Clear cell stromal tumor of the lung with multinucleated giant cells: a report of a case with YAP1-TFE3 fusion.

BACKGROUND: Clear cell (hemangioblastoma-like) stromal tumor of the lung (CCSTL) is a rare pulmonary neoplasm. Recently, 9 cases of CCSTL harboring the YAP1-TFE3 gene fusion have been described, and it has been suggested that this aberration could be a characteristic feature of this tumor. CASE PRESENTATION: We here report another case of CCSTL in a 57-year-old male, which presented as a solitary lung nodule 45 mm in the greatest dimension. Microscopically, the tumor consisted of epithelioid to spindled cells with mild-to-moderate nuclear atypia, finely granular or vesicular chromatin, and small nucleoli. Nuclear indentations were a common finding. There were up to 3 mitoses per 10 HPF. The cytoplasm was slightly eosinophilic or clear. Scattered non-tumor large multinucleated cells were present. Immunohistochemically, the tumor cells showed diffuse positivity for TFE3, CD10, vimentin, and IFITM1. Other markers examined were negative, and the expression of lineage-specific markers was not found. NGS analysis revealed a fusion transcript of the YAP1 and TFE3 genes, and a pathogenic variant of the MUTYH gene. CONCLUSION: Our finding supports the recent data suggesting that CCSTL represents a distinct entity characterized by the recurrent YAP1-TFE3 fusion.

Single-cell RNA-seq reveals the genesis and heterogeneity of tumor microenvironment in pancreatic undifferentiated carcinoma with osteoclast-like giant-cells.

BACKGROUND: Undifferentiated carcinoma with osteoclast-like giant cells (OGCs) of pancreas (UCOGCP) is a rare subtype of pancreatic ductal adenocarcinoma (PDAC), which had poorly described histopathological and clinical features. METHODS: In this study, single-cell RNA sequencing (scRNA-seq) was used to profile the distinct tumor microenvironment of UCOGCP using samples obtained from one UCOGCP patient and three PDAC patients. Bioinformatic analysis was carried out and immunohistochemical (IHC) staining was used to support the findings of bioinformatic analysis. After quality control of the raw data, a total of 18,376 cells were obtained from these four samples for subsequent analysis. These cells were divided into ten main cell types following the Seurat analysis pipeline. Among them, the UCOGCP sample displayed distinct distribution patterns from the rest samples in the epithelial cell, myeloid cell, fibroblast, and endothelial cell clusters. Further analysis supported that the OGCs were generated from stem-cell-like mesenchymal epithelial cells (SMECs). RESULTS: Functional analysis showed that the OGCs cluster was enriched in antigen presentation, immune response, and stem cell differentiation. Gene markers such as LOX, SPERINE1, CD44, and TGFBI were highly expressed in this SMECs cluster which signified poor prognosis. Interestingly, in myeloid cell, fibroblasts, and endothelial cell clusters, UCOGCP contained higher percentage of these cells and unique subclusters, compared with the rest of PDAC samples. CONCLUSIONS: Analysis of cell communication depicted that CD74 plays important roles in the formation of the microenvironment of UCOGCP. Our findings illustrated the genesis and function of OGCs, and the tumor microenvironment (TME) of UCOGCP, providing insights for prognosis and treatment strategy for this rare type of pancreatic cancer.

An intra-cytoplasmic route for SARS-CoV-2 transmission unveiled by Helium-ion microscopy.

SARS-CoV-2 virions enter the host cells by docking their spike glycoproteins to the membrane-bound Angiotensin Converting Enzyme 2. After intracellular assembly, the newly formed virions are released from the infected cells to propagate the infection, using the extra-cytoplasmic ACE2 docking mechanism. However, the molecular events underpinning SARS-CoV-2 transmission between host cells are not fully understood. Here, we report the findings of a scanning Helium-ion microscopy study performed on Vero E6 cells infected with mNeonGreen-expressing SARS-CoV-2. Our data reveal, with unprecedented resolution, the presence of: (1) long tunneling nanotubes that connect two or more host cells over submillimeter distances; (2) large scale multiple cell fusion events (syncytia); and (3) abundant extracellular vesicles of various sizes. Taken together, these ultrastructural features describe a novel intra-cytoplasmic connection among SARS-CoV-2 infected cells that may act as an alternative route of viral transmission, disengaged from the well-known extra-cytoplasmic ACE2 docking mechanism. Such route may explain the elusiveness of SARS-CoV-2 to survive from the immune surveillance of the infected host.

