was successfully completed in 46 patients. We reviewed and analyzed the characteristics of the patients in addition to intraoperative parameters, chest tube duration, length of hospital stay, morbidity, and mortality. A total of 46 patients underwent VATS left pneumonectomy. Of these, 43 patients had malignant tumors and 3 patients had destroyed lung. The histologic types were squamous cell carcinoma in 24 patients, adenocarcinoma in 11, large cell carcinoma in 2, sarcomatoid carcinoma in 1, follicular dendritic cell sarcoma in 1, and small cell carcinoma in 4. Primary lung cancers were classified as stage IA1 in 2 patients, IA2 in 2, IA3 in 1, IB in 3, IIA in 3, IIB in 11, IIIA in 18, and IIIB in 3. The mean operation time was 160.54 ± 43.44 minutes, and the mean blood loss was 401.09 ± 284.32 mL. There was no perioperative mortality and no secretion retention and bronchopleural fistula. Arrhythmia was found in three patients. Pneumonia was found in four patients. The median follow-up time in this cohort was 25 months. A total of 15 patients (34.8%) developed recurrent diseases, 12 developed distant or multiple metastasis, and 3 developed locoregional recurrence. VATS pneumonectomy is a safe, feasible treatment for complicated diseases that induces acceptable damage and has lower morbidity.

Eosinophil-rich Variant of Follicular Dendritic Sarcoma of Cervical Lymph Node: An Extremely Rare Entity

Follicular dendritic cell neoplasms are extremely rare. Information regarding the accurate treatment and prognosis is limited owing to their rarity; thus, this tumor encompasses a domain to be brought into focus. Clinical and pathological diagnoses warrant a high index of suspicion as this entity is not considered in routine clinical practice. Histopathologically it mimics various other neoplasms which lead to higher chances of misdiagnosis at initial evaluation. Use of follicular dendritic cell immunohistochemical markers CD 21 and CD 35 helps in rendering a definitive diagnosis.

Clinical and molecular characteristics of unicentric mediastinal Castleman disease.

Unicentric mediastinal Castleman disease (CD) is a rare condition, poorly characterized due to the small number of cases and the absence of genomic study. We analyzed clinical, radiological, histological and genomic patterns associated with mediastinal CD in a substantial case series.Methods: We retrospectively reviewed cases of unicentric mediastinal CD managed in 2 French thoracic surgery departments between 1988 and 2012. Clinical, radiological, surgical and pathological data were recorded. On available FFPE blocks we performed mutation screening by next-generation-sequencing, using AmpliSeq™ Cancer Hotspot v2 (Life Technologies) and immunohistochemistry (IHC) (AKT-mTOR pathway). Eleven patients were identified (mean age 41±15 years, sex-ratio 0.8, median follow-up 78 months). Surgical approach was thoracotomy (n=6), sternotomy (n=4), and VATS (n=1). Additional procedures included thymectomy in three cases, mediastinal lymphadenectomy in two cases, and bilobectomy in one case. One patient presented local relapse as a follicular dendritic cell sarcoma, leading to death 48 months after the first resection. Within 9 patients whose FFPE blocks were available, 2 mutations were found: VHL (p.F119L, 35%, n=1) and JAK3 (p.V718L, 53%, n=1). Phospho-AKT and phospho-mTOR stainings were negative in all cases, whereas phospho-S6RP staining was positive in eight cases, mainly in interfollicular cell cytoplasm. From this series of patients with unicentric mediastinal CD, we observed 2 cases of potential driver mutations and 8 cases of phospho-S6RP activation not related to AKT-mTOR. Larger studies are required to decipher more precisely the molecular abnormalities and potential therapeutic targets underlying this uncommon condition.

Inflammatory pseudotumor-like follicular dendritic cell tumors misdiagnosed as liver cancer: a case report

Inflammatory pseudotumor-like follicular dendritic cell tumors misdiagnosed as liver cancer: a case report

Next-generation sequencing of idiopathic multicentric and unicentric Castleman disease and follicular dendritic cell sarcomas

