Cytokeratin-positive fibroblastic reticular cell tumor with follicular dendritic cell features: a case report and review of the literature.

Fibroblastic reticular cell (FRC) neoplasms, which are one of the histiocyte tumor types, are very rare. Here we report a cytokeratin (CK)-positive FRC neoplasm having features of follicular dendritic cells in a 54-year-old woman with right axillary lymph node swelling. The resected lymph node showed multiple nodular aggregations simulating and replacing normal follicles. The tumor cells had a uniform, large and oval to polygonal shape, abundant cytoplasm, and various sizes of nuclei with central eosinophilic nucleoli and coarse nuclear chromatin. They were positive for CK AE1/AE3+CAM5.2, CK7, tenascin C, l-caldesomone, and CD21, weakly positive for S100, and negative for CD1a. Ultrastructurally, the tumor cells had long interdigitating microvillus-like cell processes and oval to elongated vesicular nuclei. In addition, the intercellular spaces contained accumulations of collagen, and some tumor cells had desmosomal-like junctions. These findings suggest that the present case is a CK-positive FRC tumor with follicular dendritic cell features.

Clinicopathologic characteristics of inflammatory pseudotumor-like follicular dendritic cell sarcoma.

Inflammatory pseudotumor (IPT)-like follicular dendritic cell (FDC) sarcoma is a recently described rare tumor and considered a unique entity, with different histologic appearances and behavior from those of the classical FDC sarcoma. This study analyzed the clinical and pathological findings of two such cases that the authors encountered and 36 previously reported cases identified in the literature. Assessment of all 38 cases showed a slight female predominance (2.2:1) with a median age of 56.5 years. Seventeen patients complained of abdominal discomfort or pain, while fifteen patients had no clinical symptom. Almost all cases occurred in liver (n=20) or spleen (n=17). Except in one case, all patients underwent surgical resection of the tumor alone. Histologic features showed a mixture of chronic inflammatory cells and variable amounts of spindle cells with vesicular nuclei and distinct nucleoli. The tumor cells expressed conventional FDC markers such as CD21 (75%), CD35 (92%), CD23 (62%), clusterin (75%), and CNA.42 (100%). EBV was detected in thirty-five cases (92.1%) by Epstein-Barr virus (EBV)-encoded RNA in situ hybridization, and EBV-latent membrane protein-1 was expressed in 90% of the cases. With a median follow-up of 21 months, 29 patients (85.3%) were alive and well, 4 (11.8%) were alive with disease, one patient (2.9%) died of disease. Only four patients with hepatic tumors underwent recurrence or metastasis after initial treatment. Epstein-Barr virus is thought to play a role in the development of the tumor; however, the pathogenesis of the disease and the origin of tumor cells remain unclear.

Primary cutaneous follicular helper T-cell lymphoma treated with allogeneic bone marrow transplantation: immunohistochemical comparison with angioimmunoblastic T-cell lymphoma.

Primary cutaneous follicular helper T (TFH)-cell lymphoma has recently been proposed, and is characterized by proliferation of malignant T cells expressing TFH-cell markers, such as CXCL13, accompanied by numerous reactive B cells. We report here a patient whose skin histology showed massive infiltration of both T and B cells, with a proliferation of arborizing high endothelial venules and follicular dendritic cells. Infiltrating T cells were positive for CXCL13, programmed death (PD)-1, inducible T-cell co-stimulator, and BCL-6. Southern blot analyses using DNA from the skin revealed monoclonality of both T and B cells. The patient had marked resistance to treatments, and complete remission was achieved only after allogeneic stem cell transplantation. The present case showed overlapping features with angio-immunoblastic T-cell lymphoma (AITL), although systemic symptoms were not observed. Further study is needed to define the criteria of this provisional entity, representing the cutaneous counterpart of the nodal follicular peripheral T-cell lymphoma or AITL.