Uterine leiomyosarcomas with osteoclast-like giant cells associated with high expression of RUNX2 and RANKL.

Uterine leiomyosarcoma (ULMS) with osteoclast-like giant cells (OLGCs) has been reported as a rare phenomenon in ULMS, and its clinico-pathological features and tumorigenesis remain unclear. We recently reported high expression of receptor activator of nuclear factor κB ligand (RANKL) in ULMS with OLGCs. As osteoblasts produce RANKL, in this study, we analyzed the expression of Runt-related transcription factor 2 (RUNX2), a critical transcription factor for osteoblasts, and osteoclast-related proteins in three cases of ULMS with OLGCs as well as five conventional ULMSs and nine leiomyomas. Immunohistochemistry and real-time reverse transcription quantitative polymerase chain reaction analyses showed high expression of RUNX2 and RANKL in ULMS with OLGCs. In these cases, macrophages expressed receptor activator of nuclear factor κB (RANK), and OLGCs expressed osteoclast-related proteins (nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and cathepsin K). Accumulation sites of cathepsin K-positive OLGCs showed hemorrhagic appearance and degraded type IV collagen. We reviewed reported cases of ULMS with OLGCs, including ours, and found that they presented an aggressive course even at stage I. Furthermore, metastatic lesions showed similar histological features to those of OLGC association in ULMS. Here, we show that tumor cells in ULMS with OLGCs highly express RUNX2 and RANKL and that osteoclastic differentiation of macrophages occurs in the tumor tissue.

CCS52 and DEL1 function in root-knot nematode giant cell development in Xinjiang wild myrobalan plum (Prunus sogdiana Vassilcz).

Root-knot nematodes (RKNs) are highly invasive plant parasites that establish permanent feeding sites within the roots of the host plant. Successful establishment of the feeding site is essential for the survival of RKN. The formation and development of the feeding cell, also called giant cell, involve both cell division and endoreduplication. Here, we examined giant cell development and endoreduplication in Prunus sogdiana infected with the RKN. We found that feeding sites were established 3-5 days post inoculation (dpi) and matured at 21-28 dpi. The giant cells began to form 5 dpi and continued to increase in size from 7 to 21 dpi. The large numbers of dividing nuclei were observed in giant cells from 7 to 14 dpi. However, nuclear division was rarely observed after 28 days. RT-PCR and in situ hybridization analyses revealed that PsoCCS52A was abundantly expressed at 7-21 dpi and the PsoCCS52A signal observed in giant cell nucleus at 7-14 dpi. The PsoCCS52B is highly expressed at 14 dpi, and the hybridization signal was mainly in the cytoplasm of giant cells. The PsoDEL1 expression was lowest 7-21 dip, with negligible transcript detected in the giant cells. This indicates that the PsoCCS52A plays a role in the process of cell division, while the CCS52B plays a role in the development of giant cells. The PsoDEL1 plays a negative regulatory role in megakaryocyte nuclear replication. These data suggest that an increased expression of PsoCCS52A promotes nuclear division and produces a large number of polyploid nuclei, the area of giant cells and feeding sites increase, ultimately leading to the formation of galls in Prunus sogdiana.

Lysosome-Associated Membrane Proteins Support the Furin-Mediated Processing of the Mumps Virus Fusion Protein.