AbstractCastleman disease (CD) is a rare lymphoproliferative disorder subclassified as unicentric CD (UCD) or multicentric CD (MCD) based on clinical features and the distribution of enlarged lymph nodes with characteristic histopathology. MCD can be further subtyped based on human herpes virus 8 (HHV8) infection into HHV8-associated MCD, HHV8−/idiopathic MCD (iMCD), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin change (POEMS)–associated MCD. In a subset of cases of UCD, an associated follicular dendritic cell sarcoma (FDCS) may be seen. Although numerous reports of the clinical and histologic features of UCD, MCD, and FDCS exist, an understanding of the genetic and epigenetic landscape of these rare diseases is lacking. Given this paucity of knowledge, we analyzed 15 cases of UCD and 3 cases of iMCD by targeted next-generation sequencing (NGS; 405 genes) and 3 cases of FDCS associated with UCD hyaline vascular variant (UCD-HVV) by whole-exome sequencing. Common amplifications of ETS1, PTPN6, and TGFBR2 were seen in 1 iMCD and 1 UCD case; the iMCD case also had a somatic DNMT3A L295Q mutation. This iMCD patient also showed clinicopathologic features consistent with a specific subtype known as Castleman-Kojima disease (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly [TAFRO] clinical subtype). Additionally, 1 case of UCD-HVV showed amplification of the cluster of histone genes on chromosome 6p. FDCS associated with UCD-HVV showed mutations and copy number changes in known oncogenes, tumor suppressors, and chromatin structural-remodeling proteins.

Reduced lymphotoxin-beta production by tumour cells is associated with loss of follicular dendritic cell phenotype and diffuse growth in follicular lymphoma.

Cytokine production is essential for follicular dendritic cell (FDC) maintenance and organization of germinal centres. In follicular lymphoma, FDCs are often disarrayed and may lack antigens indicative of terminal differentiation. We investigated the in situ distribution of cells producing lymphotoxin‐beta (LTB), lymphotoxin‐alpha (LTA), and tumour necrosis factor‐alpha (TNFA) transcripts in human reactive lymph nodes and in follicular lymphomas with follicular or diffuse growth pattern. LTB was the cytokine most abundantly produced in germinal centres. LTB was present in nearly 90% of germinal centre cells whereas LTA and TNFA were detected in 30 and 50%, respectively. Moreover, the amount of LTB expressed in reactive germinal centre cells was 80‐fold higher than that of LTA and 20‐fold higher than that of TNFA. LTB‐positive cells were more numerous in the germinal centre dark zone, whereas expression of the FDC proteins CD21, CD23, VCAM, and CXCL13 was more intense in the light zone. Tumour cells of follicular lymphomas produced less LTB than reactive germinal centre cells. The results of the in situ study were confirmed by RT‐PCR; LTB was significantly more abundant in reactive lymph nodes than in follicular lymphoma, with the lowest values detected in predominantly diffuse follicular lymphoma. In neoplastic follicles, low production of LTB by tumour B cells was associated with weaker expression of CD21+/CD23+ by FDCs. Our findings detail for the first time the distribution of LTA‐, LTB‐, and TNFA‐producing cells in human reactive germinal centres and in follicular lymphoma. They suggest the possibility that impaired tumour‐cell LTB production may represent a determinant of FDC phenotype loss and for defective follicular organization in follicular lymphoma.

Prolonged follicular helper T cell responses in ME7 scrapie-infected mice

ABSTRACTWe previously reported that mice intracerebrally inoculated with the mouse-adapted scrapie strain ME7 have markedly diminished T zones in the spleen due to the decreased expression of CCL19 and CCL21. In addition, follicular dendritic cell networks in germinal centers were larger in ME7-infected spleens compared to uninfected spleens. As an extension of that study, we set out to determine how ME7 infection affects spleen structure and follicular helper T (Tfh) cell responses in mice. For this study, mice were intraperitoneally inoculated with brain homogenate of the ME7 inoculum and spleens were analyzed 50, 130, and 200 days after inoculation and compared with those from uninfected mice. The result showed that ME7- infected mice had increased Tfh cell responses which were maintained until end-stage prion disease. Although CD4 T cells decreased in white pulps, they increased in germinal centers, and expressed higher levels of the Tfh-related genes, such as Bcl6, Il21, Cxcr5, Icos, and Pdcd1. In addition, ME7-infected spleens had increased numbers of CD4 memory T cells. These data indicate that although ME7 infection led to impaired splenic white pulp structure, CD4 memory T cells were increased and Tfh cell responses were required and prolonged to provide help for the replication and accumulation of pathogenic prion protein in germinal centers.

Follicular dendritic cell sarcoma: an unsual entity

Folicular dendritic cell sarcoma is an extremelly rare lymphoid neoplasm. Lymph nodes are predominantly affected, but occasionallu extranodal compromise is seen. Definitive diagnosis requires confirmation by inmunohistochemistry. The clinical features and management are not well know. We present the case follicular dendritic cell sarcoma with axilary affectation.