Immunohistochemical analysis for CD21, CD35, Caldesmon and S100 protein on dendritic cells types in oral lymphomas

OBJECTIVE: Follicular dendritic cells (FDCs) and interdigitating dendritic cells (IDCs) are dendritic cells found in lymphoid follicles, reactive follicles and in lymphomas. The goal of this study was to evaluate the presence and distribution of FDCs and IDCs in oral lymphomas. MATERIAL AND METHODS: Immunohistochemistry reactions were applied to 50 oral lymphomas using the antibodies anti-CD21, anti-CD35 and anti-caldesmon to FDCs, and anti-S100 protein to IDCs. Caldesmon+/FDCs and S100+/IDCs were quantified in Imagelab® software. RESULTS: FDCs revealed by CD21 and CD35 were positively stained in two cases of diffuse large B-cell lymphoma, one MALT lymphoma, and in one case of mantle cell lymphoma. FDCs were immunopositive to caldesmon in all cases, as well as IDCs to S100 protein. Burkitt lymphoma presented a lower amount of caldesmon+/FDCs and S100+/IDCs than diffuse large B-cell lymphoma and plasmablastic lymphoma of the oral mucosa type. CONCLUSIONS: The microenvironment determined by neoplastic lymphoid cells in oral lymphomas is responsible by the development and expression of dendritic cells types.

Immunohistochemical analysis for CD21, CD35, Caldesmon and S100 protein on dendritic cells types in oral lymphomas.

OBJECTIVE: Follicular dendritic cells (FDCs) and interdigitating dendritic cells (IDCs) are dendritic cells found in lymphoid follicles, reactive follicles and in lymphomas. The goal of this study was to evaluate the presence and distribution of FDCs and IDCs in oral lymphomas. MATERIAL AND METHODS: Immunohistochemistry reactions were applied to 50 oral lymphomas using the antibodies anti-CD21, anti-CD35 and anti-caldesmon to FDCs, and anti-S100 protein to IDCs. Caldesmon+/FDCs and S100+/IDCs were quantified in Imagelab software. RESULTS: FDCs revealed by CD21 and CD35 were positively stained in two cases of diffuse large B-cell lymphoma, one MALT lymphoma, and in one case of mantle cell lymphoma. FDCs were immunopositive to caldesmon in all cases, as well as IDCs to S100 protein. Burkitt lymphoma presented a lower amount of caldesmon+/FDCs and S100+/IDCs than diffuse large B-cell lymphoma and plasmablastic lymphoma of the oral mucosa type. CONCLUSIONS: The microenvironment determined by neoplastic lymphoid cells in oral lymphomas is responsible by the development and expression of dendritic cells types.

Hyperplastic lymphoid tissue in HIV/AIDS: an electron microscopic study.

The purpose of this study was to characterize the ultrastructure of lymphoid tissue from HIV/AIDS patients and to evaluate it as a reservoir and source of HIV. HIV has been demonstrated in lymph nodes and tonsils and adenoids, by immunohistochemistry (IHC), in situ hybridization (ISH), and transmission electron microscopy (TEM), to be associated with germinal center (GC) follicular dendritic cells (FDC). The presence of HIV in the larger gastrointestinal tract-associated lymphoid tissue (GALT) has been much less studied. Whether FDC themselves are productively infected by HIV in any of the lymphoid sites is controversial. Lymph nodes, tonsils, and gastrointestinal biopsies were fixed in neutral buffered glutaraldehyde and prepared for TEM. Mature HIV particles were abundant in GC of hyperplastic lymph nodes, tonsils, and the GALT. They were enmeshed within an electron-dense matrix associated with an all-encompassing branching FDC network of processes. HIV particles were seen budding from both FDC and lymphocytes. The greatest numbers of particles were seen in hyperplastic lymphoid tissue from untreated individuals and in lymph nodes co-infected with opportunistic organisms, such as Mycobacterium avium complex. In addition to HIV, unidentifiable "particles" of varying sizes, possibly including other viruses, were regularly seen in association with FDC. Ultrastructural study graphically demonstrated the abundance of HIV particles associated with the complex FDC network of hyperplastic lymph nodes, tonsils, and GALT. HIV was shown to productively infect FDC, as well as lymphocytes.