Mumps virus (MuV), an enveloped RNA virus of the Paramyxoviridae family and the causative agent of mumps, affects the salivary glands and other glandular tissues as well as the central nervous system. The virus enters the cell by inducing the fusion of its envelope with the plasma membrane of the target cell. Membrane fusion is mediated by MuV envelope proteins: the hemagglutinin-neuraminidase and fusion (F) protein. Cleavage of the MuV F protein (MuV-F) into two subunits by the cellular protease furin is a prerequisite for fusion and virus infectivity. Here, we show that 293T (a derivative of HEK293) cells do not produce syncytia upon expression of MuV envelope proteins or MuV infection. This failure is caused by the inefficient MuV-F cleavage despite the presence of functional furin in 293T cells. An expression cloning strategy revealed that overexpression of lysosome-associated membrane proteins (LAMPs) confers on 293T cells the ability to produce syncytia upon expression of MuV envelope proteins. The LAMP family comprises the ubiquitously expressed LAMP1 and LAMP2, the interferon-stimulated gene product LAMP3, and the cell type-specific proteins. The expression level of the LAMP3 gene, but not of LAMP1 and LAMP2 genes, differed markedly between 293T and HEK293 cells. Overexpression of LAMP1, LAMP2, or LAMP3 allowed 293T cells to process MuV-F efficiently. Furthermore, these LAMPs were found to interact with both MuV-F and furin. Our results indicate that LAMPs support the furin-mediated cleavage of MuV-F and that, among them, LAMP3 may be critical for the process, at least in certain cells.IMPORTANCE The cellular protease furin mediates proteolytic cleavage of many host and pathogen proteins and plays an important role in viral envelope glycoprotein maturation. MuV, an enveloped RNA virus of the Paramyxoviridae family and an important human pathogen, enters the cell through the fusion of its envelope with the plasma membrane of the target cell. Membrane fusion is mediated by the viral attachment protein and the F protein. Cleavage of MuV-F into two subunits by furin is a prerequisite for fusion and virus infectivity. Here, we show that LAMPs support the furin-mediated cleavage of MuV-F. Expression levels of LAMPs affect the processing of MuV-F and MuV-mediated membrane fusion. Among LAMPs, the interferon-stimulated gene product LAMP3 is most critical in certain cells. Our study provides potential targets for anti-MuV therapeutics.

Poorly differentiated thyroid carcinoma with pleomorphic giant cells-a case report.

Poorly differentiated thyroid carcinoma (PDTC) refers to a malignant tumour that displays an intermediate prognosis between well-differentiated carcinomas and anaplastic thyroid carcinomas (ATC). In the thyroid, pleomorphic giant cells are observed in ATC or in some non-neoplastic thyroid diseases. We described the case of a 43-year-old woman with a 34-mm nodule in her thyroid right lobe. Microscopic examination revealed an encapsulated tumour with a main solid growth pattern and extensive capsular invasion. Multiple images of angioinvasion were observed. There was neither necrosis nor inflammation. Most of the tumour cells were medium-sized and intermingled with pleomorphic giant tumour cells with bizarre features. The immunoprofile (keratins +, TTF1+, Pax 8+) proved their thyroid origin. By NGS, no molecular alteration was identified. The patient was treated by surgery and radioiodine therapy and she has no recurrence after a follow-up of 24 months. Our case meets all the histological criteria of the Turin proposal for PDTC but with pleomorphic giant cells and is very different from ATC according to clinical, histological and immunohistochemical features. Pleomorphic tumour giant cells in thyroid carcinomas could be present in PDTC and do not always represent dedifferentiation and more aggressive carcinoma, thyroid neoplasm.

Placental inflammation by HMGB1 activation of TLR4 at the syncytium.

INTRODUCTION: Normal pregnancy is characterized by an elevated inflammatory state involving the placenta. The placental inflammation is further increased in preeclampsia, resulting in release of harmful danger signals to the maternal circulation. Activation of toll-like receptors (TLR)2 and TLR4 by endogenous danger signals plays a role in inflammatory diseases. Placental TLR2 and TLR4 expression has been reported, and high mobility group box 1 (HMGB1) is a likely endogenous activator of these receptors. We aimed to examine HMGB1 activation of TLR2 and TLR4 as mechanisms of placental inflammation in normal and preeclamptic pregnancies, by combined analysis of expression and function of the ligand HMGB1, the receptors TLR2 and TLR4, and the cytokine responder interleukin (IL)-8. METHODS: Protein expression was analyzed in placental tissue from normal and preeclamptic pregnancies, and cytokine responses to two distinct HMGB1 isoforms were examined in placental explants and trophoblasts. Inflammatory and anti-angiogenic markers were measured in maternal serum. RESULTS: We demonstrated strong co-localized expression of HMGB1, TLR4 and IL-8 in the syncytium layer of the placenta. Syncytium TLR4 expression and maternal serum levels of IL-8 were significantly increased in preeclamptic compared to normal pregnancies. Functionality was confirmed by TLR4-dependent release of IL-8 from placental explants and trophoblasts in response to the inflammatory isoform of HMGB1. DISCUSSION: This demonstrates a role for the HMGB1-TLR4 pathway at the syncytium layer and suggests involvement in placental inflammation and preeclampsia.