Tumor-targeting Salmonella typhimurium A1-R is a highly effective general therapeutic for undifferentiated soft tissue sarcoma patient-derived orthotopic xenograft nude-mouse models

Undifferentiated soft tissue sarcoma (USTS) is a recalcitrant and heterogeneous subgroup of soft tissue sarcoma with high risk of metastasis and recurrence. Due to heterogeneity of USTS, there is no reliably effective first-line therapy. We have generated tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R), which previously showed strong efficacy on single patient-derived orthotopic xenograft (PDOX) models of Ewing's sarcoma and follicular dendritic cell sarcoma. In the present study, tumor resected from 4 patients with a biopsy-proven USTS (2 undifferentiated pleomorphic sarcoma [UPS], 1 undifferentiated sarcoma not otherwise specified [NOS] and 1 undifferentiated spindle cell sarcoma [USS]) were grown orthotopically in the biceps femoris muscle of mice to establish PDOX models. One USS model and one UPS model were doxorubicin (DOX) resistant. One UPS and the NOS model were partially sensitive to DOX. DOX is first-line therapy for these diseases. S. typhimurium A1-R arrested tumor growth all 4 models. In addition to arresting tumor growth in each case, S. typhimurium A1-R was significantly more efficacious than DOX in each case, thereby surpassing first-line therapy. These results suggest that S. typhimurium A1-R can be a general therapeutic for USTS and possibly sarcoma in general.

The degree of overlap between the follicular dendritic cell meshwork and tumor cells in mantle cell lymphoma is associated with prognosis

This study concerning mantle cell lymphoma (MCL) investigated retrospectively an association between patient prognosis and the percentage of the total number of lymphoma cells found in the follicular dendritic cell (FDC) meshwork, that is, the degree of overlap of lymphoma cells. Two hundred and nine MCL patients were apportioned to grades I–III, in which the CD21-positive FDC meshwork covered ≤50%, 51%–89%, and ≥90% of the tumor area, respectively. Significant differences among the grades (all, P < 0.01) were found in the following: duration of disease (from onset of clinical manifestation to diagnosis); clinical staging; extranodal involvement (non-lymphoid organs); histological subtype; and Ki-67 proliferation index (PI). After removing the aggressive variants, the overall survival rates of grade I (n = 92) and II (n = 57) patients were similar. The overall survival rates of grade III (n = 46) patients differed from that of grade I + II patients (P < 0.01). The grades negatively correlated with the Ki-67 PI value (r = −0.234, P = 0.001). At each grade the OSR of patients with Ki-67 PI ≤30% was similar to that of patients with Ki-67 >30%. In the Ki-67 PI ≤30% group, the OSRs of the patients differed significantly among the grades. In the Ki-67 >30% group the OSRs of the grades were similar. The results of multivariate Cox regression analysis showed that the degree of overlap, age and Ki-67 PI was the independent prognostic factors of the OSRs of MCL patients. Our data suggests that MCL patients in whom there was a high degree of overlap between the FDC meshwork and tumor area have a better clinical prognosis. The degree of overlap correlates well with the Ki-67 PI, which can be used to predict the prognosis of patients.

Clinicopathologic features and prognosis of inflammatory pseudotumor-like follicular dendritic cell sarcomas in liver and spleen: an analysis of seven cases

Objective: To investigate the clinicopathological features and prognostic parameters of the inflammatory pseudotumor-like follicular dendritic cell sarcoma (IPT-like FDCS) of liver and spleen. Methods: Ninteen cases of inflammatory pseudotumor (IPT) and 5 cases of IPT-like FDCS of the liver and spleen were collected at the First Affiliated Hospital, Army Medical University from 2006 to 2016. HE sections, immunohistochemical staining, and Epstein-Barr virus encoded nuclear RNA (EBER) in situ hybridization were reviewed along with a summary of the literature. Results: Among the previously diagnosed 19 cases of IPT of the liver and spleen, 2 cases were misdiagnosed (the ratio of 2/19). Among 7 new cases including 3 males and 4 females, 3 cases involved the liver and 4 cases involved the spleen. The age range was 37-64 years (mean 53 years). The maximum tumor diameter ranged from 3.0 to 11.0 cm (mean 6.5 cm). Surgical resections were performed in all patients with follow-up time ranging from 3 to 84 months.All patients were disease-free.7 new cases were all positive for EBER, and showed the expression of at least one of the FDC markers, including CD21, CD23, and CD35. The rest of 17 cases of IPT were all negative for EBER and essentially negative for FDC markers, but were all positive for SMA. Conclusions: IPT-like FDCS of the liver and spleen is a rare low-grade malignant tumor morphologically mimicking inflammatory pseudotumor, and is easy to be misdiagnosis due to under-recognition. EBER in situ hybridization and FDC markers are indispensable for confirming the diagnosis.

