CSF1 expression in xanthogranulomatous epithelial tumor/keratin-positive giant cell-rich tumor.

"Xanthogranulomatous epithelial tumor" (XGET) and "keratin-positive giant cell-rich soft tissue tumor" (KPGCT), two recently described mesenchymal neoplasms, likely represent different aspects of a single entity. Both tumors are composed of only a small minority of tumor cells surrounded by large numbers of non-neoplastic inflammatory cells and histiocytes, suggesting production of a paracrine factor with resulting "landscape effect," as seen in tenosynovial giant cell tumor. Recent evidence suggests that the paracrine factor in XGET/KPGCT may be CSF1, as in tenosynovial giant cell tumor. We hypothesized that CSF1 is overexpressed in XGET/KPGCT. To test our hypothesis, we performed quantitative real time PCR (qPCR) for CSF1 expression and CSF1 RNAscope chromogenic in situ hybridization (CISH) on 6 cases of XGET/KPGCT. All cases were positive with CSF1 CISH and showed increased expression of CSF1 by qPCR. Our findings provide additional evidence that the CSF1/CSF1R pathway is involved in the pathogenesis of XGET/KPGCT. These findings suggest a possible role for CSF1R inhibition in the treatment of unresectable or metastatic XGET/KPGCT.

Intramuscular Tenosynovial Giant Cell Tumor Harboring a Novel CSF1-CD96 Fusion Transcript.

Tenosynovial giant cell tumors typically arise in the synovium of joints, bursae, or tendon sheaths. They may occur in an intra- or extra-articular location and can be divided into localized and diffuse types. The neoplastic nature of the lesion has been supported by a recurrent CSF1 gene rearrangement in a small subset of lesional cells, of which the most common fusion partner is COL6A3. Herein, we report a case of intramuscular localized tenosynovial giant cell tumor harboring a novel CSF1-CD96 fusion transcript, thus expanding the molecular profile of this tumor.

Assessment of Tumor Angiogenesis by Expression of CD 105 in Ameloblastoma, Odontogenic Keratocyst and Central Giant Cell Lesion.

BACKGROUND: Angiogenesis is critical for tumor growth and reflects the aggressive behavior of invasive odontogenic lesions [like Ameloblastoma (AM), Odontogenic Keratocyst (OKC) and Central giant cell lesion (CGCL)]. Mean vascular density (MVD) shows the angiogenic potential and CD105 is an ideal endothelial biomarker due to its specificity to new blood vessels for MVD detection. The aim of the study was to compare the MVD (angiogenic potential) among AM, OKC and CGCL in comparison to Pyogenic Granuloma (PG) using CD105 biomarker. METHODS: Sixty-four primary cases of odontogenic invasive tumors (AM, OKC and CGCL) and PG, diagnosed clinically and histologically were included in the study, with 16 samples in each group. Tissue samples of peripheral AM, Peripheral GCL of jaws, malignant AM, and specimen with insufficient tissue were excluded. Tissue sections were embedded, processed and stained using Hematoxylin and Eosin (H and E). Immunohistochemistry was performed using antibodies against CD105, with positive brown cytoplasmic staining in the endothelial cells of neo-vasculature. Distinct countable, positively stained endothelial cell or clusters were evaluated under light microscope for identification of MVD. ANOVA and t-test were applied for statistical analysis of data. RESULTS: Highest MVD was displayed in CGCL (32.99±0.77) and the minimum was observed in OKC (7.21± 0.75) respectively. CGCL showed significantly higher MVD to AM, OKC and PG lesions (p <0.05). AM (8.07± 0.36) and Odontogenic Keratocyst (7.21± 0.75) showed comparable MVD, which was lower than PG (14.7± 0.96) and CGCL vascular density (p < 0.01) respectively. CONCLUSION: CGCL was most aggressive, with highest MVD among the investigated odontogenic lesions (OKC, AM and PG). The proliferative aggressive behavior of Odontogenic Keratocyst is comparable to AM due to comparable mean vascular density.
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Clinical Characteristics and Prognosis of Osteoclast-like Giant Cell Tumors of the Pancreas Compared with Pancreatic Adenocarcinomas: A Population-Based Study.