Pleomorphic lobular carcinoma of the breast with osteoclast-like giant cells: a case report and review of the literature.

BACKGROUND: Breast carcinoma with osteoclast-like giant cells (OGCs) is infrequent, being most reported cased described as ductal invasive carcinomas. Invasive pleomorphic lobular carcinoma (PLC) is a distinct morphological variant of invasive lobular carcinoma characterized by higher nuclear atypia and pleomorphism than the classical type. In the best of our knowledge, a PLC with OGCs has not been previously reported. CASE PRESENTATION: We report the case of a 72-year-old woman presenting with a pleomorphic tumor of the left breast with a dense infiltration by OGCs and T lymphocytes with a 10:1 predominance of CD8+ over CD4+ cells. The diagnosis of a lymphoid or mesenchymal neoplasia was excluded after demonstrating keratin expression by the neoplastic cells. The absence of E-cadherin expression and the morphological features were consistent with the diagnosis PLC with OGCs. In addition, we demonstrated the deleterious mutation C.del866C in CDH1gene, but no mutations in any of the other 33 genes analyzed by next generation sequencing. CONCLUSIONS: Breast carcinoma with stromal osteoclast-like giant cells is a very rare tumor, for that reason, the use of the cytologic features and growth patterns in combination with immunohistochemically studies is mandatory for a correct diagnosis of lobular carcinoma. In addition, further studies are necessary to clarify the influence of OGCs in the prognosis of these patients.

Prostatic Adenocarcinoma With Focal Pleomorphic Giant Cell Features: A Series of 30 Cases.

Prostatic adenocarcinoma with focal pleomorphic giant cell features is rare with the only prior series consisting of 6 cases. From 2005 to 2018, we identified 29 cases from our consult service and 1 case from our own institution. Men ranged in age from 39 to 90 years (median=75.5). Diagnostic specimens consisted of needle biopsies (n=13); transurethral resections (n=7), urethral/bladder biopsies (n=8), radical prostatectomy (n=1), and orchiectomy (n=1). In all cases, there was usual acinar prostatic adenocarcinoma, where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). On average, 68% of the involved cores had cancer with a maximum percent of cancer averaging 55%; on average, transurethral resections had 85% of the area involved by cancer. Areas of cancer showing pleomorphic giant cell features were focal (<5%). Two of the needle biopsies showed extraprostatic extension. The radical prostatectomy had seminal vesicle invasion and positive margins with lymphovascular invasion. Prostatic adenocarcinoma with focal pleomorphic giant cell features is always accompanied by extensive usual acinar prostate adenocarcinoma where the highest grade in all cases was Gleason score 9 to 10 (Grade Group 5). Although the pleomorphic component is focal, it can mimic urothelial carcinoma. IHC can be misleading as PSA staining is often negative or focal in both the pleomorphic and usual prostatic adenocarcinoma components. NKX3.1 is the most sensitive prostate marker, but was still focal in 1 usual prostatic adenocarcinoma and negative in 2 pleomorphic components. Prostatic adenocarcinoma with focal pleomorphic giant cell features has a dismal prognosis. In men with no prior diagnosis of prostate adenocarcinoma and >1-year follow-up, 7/19 (37%) were dead at a median of 8 months after diagnosis. Of the 7 men with a prior history of prostate adenocarcinoma, 4/7 (57%) were dead at a median of 7 months after diagnosis of recurrent prostate adenocarcinoma with pleomorphic giant cell features.

Macrophages and Dendritic Cells Are the Predominant Cells Infected in Measles in Humans.