Dendritic cell neoplasms: an overview.

Dendritic cell neoplasms are rare tumors that are being recognized with increasing frequency. They were previously classified as lymphomas, sarcomas, or histiocytic neoplasms. The World Health Organization (WHO) classifies dendritic cell neoplasms into five groups: Langerhans' cell histiocytosis, Langerhans' cell sarcoma, Interdigitating dendritic cell sarcoma/tumor, Follicular dendritic cell sarcoma/tumor, and Dendritic cell sarcoma, not specified otherwise (Jaffe, World Health Organization classification of tumors 2001; 273-289). Recently, Pileri et al. provided a comprehensive immunohistochemical classification of histiocytic and dendritic cell tumors (Pileri et al., Histopathology 2002;59:161-167). In this article, a concise overview regarding the pathological, clinical, and therapeutic aspects of follicular dendritic, interdigitating dendritic, and Langerhans' cell tumors is presented.

Follicular dendritic cell tumor as an unknown primary tumor.

A 70-year-old Japanese man presented to our hospital with a 1-month history of progressive general fatigue and anorexia. A physical examination revealed severe anemic condition, mild persistent splenomegaly, and no palpable surface lymph nodes. He had pleural effusion and ascites, though no malignant cells were detected in the effusion. He eventually died without any diagnosis of his disease. Immunohistochemical staining of his tumor after autopsy showed atypical cells that were negative for epithelial membrane antigen (EMA), keratin (AE1/3), keratin-20, vimentin, factor VIII, leukocyte common antigen (LCA/T200; CD45), myeloperoxidase (MPO), terminal deoxynucleotidyl transferase (TdT), lysozyme, CD1a, CD3, CD4, CD10, CD15, CD20 (L26), CD21, CD23, CD34, CD43, CD56, CD68, CD79a, CD138, and EBER-1 in situ. Only a few scattered cells expressed CD30, but they showed no staining for anaplastic large-cell lymphoma kinase (ALK). A few scattered cells expressed S-100 antigen and the majority of cells dominantly expressed dendritic cell-associated antigens (CD35, FDC, Ki-M1p). In conclusion, we found this unknown primary tumor to be consistent with a follicular dendritic cell tumor with anaplastic features.

Mediastinal follicular dendritic cell sarcoma involving bone marrow: a case report and review of the literature.

We report a rare case of mediastinal follicular dendritic cell (FDC) sarcoma involving the bone marrow. The patient, a 46-year-old woman, had a clinically aggressive tumor in the anterior mediastinum that was initially diagnosed as a diffuse B-cell lymphoma. She received chemotherapy but showed no significant improvement. One year later, the patient presented at our institution with pelvic bone metastases. Biopsy specimens of the sacrum lesion and bone marrow were obtained. The diagnosis of FDC sarcoma was made based on histological examination and immunohistochemical findings, including strong positive staining of tumor cells for CD21, CD23, clusterin, and epidermal growth factor receptor (EGFR) and negative staining for CD20, CD30, CD45, CD1a, S-100, vimentin, and keratin cocktail. Histological examination and immunohistochemical studies of a previous biopsy of the mediastinal mass confirmed the diagnosis of mediastinal FDC sarcoma. The patient was treated with an appropriate chemotherapy regimen; 1 month later, follow-up bone marrow biopsy revealed no tumor cells. Although FDC sarcoma is considered a low-grade tumor, the tumor in the present case not only developed at an unusual location with bone metastasis but also involved bone marrow. To our knowledge, this is the first such case ever reported. This case also highlights the utility of EGFR as an immunohistochemical marker of dendritic cell tumors that could be used as a diagnostic tool and guide for choosing appropriate chemotherapy regimens.

Peripheral T-cell lymphoma with extensive dendritic cell network mimicking follicular dendritic cell tumor: a case report with pathologic, immunophenotypic, and molecular findings.