BACKGROUND The incidence of osteoclast-like giant cell tumor of the pancreas (OGTP) is very low, and relatively little OGTP clinical data is available. The present study, therefore, sought to conduct a more comprehensive analysis of the clinical characteristics and prognosis of OGTP. MATERIAL AND METHODS A large population-based cohort analysis was conducted using the Surveillance, Epidemiology and End Results (SEER) registry. We conducted a systematic assessment of the demographic and clinical characteristics of these patients, in addition to assessing available prognostic and therapeutic data corresponding to their disease. We further compared overall survival (OS) in these OGTP and pancreatic adenocarcinoma (PA) patient cohorts, adjusting for sex, grade, stage, and surgical treatment by propensity score matching (PSM). RESULTS We included a total of 47 OGTP patients and 73 150 PA patients in the present analysis. The mean ages of PA and OGTP diagnosis were 68.0 and 62.8 years, respectively. Compared with PA patients, OGTP patients were more likely to be female (70.2% versus 48.7%, P<0.01), to have early-stage disease, to have lower rates of lymph node metastasis (17.0% versus 28.8%, P<0.01) and distant metastasis (17.0% versus 45.1%, P<0.01), and to have higher rates of tumor resection (70.2% versus 15.4%, P<0.01). OGTP patients also had a significantly longer median OS than did PA patients (13 months versus 6 months; hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.37-0.57, P<0.0001). No significant differences in tumor site preferences were detected. Our findings also suggested that being female, having early-stage disease, and undergoing surgical resection may be associated with a more favorable prognosis in patients with OGTP. CONCLUSIONS OGTP patients had distinctive clinical characteristics and a better prognosis compared with PA patients. Understanding these differences will help clinicians accurately recognize these diseases. Radical resection was beneficial to the survival of OGTP patients.

Mediastinal 99mTc-Methylene Diphosphonate Accumulation in a Patient With Primary Mediastinal Soft Tissue Giant Cell Tumor.

Soft tissue giant cell tumor (GCT) is rare. It usually involves the extremities. We report the case of a 37-year-old woman who was suspected of having mediastinal tumor on radiograph. Thoracic CT revealed the tumor had extensive calcification and invaded the adjacent vertebrae and spinal canal. It intensively accumulated Tc-methylene diphosphonate on bone scan. The tumor showed hypointensity on T1-weighted and mixed intensity on T2-weighted fat-saturated sagittal images. Finally, a soft tissue GCT was confirmed by pathology. The case cautions us soft tissue GCT should be in the differential diagnosis spectrum in a calcified posterior mediastinal mass with Tc-methylene diphosphonate accumulation.

Association and clinicopathologic significance of p38MAPK-ERK-JNK-CDC25C with polyploid giant cancer cell formation.

BACKGROUND: We previously showed that cobalt chloride (CoCl2) induction of polyploid giant cancer cells (PGCCs) was characterized by abnormal cell cycle-related protein expression and G2/M arrest. The role of the p38MAPK-ERK-JNK signaling pathway in cell cycle regulation has been reported, but the mechanism by which p38MAPK-ERK-JNK regulates PGCCs formation remains unclear. This study examined p38MAPK-ERK-JNK-CDC25C expression in PGCCs and their daughter and control cells and assessed the clinicopathological significance of p38MAPK, ERK, JNK, and CDC25C expression in human ovarian and breast cancers. METHODS: CoCl2 was used to induce the formation of PGCCs in HEY and BT-549 cells. Western blotting and immunocytochemical staining were used to compare the expression and subcellular localization of p38MAPK, ERK, JNK, and CDC25C in the control group and CDC25C knockdown before and after CoCl2 treatment. The specific combination of p38MAPK and ERK with pCDC25C-Ser216 was detected by immunoprecipitation. In addition, p38MAPK, ERK, JNK, and CDC25C immunohistochemical staining were performed to compare the clinicopathologic significances in 81 cases of ovarian cancer tissue, including 20 cases of primary breast cancer with lymph node metastasis (group I), and their corresponding metastatic lymph nodes (group II), 31 cases of primary breast cancer without metastasis (group III), and 10 cases of benign breast tumors (group IV). Breast tumor tissue from 229 was divided into two groups: 167 cases of primary invasive breast cancer (group 1) and 62 cases of lymph node metastatic breast cancer (group 2). RESULTS: Compared to the control cells, p38MAPK and JNK expression were higher and CDC25C expression was lower in CoCl2-treated cells. Moreover, ERK displayed a trend of increased expression in HEY PGCCs and decreased expression in BT-549 PGCCs. p38MAPK and ERK regulated CDC25C by phosphorylating the CDC25C-Ser216 site and participated in the G2/M phase transition. Immunohistochemical (IHC) analysis of the ovarian tumor tissues showed significant positive staining rates of p38MAPK (P = 0.001), ERK (P = 0.002), JNK (P = 0.000), and CDC25C (P = 0.000) among the four groups. In breast tumor tissues, the overall expression in p38MAPK (P = 0.029), ERK (P = 0.002), JNK (P = 0.013), and CDC25C (P = 0.001) also differed significantly between the two groups. CONCLUSION: The p38MAPK-ERK-JNK signaling pathway was involved in cell cycle progression and the formation of PGCCs by regulation of CDC25C.