Clusterin in Neuroendocrine Epithelial Neoplasms: Absence of Expression in a Well-differentiated Tumor Suggests a Jejunoileal Origin.

Clusterin, a widely expressed, tissue-specific glycoprotein, is a diagnostic marker of several tumor types, including anaplastic large cell lymphoma, follicular dendritic cell sarcoma, and tenosynovial giant cell tumor. A recent study has suggested it is highly expressed by well-differentiated neuroendocrine tumors (NET) arising at most anatomic sites, with the exception of jejunoileal tumors, and that it is similarly not expressed by poorly differentiated neuroendocrine carcinomas (NEC). We sought to validate this result in a large cohort of NETs and NECs. Clusterin immunohistochemistry was performed on tissue microarrays of 255 NETs [45 lung, 4 stomach, 8 duodenum, 75 pancreas (62 primary, 13 metastatic), 107 jejunoileum (69 primary, 38 metastatic), 16 appendix] and 88 NECs (43 visceral, 45 Merkel cell). Extent (%) and intensity (0, 1+, 2+, 3+) of staining were assessed and an H-score (extent x intensity) calculated. An average H-score >5 was considered positive. Clusterin expression was noted in 82.4% of 148 nonjejunoileal NETs (average H-score 183) and only 8.4% of 107 jejunoileal NETs (average H-score, 31), as well as 19.3% of NECs (average H-score, 36). Clusterin is frequently, strongly expressed by NETs of diverse anatomic sites, with the exception of jejunoileal tumors, in which it is only rarely, weakly expressed. It is occasionally, weakly expressed by NECs. Most metastatic NETs of occult origin arise in the pancreas or the jejunoileum. For cases in which an initial site of origin immunopanel (eg, islet 1, PAX6, CDX2) is ambiguous, addition of clusterin may be diagnostically useful, with absence of expression suggesting a jejunoileal origin.

Intraabdominal follicular dendritic cell sarcoma: a report of three cases and review of the literature.

Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that originates from follicular dendritic cells in lymphoid follicles. FDCS has been increasingly reported in recent years. However, data on FDCS are mostly based on single case reports or case series and its natural history and standard treatment are not clear. To increase the understanding of this rare disease, we report our experience of three cases of FDCS with an analysis of the morphological and immunophenotypic characteristics, clinical course, treatment options and response to treatment. In addition, we reviewed the literature on FDCS.

Expression of enhancer of zeste homolog 2 (EZH2) protein in histiocytic and dendritic cell neoplasms with evidence for p-ERK1/2-related, but not MYC- or p-STAT3-related cell signaling.

EZH2 is an important enzymatic subunit of the epigenetic regulator polycomb repressive complex 2 (PRC2), which controls gene silencing through post-translational modification, and is overexpressed in various carcinomas and hematopoietic neoplasms. We found that the majority of cases of histiocytic and dendritic cell neoplasms, including histiocytic sarcoma, follicular dendritic cell sarcoma, Langerhans cell histiocytosis, and interdigitating dendritic cell sarcoma, show strong EZH2 expression by immunohistochemical staining, in contrast to benign histiocytic lesions and normal cellular counterparts, which did not show EZH2 expression, suggesting that this molecule may function as an oncogenic protein in these neoplasms. We correlated EZH2 expression with that of p-ERK1/2, MYC, and p-STAT3, potential regulators of EZH2, and found that 60-80% of these cases showed strong p-ERK1/2 expression, and only a minority of cases showed positivity for MYC or p-STAT3 in neoplastic cells. In cases of follicular dendritic cell sarcoma, Langerhans cell histiocytosis, histiocytic sarcoma, and interdigitating dendritic cell sarcoma with strong EZH2 expression, 90%, 89%, 70%, and 100% of cases showed co-expression of p-ERK1/2 with EZH2, respectively, while only a small percentage of these cases showed MYC or p-STAT3 co-expression with EZH2 (≤30%). These findings suggest that the p-ERK1/2 signaling cascade, but not the p-STAT3 and MYC signaling cascades, may regulate EZH2 expression in histiocytic and dendritic cell neoplasms, and that EZH2 and the p-ERK1/2 signaling cascade could serve as therapeutic targets for the treatment of these neoplasms. Interestingly, only a minority of cases of blastic plasmacytoid dendritic cell neoplasm exhibited high EZH2 expression, and only a minority of these cases showed p-ERK1/2 co-expression, suggesting that alternative mechanisms may contribute to tumorigenesis in this aggressive neoplasm.