Characterization of human measles cases is essential in order to better assess the data generated in model systems of morbillivirus infection. To this end, we collected formalin-fixed tissue samples from 23 natural measles cases from different areas in the world and different phases of disease ranging from prodromal and acute measles to a persistent infection in an immunocompromised subject. We show that the vast majority of measles virus (MV)-infected cells in epithelia were intraepithelial immune cells that were, in most cases, positive for the CD11c myeloid cell marker. Small numbers of measles virus-infected cytokeratin-positive epithelial cells were also detected in bronchial and appendix epithelia. Dissolution and disruption of uninfected and MV-infected alveolar and bronchial epithelia were prominent features of the measles cases, especially in the established and late phases of the disease. In some instances, this was associated with the formation of MV-infected multinucleated giant cells which expressed CD11c and/or macrophage cell marker 68, a pathological feature also prominently observed in closely associated mucosa-associated lymphoid tissue. Collectively, these data show that resident and inflammatory infiltrating immune cells alter the architecture of respiratory tract epithelia and highlight the necessity for additional research into the function(s) and expression of nectin-4 in human tissues.IMPORTANCE We have brought together a unique collection of 23 human cases of measles infection and studied the types of cells that are infected. This work has not been done with modern technologies such as double labeling with antibodies and confocal microscopy in human cases primarily due to the fact that it is difficult to obtain the material because, fortunately, measles is fatal in only a very small fraction of infected patients. During the past decades, the receptors for measles virus have been elucidated and monkey models have been developed. We found that, in most cases, independently of whether the tissues were obtained early or later in the infection, the primary cell types that were infected were those of the immune system such as lymphocytes, macrophages, and dendritic cells. A very small number of epithelial cells were also found to be infected.

Nucleosomes of polyploid trophoblast giant cells mostly consist of histone variants and form a loose chromatin structure.

Trophoblast giant cells (TGCs) are one of the cell types that form the placenta and play multiple essential roles in maintaining pregnancy in rodents. TGCs have large, polyploid nuclei resulting from endoreduplication. While previous studies have shown distinct gene expression profiles of TGCs, their chromatin structure remains largely unknown. An appropriate combination of canonical and non-canonical histones, also known as histone variants, allows each cell to exert its cell type-specific functions. Here, we aimed to reveal the dynamics of histone usage and chromatin structure during the differentiation of trophoblast stem cells (TSCs) into TGCs. Although the expression of most genes encoding canonical histones was downregulated, the expression of a few genes encoding histone variants such as H2AX, H2AZ, and H3.3 was maintained at a relatively high level in TGCs. Both the micrococcal nuclease digestion assay and nucleosome stability assay using a microfluidic device indicated that chromatin became increasingly loose as TSCs differentiated. Combinatorial experiments involving H3.3-knockdown and -overexpression demonstrated that variant H3.3 resulted in the formation of loose nucleosomes in TGCs. In conclusion, our study revealed that TGCs possessed loose nucleosomes owing to alterations in their histone composition during differentiation.

Evaluation of the osteopontin in oral peripheral and central giant cell granuloma.

AIM: Peripheral giant cell granuloma (PGCG) and central giant cell granuloma (CGCG) of the jaws are benign proliferations of spindle-shaped mesenchymal cells and multinucleated giant cells. Despite the histopathologic similarities, they have markedly different clinical behavior. PGCG shows low recurrence rate whereas CGCG shows a variable clinical behavior ranging from nonaggressive lesions to aggressive lesions characterizing by pain, rapid growth, and high recurrence rate. Therefore, the aim of the study was to compare CGCG with PGCG by immunohistochemistry using Ki-67, osteopontin (OPN), and integrin αvantibodies. SUBJECTS AND METHODS: Twenty PGCG and 20 CGCG were selected for immunohistochemical evaluation of OPN, integrin αv, and Ki-67 in multinucleated giant cells and mononucleated cells of PGCG and CGCG. RESULTS: PGCG showed higher Ki-67 immunoreactivity in mononucleated cells compared to CGCG (P < 0.05). There was no reactivity with Ki-67 in multinucleated giant cells of both groups. Mononucleated cells in CGCGs demonstrated increased OPN and integrin αvexpressions in comparison with PGCGs (P < 0.05). CONCLUSIONS: The clinic behavior of CGCG being more aggressive than PGCG might be explained by the high expression of OPN and integrin αv. Further studies are necessary to evaluate the other OPN receptors and their role on the biologic behavior of these lesions.

Cytologic Features of Malignant Melanoma with Osteoclast-Like Giant Cells.