Endothelin-1 Activates the Notch Signaling Pathway and Promotes Tumorigenesis in Giant Cell Tumor of the Spine.

STUDY DESIGN: Experimental study. OBJECTIVE: To examine the role of endothelin-1 (ET-1) and the Notch signaling pathway in giant cell tumor (GCT) of the spine. SUMMARY OF BACKGROUND DATA: Previously published studies have shown that the Notch signaling pathway has a role in tumor invasion and that ET-1 is involved in tumor invasion and angiogenesis. However, the roles of both Notch signaling and ET-1 in GCT of the spine remain unknown. METHODS: Expression of ET-1 in tissue samples from patients with spinal GCT, and adjacent normal tissue, were analyzed by immunohistochemistry and western blot. GCT stromal cells (GCTSCs) were isolated and ET-1 expression was demonstrated by immunofluorescence. Cell viability and cell migration of GCTSCs and human vascular endothelial cells following ET-1 treatment were assessed using the cell counting kit-8 assay and a transwell assay. Receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) mRNA expression was determined following ET-1 treatment of GCTSCs using quantitative real-time polymerase chain reaction. In GCTSCs treated with ET-1 and the ET-1 signaling antagonist, BQ-123, levels of cyclin D1, vascular endothelial growth factor, matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), Jagged1, Hes1, Hey2, and Notch intracellular domain were examined by western blot. RESULTS: Compared with normal adjacent tissue, ET-1 was highly expressed in GCT tissue. In GCTSCs studied in vitro, treatment with ET-1 significantly increased GCTSC and human vascular endothelial cells growth and migration and increased the expression of RANKL and OPG, meanwhile the ratio of RANKL/OPG was increased, in GCTSCs, it upregulated the production of cyclin D1, vascular endothelial growth factor, MMP-2, MMP-9, Jagged1, Hes1, Hey2, and Notch intracellular domain expression in a dose-dependent manner. Treatment with BQ-123 reversed these effects. CONCLUSION: In GCT of the spine, ET-1 showed increased expression. In cultured GCTSCs, ET-1 treatment activated the Notch signaling pathway. LEVEL OF EVIDENCE: 2.

Tumor-induced Osteomalacia in a 3-Year-Old With Unresectable Central Giant Cell Lesions.

Tumor-induced osteomalacia (TIO) is a rare cause of hypophosphatemia involving overproduction of fibroblast growth factor 23. TIO has been described largely in adults with small mesenchymal tumors. We report a case of TIO in a child who presented with knee pain and radiographic findings concerning for rickets, and was found to have maxillomandibular giant cell lesions. The patient was treated with oral phosphorus and calcitriol, surgical debulking, and intralesional corticosteroids, which resulted in tumor regression and normalization of serum fibroblast growth factor 23 and phosphorus. This case illustrates the occurrence of this rare paraneoplastic syndrome in children and adds to our knowledge about clinical manifestations and pathologic findings associated with pediatric TIO.

Thallium-201 Uptake of Giant Cell Tumor: One Step Toward the Differential Diagnosis to Atypically Presenting Osteosarcoma.