Peripheral T-cell lymphoma (PTCL) with a nodular pattern of growth is uncommon and may be misdiagnosed initially as a B-cell lymphoma or reactive process. We report a case of a rapidly growing PTCL with a distinctly nodular pattern in an axillary lymph node from an 89-year-old man. Immunohistochemical stains for CD21, CD23, and CD35 highlighted an extensive dendritic cell network that imparted the nodular appearance and, in addition, was associated intimately with the neoplastic cells. The neoplastic cells otherwise had an immunophenotype similar to previously reported cases of PTCL with a nodular pattern and germinal center origin (CD3+, CD4+, CD5+, bcl-6+, CD31+, subset CD10+, subset CXCL13+, and subset CD79a+). Molecular studies confirm a clonal T-cell receptor g gene rearrangement. This case emphasizes unusual morphologic features in a PTCL that may be mistaken for follicular lymphoma or a tumor of follicular dendritic cell origin.

Follicular dendritic cell sarcoma mimicking giant cell carcinoma of the pancreas.

Extranodal follicular dendritic cell (FDC) tumors are rare. Recognition of the morphological spectrum of FDC tumors is important to clinical diagnosis. Herein is presented a case of pancreatic FDC sarcoma with unusual clinicopathological features. A 64-year-old male patient presented with weight loss, poor appetite, abdominal fullness, mild anemia and mild peripheral eosinophilia. Histologically, the tumor was composed of both epithelioid and spindle cells with abundant intracytoplasmic hyaline globules. These tumor cells were positive for CD21, CD23, CD35, S-100 protein, fascin and clusterin. Both epithelioid and spindle tumor cells independently colonized the liver and formed two tumor nodules 18 months after the initial resection. Notably, the two hepatic metastases additionally acquired patchy expression of human leukocyte antigen-DR. The epithelioid FDC in one of the hepatic lesions transformed into numerous bizarre giant cells, which could easily be confused with a metastatic giant cell carcinoma from the pancreas. FDC tumor should therefore be included in the differential diagnoses when dealing with a giant cell tumor.

Clusterin expression in follicular dendritic cells associated with prion protein accumulation.

Peripheral accumulation of abnormal prion protein (PrP) in variant Creutzfeldt-Jakob disease and some animal models of transmissible spongiform encephalopathies (TSEs) may occur in the lymphoreticular system. Within the lymphoid tissues, abnormal PrP accumulation occurs on follicular dendritic cells (FDCs). Clusterin (apolipoprotein J) has been recognized as one of the molecules associated with PrP in TSEs, and clusterin expression is increased in the central nervous system where abnormal PrP deposition has occurred. We therefore examined peripheral clusterin expression in the context of PrP accumulation on FDCs in a range of human and experimental TSEs. PrP was detected immunohistochemically on tissue sections using a novel highly sensitive method involving detergent autoclaving pretreatment. A dendritic network pattern of clusterin immunoreactivity in lymphoid follicles was observed in association with the abnormal PrP on FDCs. The increased clusterin immunoreactivity appeared to correlate with the extent of PrP deposition, irrespective of the pathogen strains, host mouse strains or various immune modifications. The observed co-localization and correlative expression of these proteins suggested that clusterin might be directly associated with abnormal PrP. Indeed, clusterin immunoreactivity in association with PrP was retained after FDC depletion. Together these data suggest that clusterin may act as a chaperone-like molecule for PrP and play an important role in TSE pathogenesis.

Multispectral imaging of clinically relevant cellular targets in tonsil and lymphoid tissue using semiconductor quantum dots.