BACKGROUND: Malignant melanoma showing numerous osteoclast-like giant cells (OGCs) is an uncommon morphologic phenomenon, rarely mentioned in the cytologic literature. The few reported cases seem to have an aggressive clinical behavior. Although most findings support monocyte/macrophage differentiation, the exact nature of OGCs is not clear. CASE: A 57-year-old woman presented with an inguinal lymphadenopathy. Sixteen years before, cutaneous malignant melanoma of the lower limb had been excised. Needle aspiration revealed abundant neoplastic single cells as well as numerous multinucleated OGCs. Occasional neoplastic giant cells were also present. Nuclei of OGCs were monomorphic with oval morphology and were smaller than those of melanoma cells. The immunophenotype of OGCs (S100-, HMB45-, Melan-A-, SOX10-, Ki67-, CD163-, BRAF-, CD68+, MiTF+, p16+) was the expected for reactive OGCs of monocyte/macrophage origin. The tumor has shown an aggressive behavior with further metastases to the axillary lymph nodes and oral cavity. CONCLUSION: Numerous OGCs are a rare and relevant finding in malignant melanoma. Their presence should not induce confusion with other tumors rich in osteoclastic cells. Since a relevant number of OGCs in melanoma may mean a more aggressive behavior, and patients may benefit from specific treatments, their presence should be mentioned in the pathologic report.

Fine Needle Aspiration Cytology of Diffuse-Type Tenosynovial Giant Cell Tumors.

BACKGROUND: Tenosynovial giant cell tumor (TSGCT), also known as giant cell tumor of tendon sheath or pigmented villonodular synovitis, is the most common benign tumor of the tendon and synovium. The intra-articular diffuse type can present as a large infiltrative mass involving adjacent soft tissue and sometimes causes secondary destruction of bone, which leads to radiographic and clinical concern for malignancy. The tumor may also be purely extra-articular. CASE: Here, we report the fine needle aspiration cytology findings of 2 cases of diffuse-type TSGCT with large mononuclear cells with eccentric nuclei, finely granular cytoplasm, and a peripheral well-defined cytoplasmic rim of hemosiderin ("ladybird cells"). CONCLUSION: Although the presence of ladybird cells has been described in tissue sections of TSGCT, their identification in cytological specimens has not been reported to our knowledge. When observed, their presence may aid in differentiating TSGCT from other lesions with multinucleated osteoclast-type giant cells occurring at or near joints.

[Distribution and content of transforming growth factor-ß1 and vascular endothelial growth factor in each layer of concentrated growth factors].

OBJECTIVE: To investigate the distribution and content of transforming growth factor-ß1 (TGF-ß1) and vascular endothelial growth factor (VEGF) in concentrated growth factors (CGF) gel, and to clarify the difference among different layers of CGF. METHODS: Venous blood samples were collected from 6 healthy volunteers to prepare CGF. The distribution, integrated optical density (IOD) and average optical density (AOD) of TGF-ß1 and VEGF in CGF gel and red blood cell (RBC) layer were measured using immunohistochemistry. The concentrations of TGF-ß1 and VEGF in the supernatant serum at baseline and the CGF releasate after 1 day were evaluated with enzyme-linked immunosorbent assays. RESULTS: Abundant TGF-ß1 and VEGF were concentrated in CGF gel. However, only a little could be found in polykaryocytes and sporadic platelets in RBC layer. Platelets and leukocytes were concentrated in between the two layers with high expression of TGF-ß1. The concentrations of TGF-ß1 and VEGF in the CGF releasate(55 236.78±3 686.34), (610.99±148.81) ng/L were significantly higher than those in the supernatant serum (20 710.20±4 523.14), (335.20±51.69) ng/L (P<0.001). CONCLUSION: CGF contains high quantities of TGF-ß1 that can promote new bone formation and tissue healing. We suggest that CGF gel should be used right after being prepared. Supernatant serum and the area between CGF gel and RBC layer could also be mixed with bone substitute materials.

Defining a new aggressiveness classification and using NFATc1 localization as a prognostic factor in cherubism.

Cherubism is a rare genetic disease characterized by bilateral giant cell reparative granuloma of the jaws consisting of a fibrotic stroma with giant multinucleated cells (GMCs) and osteoclastic features. Cherubism severity is highly variable, and recurrence after surgery is the most important risk. Currently, there are no prognostic indicators. The aims of this study were to evaluate the osteoclastogenesis phenotype by histologic examination of nuclear factor of activated T cells 1 (NFATc1) localization and tartrate-resistant acid phosphatase (TRAP) activity and to correlate the results to disease aggressiveness to define prognostic indicators. Based on cherubism evolution 1 year after surgery, 3 classes of cherubism aggressiveness were identified: mild (group A), moderate (group B), and severe (group C). Histologically, in grade A and B cherubism lesions, GMCs were negative for both TRAP activity and NFATc1 nuclear localization. In contrast, in grade C cherubism lesions, GMCs were all positive for TRAP activity and NFATc1 nuclear localization and displayed osteoclast-like features. Other histopathologic findings were not different among the 3 groups. Our results establish that TRAP activity and NFTAc1 nuclear localization are associated with aggressive cherubism and therefore could be added to routine pathologic examination to aid in prognosis and management of the disease. The finding of NFATc1 nuclear localization in aggressive tumors supports the addition of anticalcineurin treatment to the therapeutic arsenal for cherubism.