OBJECTIVE: The radiologic differential diagnosis of giant cell tumors (GCTs) is challenging because there is a risk of misdiagnosis of GCTs as malignant lesions such as atypically presenting osteosarcomas (OSs). This study aims to assess the feasibility of 201Tl scintigraphy for the differential diagnosis of GCT and atypical OS. MATERIALS AND METHODS: Thallium-201 scintigraphy scans obtained between January 2006 and October 2015 of patients with histologically proven GCT (23 patients [male-to-female ratio, 15:8]; median age, 33.0 years; age range, 20-61 years) and patients with atypically presenting OS (20 patients [male-to-female ratio, 11:9]; median age, 30.0 years; age range, 12-69 years) were retrospectively reviewed. Morphologic classification of osseous lesions was performed on radiographs and CT scans. The 201Tl scintigraphy-based tumor-to-background contrast (TBC) and washout rate (WR) were calculated on early phase and delayed phase scans. The laboratory parameters lactate dehydrogenase (LDH), C-reactive protein (CRP), and alkaline phosphatase were obtained. Statistical significance was estimated using the Mann-Whitney U test. Cutoff values were calculated for early phase TBC and delayed phase TBC. RESULTS: Twenty-two of 23 GCTs were detected on the initial radiographs, whereas only six of 20 atypical OSs were detected on the initial radiographs. The early phase TBC was increased in GCT (median, 2.59; range, 0.51-12.26) compared with atypical OS (median, 1.68; range, 0.90-6.45) (p = 0.07). The delayed phase TBC was increased in GCT (median, 1.65; range, 0.22-5.26) compared with atypical OS (median, 0.96; range, 0.39-3.76) (p = 0.02). The median WR was not significantly decreased in GCT. The cutoff value for the early phase TBC was 3.90, and the cutoff value for the delayed phase TBC was 1.64; these cutoff values for early and delayed phase TBC yielded a sensitivity of 80.0% and a specificity of 47.8% and 52.2% respectively. Serum LDH (mean: atypical OS vs GCT, 215.5 vs 170.5 U/L, respectively; p = 0.01), alkaline phosphatase (median: 355.0 vs 252.0 U/L; p = 0.03), and CRP (median: 0.21 vs 0.09 mg/dL; p = 0.04) values were significantly increased in atypical OS compared with GCT. CONCLUSION: The intense 201Tl uptake of GCT in combination with laboratory OS biomarkers facilitate the differential diagnosis of GCT and atypically presenting OS.

Histochemical analysis of collagen fibers in giant cell fibroma and inflammatory fibrous hyperplasia.

OBJECTIVE: The aim was to investigate collagen fibers in giant cell fibroma, inflammatory fibrous hyperplasia, and oral normal mucosa. MATERIALS AND METHODS: Sixty-six cases were stained with picrosirius red. The slides were observed under polarization, followed by the measurement of the area and the percentage of the type I and type III collagens. The age and gender were obtained from the clinical records. RESULTS: No differences could be observed in both the area and percentage of the type I and type III collagens within the categories of lesions and normal mucosa. In the giant cells fibroma, a greater area and percentage of type I collagen could be identified in individuals of less than 41.5 years (p<0.05). CONCLUSION: The distribution of type I and type III collagen fibers in the studied lesions followed a similar pattern to that observed in the normal mucosa, indicating a normal collagen maturation process of type III to I. The study supports that multinucleated and stellate cells of the giant cell fibroma appear to be functional within collagen types III and I turnover. The greater amount of type I collagen identified in giant cell fibroma in individuals of less than 41.5 years reinforce the neoplastic nature of lesion.

Osteoclast-Like Giant Cell Tumor of the Parotid Gland: Report of a Case Diagnosed on Fine-Needle Aspiration Cytology With Histological and Immunohistochemical Findings.