Determination of the expression and spatial distribution of molecular epitopes, or antigens, in patient tissue specimens has substantially improved the pathologist's ability to classify disease processes. Certain disease pathophysiologies are marked by characteristic increased or decreased expression of developmentally controlled antigens, defined as Cluster of Differentiation markers, that currently form the foundation for understanding lymphoid malignancies. While chromogens and organic fluorophores have been utilitized for some time in immunohistochemical analyses, developments in synthetic, inorganic fluorophore semiconductors, namely quantum dots, offer a versatile alternative reporter system. Quantum dots are stable fluorophores, are resistant to photobleaching, and are attributed with wide excitation ranges and narrow emission spectra. To date, routinely processed, formalin-fixed tissues have only been probed with two quantum dot reporters simultaneously. In the present study, streptavidin-conjugated quantum dots with distinct emission spectra were tested for their utility in identifying a variety of differentially expressed antigens (surface, cytoplasmic, and nuclear). Slides were analyzed using confocal laser scanning microscopy, which enabled with a single excitation wavelength (488 nm argon laser) the detection of up to seven signals (streptavidin-conjugated quantum dots 525, 565, 585, 605, 655, 705 and 805 nm) plus the detection of 4'6-DiAmidino-2-PhenylIndole with an infra-red laser tuned to 760 nm for two photon excitation. Each of these signals was specific for the intended morphologic immunohistochemical target. In addition, five of the seven streptavidin-conjugated quantum dots tested (not streptavidin-conjugated quantum dots 585 or 805 nm) were used on the same tissue section and could be analyzed simultaneously on routinely processed formalin-fixed, paraffin-embedded sections. Application of this multiplexing method will enable investigators to explore the clinically relevant multidimensional cellular interactions that underlie diseases, simultaneously.

Hepatic follicular dendritic cell sarcoma without Epstein-Barr virus expression.

Follicular dendritic cell sarcoma of the liver is an uncommon pathologic entity, and only 5 cases have been reported previously. Herein, we report the first case, to our knowledge, of hepatic follicular dendritic cell sarcoma without evidence of Epstein-Barr virus infection. The patient is an elderly man who was found to have an incidental liver mass and then developed weight loss and fever. The diagnosis was based on the typical morphologic appearance of spindle cell proliferation associated with a brisk lymphoplasmacytic infiltrate and strong immunoreactivity to CD21 and CD35. Based on our experience and a review of the published reports, we summarize the clinical and pathologic features of hepatic follicular dendritic cell sarcoma and its surgical management.

Lymphotoxin-beta receptor-dependent genes in lymph node and follicular dendritic cell transcriptomes.

Affinity maturation and Ab class switches occur in lymphoid germinal centers (GCs), in which differentiation and maintenance depend on lymphotoxin (LT) signaling and include differentiation of follicular dendritic cells (FDCs). The events leading to FDC and GC maturation are poorly defined. Using several approaches of functional genomics, we enumerated transcripts affected in mice by suppressing LT beta receptor (LTbetaR) signaling and/or overrepresented in FDC-enriched GC isolates. Protein expression analysis of 3 of 12 genes both enriched in FDCs and down-regulated by LTbetaR signaling suppression validated them as FDC markers. Functional analysis of one of these three, clusterin, suggests a role as an FDC-derived trophic factor for GC B cells. Hence, the set of genes presented in this study includes markers emanating from LTbetaR signaling and transcripts relevant to GC and FDC function.

Fine-needle aspiration cytology of a liver metastasis of follicular dendritic cell sarcoma.

Follicular dendritic cell sarcoma (FDCS) is an uncommon neoplasm derived from FDCs in lymphoid tissue. Metastatic FDCS to the liver is rare. We present a case of a 65-yr-old woman who was referred to our institution 1 mo after splenectomy for FDCS of the spleen. An abdominal CT scan revealed a 2.0-cm liver lesion, which led to fine-needle aspiration (FNA) biopsy. Smears of the aspiration obtained were hypercellular showing a pleomorphic population of large oval to spindle-shaped tumor cells against a background of small mature lymphocytes, plasma cells, and necrotic debris. Tumor cells were arranged singly, in syncytial or fascicular patterns, and had a moderate amount of cytoplasm and indistinct cell borders. Nuclei had irregular nuclear membranes, finely granular to vesicular chromatin, and prominent nucleoli. Multinucleated and binucleated cells resembling Reed-Sternberg cells were noted occasionally. Mitotic figures, including atypical forms, were frequently identified. The diagnosis of "pleomorphic malignant spindle-cell neoplasm consistent with metastatic FDCS" was rendered and later confirmed by histological review and immunohistochemical staining of the subsequent liver resection specimen. Although cytological features of FDCS are characteristic, they are overlapping with those of many other tumors. We review the literature on this entity with emphasis on FNA cytomorphology, differential diagnosis, and immunohistochemical findings.