Oral Paracoccidioidomycosis Granulomas are Predominantly Populated by CD163+ Multinucleated Giant Cells.

Multinucleated giant cells (MGC) are considered to be a hallmark of granulomatous inflammation; thus, they may play an essential role in the host response against pathogens, particularly Paracoccidioides brasiliensis. This study characterizes the MGC found in oral paracoccidioidomycosis and assesses the correlation of MGC with the amount of fungi within oral tissues. Twenty-six cases were included. They were classified as loose or dense granulomas, and the total MGC, including foreign-body and Langhans giant cells, besides the total and intracellular fungi, were taken into consideration. CD163 immunoexpression was performed, and CD163+ multinucleated giant cells were also quantified. Dense granulomas revealed more foreign-body type and total giant cells than loose granulomas (P < 0.05). Total giant cells showed a positive linear correlation with the CD163+ cells (P = 0.003; r = 0.56) and intracellular fungi quantification (P = 0.045; r = 0.40). Oral paracoccidioidomycosis lesions contain MGC that mainly belong to a CD163+ phenotype, also showing both Langhans and foreign-body arrangements. Additionally, the higher the presence of MGC, the higher the amount of phagocytized fungi.

[Tuberous sclerosis complex with refractory epilepsy: a clinicopathologic study of 14 cases].

OBJECTIVE: To study the clinicopathologic features of tuberous sclerosis complex (TSC). METHODS: The clinicopathologic data of the patients diagnosed as TSC with refractory epilepsy and resection of epileptic focus were retrospectively analyzed. RESULTS: Fourteen cases were included, the mean age was (15.8±12.9) years, with a male predominance (male to female ratio=10:4). Frontal lobe was the most common (13/14) site of involvement. MRI showed multiple patchy long T1 and long T2 signals. CT images showed multiple subependymal high density calcified nodules in nine cases. Histology showed mild to severe disruption of the cortical lamination, cortical and subcortical tubers with giant cells and/or dysmorphic neurons. The giant cells showed strong immunoreactivity for vimentin and nestin, while the dysmorphic neurons partially expressed MAP2 and NF. Vimentin also stained strongly the "reactive" astrocytes. Thirteen cases had follow-up information: Engel class I in six cases, Engel class II in six cases, and Engel class III in one case. CONCLUSIONS: Diagnosis of TSC relies on combined pathologic, clinical and neuroradiological features. Immunohistochemical staining can be helpful. Resection of epileptic focus is an effective method to treat refractory epilepsy in TSC.

S100, bcl2 and myeloperoxid protein expirations during periodontal inflammation.

BACKGROUND: Periodontal inflammation is characterized by injuries in collagen, epithelial, bone tissues. The hypotheses to be tested were relationship between the s100, bcl2 and myeloperoxidase in gingival tissues (MPO does affect the level of s100, bcl2). The object of this study was to investigate of s100 expression, bcl2 expression and myeloperoxidase expression in periodontal inflammation. METHODS: 27 patients (giant-cell epulis) and 30 patients (acute and chronic inflammations) were included in the study for s100 expression, bcl2 expression and myeloperoxidase expression by immunohistochemistry and hematoxylin--eosin. RESULTS: Giant-cells in epulis positivity for myeloperoxidase has been observed in 100% However, only 75.31% of giant-cells were positive for bcl2 expression. Acute 98.2%, and chronic 89.28% inflammation was a significant positive for myeloperoxidase. The immunohistochemical findings of s100, bcl 2 and myeloperoxidase in epithelial layers have showed the result of 100%, 82,2%, 100% positive cells in acute and 100%, 78.25%, 100% in chronic process of inflammation respectively. CONCLUSION: The results indicate that the pathogenesis of periodontal inflammation might involve inhibition of cell death, through the overexpression of bcl-2, due to identifying factors myeloperoxidase (result in the DNA damage by the product of catalysis). The highest levels of s100 activity have been found at sites with chronic inflammation.