Extraosseous giant cell tumors have been described in organs like larynx, thyroid, pancreas, heart, skin, lung, colon, kidney, and soft tissues (Wu et al., Oncol Lett 2013;6:829-832). Osteoclast-like giant cell tumor of the parotid gland has been reported only rarely with the first description of primary giant cell tumour of the parotid gland (GCTPs) given in 1984 by Eusebi et al. (Am J Clin Pathol. 1984;81:666-675). However, FNAC of osteoclast-like giant cell tumor of the parotid gland has not been well described, and only one case has been reported till date (Torabinezad et al., Acta Cytol. 2006;50:80-83). Two presentations have been observed in the form of either an isolated giant cell tumor (Eusebi et al., Am J Clin Pathol. 1984;81:666-675) or tumor associated with a carcinomatous component (Yang et al., Korean J Pathol 2012;46:297-301; Pasricha et al., J Can Res Ther 2013;9:314-316). GCTPs are uncommon benign soft tissue tumors with a malignant potential. Diagn. Cytopathol. 2016;44:548-551. © 2016 Wiley Periodicals, Inc.

Imatinib promotes apoptosis of giant cell tumor cells by targeting microRNA-30a-mediated runt-related transcription factor 2.

Giant cell tumor (GCT) is an aggressive type of bone tumor consisting of multinucleated osteoclast-like giant cells. Imatinib is a selective inhibitor for certain type III tyrosine kinase receptor family members with a variety of beneficial effects. The purpose of the present study was to determine the therapeutic potential and underlying mechanism of imatinib against GCT. In the present study, cell viability and apoptosis in GCT were analyzed using the MTT assay, flow cytometry and DAPI staining assay. Caspase-3 and -9 activity in GCT cells were analyzed with colorimetric assay kits. In addition, the expression levels of runt-related transcription factor 2 (RunX2) protein and microRNA-30a (miR-30a) in GCT cells were detected using western blotting and quantitative polymerase chain reaction, respectively. Results from the present study demonstrated that imatinib treatment inhibited cell viability, increased cell apoptosis, and significantly promoted caspase-3 and -9 activity in GCT. In addition, imatinib treatment decreased the RunX2 protein expression level. Notably, imatinib was demonstrated to increase miR-30a expression. However, upregulation of miR-30a expression reduced the RunX2 protein expression level, and downregulation of miR-30a expression reversed the anticancer effect of imatinib on GCT, increasing the expression level of RunX2 protein in GCT. The results of the present study indicate that imatinib promotes apoptosis of GCT cells by targeting the miR-30a-mediated RunX2 signaling pathway.

CSF1R inhibition with emactuzumab in locally advanced diffuse-type tenosynovial giant cell tumours of the soft tissue: a dose-escalation and dose-expansion phase 1 study.

BACKGROUND: Diffuse-type tenosynovial giant cell tumour (dt-GCT) of the soft tissue (alternatively known as pigmented villonodular synovitis), an orphan disease with unmet medical need, is characterised by an overexpression of colony-stimulating factor 1 (CSF1), and is usually caused by a chromosomal translocation involving CSF1. CSF1 receptor (CSF1R) activation leads to the recruitment of CSF1R-expressing cells of the mononuclear phagocyte lineage that constitute the tumor mass in dt-GCT. Emactuzumab (RG7155) is a novel monoclonal antibody that inhibits CSF1R activation. We have assessed the safety, tolerability and activity of emactuzumab in patients with Dt-GCT of the soft tissue. METHODS: In this phase 1, first-in-human dose-escalation and dose-expansion study, eligible patients were aged 18 years or older with dt-GCT of the soft tissue with locally advanced disease or resectable tumours requiring extensive surgery, an Eastern Cooperative Oncology Group performance status of 1 or less, measurable disease according to Response Evaluation Criteria In Solid Tumors version 1.1, and adequate end-organ function. Patients with GCT of the bone were not eligible. Patients received intravenous emactuzumab at 900 mg, 1350 mg, or 2000 mg every 2 weeks in the dose-escalation phase and at the optimal biological dose in a dose-expansion phase. The primary objective was to evaluate the safety and tolerability of emactuzumab, and to determine the maximum tolerated dose or optimal biological dose. All treated patients were included in the analyses. Expansion cohorts are currently ongoing. This study is registered with ClinicalTrials.gov, number NCT01494688. FINDINGS: Between July 26, 2012, and Oct 21, 2013, 12 patients were enrolled in the dose-escalation phase. No dose-limiting toxicities were noted in the dose-escalation cohort; on the basis of pharmacokinetic, pharmacodynamic, and safety information, we chose a dose of 1000 mg every 2 week for the dose-expansion cohort, into which 17 patients were enrolled. Owing to different cutoff dates for safety and efficacy readouts, the safety population comprised 25 patients. Common adverse events after emactuzumab treatment were facial oedema (16 [64%] of 25 patients), asthenia (14 [56%]), and pruritus (14 [56%]). Five serious adverse events (periorbital oedema, lupus erythematosus [occurring twice], erythema, and dermohypodermitis all experienced by one [4%] patient each) were reported in five patients. Three of the five serious adverse events-periorbital oedema (one [4%]), lupus erythematosus (one [4%]), and dermohypodermitis (one [4%])-were assessed as grade 3. Two other grade 3 events were reported: mucositis (one [4%]) and fatigue (one [4%]). 24 (86%) of 28 patients achieved an objective response; two (7%) patients achieved a complete response. INTERPRETATION: Further study of dt-GCT is warranted and different possibilities, such as an international collaboration with cooperative groups to assure appropriate recruitment in this rare disease, are currently being assessed. FUNDING: F Hoffmann-La Roche.