A survey of clusterin and fascin expression in sarcomas and spindle cell neoplasms: strong clusterin immunostaining is highly specific for follicular dendritic cell tumor.

Clusterin, a glycoprotein implicated in many cellular functions including apoptosis, has recently been shown to be strongly expressed in follicular dendritic cell tumors, and to be absent or only weakly expressed in other dendritic cell tumors. Fascin has also been investigated as a potential marker of dendritic cell neoplasms. We evaluated staining for antibodies directed against these two antigens in 202 spindle cell tumors, including cases of follicular dendritic cell tumor (n=14), interdigitating dendritic cell tumor (n=7), leiomyosarcoma (n=17), inflammatory myofibroblastic tumor (n=13), inflammatory pseudotumor (n=2), spindle cell thymoma (n=17), synovial sarcoma (n=11), fibrosarcoma (n=14), liposarcoma (n=27), gastrointestinal stromal tumor (n=13), malignant fibrous histiocytoma (n=18), angiomatoid fibrous histiocytoma (n=4), angiosarcoma (n=10), malignant peripheral nerve sheath tumor (n=8), malignant melanoma (n=16), and spindle cell carcinoma (n=11). Among these spindle cell neoplasms, strong diffuse clusterin staining had an overall specificity of 93% and a sensitivity of 100% for follicular dendritic cell tumor. Clusterin staining was least reliable in distinguishing follicular dendritic cell tumor from spindle cell thymoma or malignant fibrous histiocytoma, but these are entities that usually can be distinguished by clinical and morphologic data. Rare cases of leiomyosarcoma, fibrosarcoma and angiosarcoma may show strong clusterin staining. Fascin staining was very nonspecific among spindle cell tumors and thus does not imply a dendritic cell lineage.

Follicular dendritic cell sarcoma of the pharyngeal region: histologic, cytologic, immunohistochemical, and ultrastructural study of three cases.

Follicular dendritic cell sarcoma is a tumor of recent description and characterization; it is often underdiagnosed because it is easily confused with other entities. Three cases of follicular dendritic cell sarcoma are described in the present article. The first occurred in the parapharyngeal space in a 29-year-old woman who developed multiple recurrences over the span of 10 years. The second was located in the left tonsil in a 48-year-old man, and the third case developed in the parapharyngeal space in a 26-year-old man. All cases were positive for CD21 and CD35 and ultrastructurally they displayed a morphologic spectrum. The first case featured spindle cells with interdigitated long cell processes joined by well-developed desmosomes. In the other two cases there were round to ovoid cells with interwoven processes connected by occasional desmosomes. Including these three cases, a total of 20 follicular dendritic cell sarcoma of the pharyngeal region have been reported to date. The clinical behavior of these tumors is similar to other low-grade sarcomas.

A 71-year-old man with spindle-cell neoplasm of unknown origin: a difficult-to-diagnose clear-cell sarcoma.

A patient initially presented in 1988 with a solitary axillary mass, diagnosed as a high-grade neuroendocrine spindle-cell neoplasm; there was no history of a primary cutaneous malignancy. After subsequent development of a pulmonary nodule in 2001 (14-years post initial diagnosis), the case was reviewed and the possibility of metastatic melanoma was raised. The histopathologic and immunohistochemical profile of this melanocytic neoplasm was diagnostic of clear cell sarcoma (CCS) of tendons and aponeuroses, although the differential diagnosis included malignant melanoma, follicular dendritic and interdigitating cell tumors, malignant peripheral nerve sheath tumor, and a category of so-called PEComas. It is the role of pathologists, particularly dermatopathologists, to distinguish CCS from malignant melanoma, and to alert the clinician, because proper diagnosis ultimately influences treatment. We discuss the immunophenotype, differential diagnosis, and molecular signatures of these neoplasms, and review the pertinent literature on these entities.