Giant Cell Tumor of the Uterus: A Report of 3 Cases With a Spectrum of Morphologic Features.

Giant cell tumors, a well-recognized neoplasm of bone, can rarely be found in the uterus. Such tumors are characterized by a dual population of mononuclear and osteoclast-like giant cells that lack epithelial and specific mesenchymal differentiation. In this study, the clinicopathologic features of 3 giant cell tumors of the uterus were reviewed. Immunohistochemistry for CD68, CD163, h-caldesmon, desmin, SMA, AE1/AE3, CD10, ER, PR, cyclin D1, CD1a, CD34, CD30, S100, myogenin/myoglobin, and Ki-67 was performed in all tumors, along with ultrastructural analysis in one. The patients were 47, 57, and 59 yr and the tumors measured 2.5, 7.5, and 16.0 cm. One neoplasm was confined to the endometrium, whereas the other 2 were myometrial. All 3 tumors showed a nodular growth comprised of mononuclear and osteoclast-like giant cells. The endometrial-confined tumor consisted of histologically benign mononuclear cells, whereas the others exhibited marked atypia. Mitotic activity was up to 5/10 HPF in the benign tumor and up to 22/10 HPF in the malignant. No cytologic atypia or mitoses were observed in the giant cells. CD68 and CD10 were strongly and diffusely expressed in both components of 3 and 2 neoplasms, respectively. Cyclin D1 was focal in the mononuclear cells and focal to diffuse in the giant cells. CD163 was diffuse in the mononuclear cells, but absent to focal in the giant cells. Ultrastructural analysis lacked diagnostic features of epithelial or specific mesenchymal differentiation. Both malignant tumors demonstrated an aggressive behavior. In summary, although rare, giant cell tumor of the uterus should be included in the differential diagnosis of benign or malignant tumors containing osteoclast-like giant cells.

Osteopontin expression in reactive lesions of gingiva.

Reactive proliferations of the gingiva comprise lesions such as pyogenic granuloma (PG), inflammatory fibroepithelial hyperplasia (IFH), peripheral ossifying fibroma (POF), and peripheral giant cell lesion. Osteopontin (OPN) has a dual role, it promotes mineralization when it is bound to solid substrate, and on the other hand, it inhibits mineralization when it is seen in association with solution. Objectives The study aimed to evaluate the expression of osteopontin in normal gingival tissue and different types of focal reactive proliferations of gingival tissue, and its role in the development of calcification within it. Material and Methods The presence and distribution of osteopontin was assessed using immunohistochemistry in five cases of normal gingival tissue and 30 cases of focal reactive proliferations of gingiva. Results There was no expression of osteopontin in normal subjects. Few cases of pyogenic granuloma, inflammatory fibroepithelial hyperplasia, and all the cases of peripheral ossifying fibroma showed positivity for osteopontin in the inflammatory cells, stromal cells, extracellular matrix, and in the calcifications. Conclusion The expression of osteopontin in all the cases of peripheral ossifying fibroma speculates that the majority of the cases of peripheral ossifying fibroma originate from the periodontal ligament cells. The treatment modalities for peripheral ossifying fibroma should differ from other focal reactive proliferations of gingiva.