The MOTION study: a randomized, phase III study of vimseltinib for the treatment of tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TGCT) is a rare, locally aggressive neoplasm that occurs in the synovium of joints, bursae, or tendon sheaths and is caused by upregulation of the CSF1 gene. Vimseltinib is an oral switch-control tyrosine kinase inhibitor specifically designed to selectively and potently inhibit the CSF1 receptor. Here, we describe the rationale and design for the phase III MOTION trial (NCT05059262), which aims to evaluate the efficacy and safety of vimseltinib in participants with TGCT not amenable to surgical resection. In part 1, participants are randomized to receive vimseltinib 30 mg twice weekly or matching placebo for ≤24 weeks. Part 2 is a long-term treatment phase in which participants will receive open-label vimseltinib.

Tenosynovial giant cell tumor (or TGCT) is a rare, noncancerous tumor that grows in the soft tissue lining the spaces of joints and bursae (fluid-filled sacs that work to reduce friction in the joints). These tumors are linked to increased levels of a protein called CSF1. While this condition is typically treated with surgery, some patients may not be candidates for surgical removal of the tumor due to factors such as location or complexity of the tumor; therefore, drug treatments are needed to help these patients. Vimseltinib is an investigational oral drug specifically designed to inhibit the receptor to which the CSF1 protein binds. In this article, we describe the rationale and design for a phase III clinical trial that will test how well vimseltinib works in participants with TGCT who are not candidates for surgery. In the first part of the study, participants are randomly assigned to receive vimseltinib 30 mg twice weekly or a matching placebo (inactive substance) for up to 24 weeks. This first part is blinded, so participants will not know if they are receiving vimseltinib or the placebo. The second part of the study is a long-term treatment phase in which all participants will receive vimseltinib (unblinded). Clinical Trial Registration: NCT05059262 (ClinicalTrials.gov).

A novel colony-stimulating factor 1 (CSF1) translocation involving human endogenous retroviral element in a tenosynovial giant cell tumor.

Tenosynovial giant cell tumors (TSGCTs) are rare tumors arising in tendons or the synoviae of joints and bursae. The localized type is benign while the diffuse type shows expansive growth leading to greater morbidity and is therefore considered locally aggressive. Typical recurrent chromosomal aberrations are found in the majority of TSCGT and the CSF1 gene is frequently involved. In this article, we describe a newly identified gene fusion mediated by an inversion in a case of diffuse TSGCT. Multicolor-fluorescence in situ hybridization (FISH) molecular karyotyping identified a pericentric inversion of chromosome 1 in 7 out of 17 analyzed cells 46,XX,inv(1)(p13.3q24.3) [7]/46,XX [10], and with interphase FISH the involvement the CSF1 locus was detected. After performing transcriptome sequencing analysis for fusion detection, only one out of five fusion gene algorithms detected a fusion involving the CSF1 gene product. The resulting chimera fuses a sequence from a human endogenous retrovirus (HERV) gene to CSF1 Exon 6 on chromosome 1, abrogating the regulatory element of the 3' untranslated region of the CSF1 gene. This new translocation involving Exon 6 of the CSF1 gene fused to 1q24.1, supports the hypothesis that a mutated CSF1 protein is likely to play a vital role in the pathogenesis of TSGCT. The role of the HERV partner identified as a translocation partner, however, remains unclear. Our data add to the complexity of involved translocation partners in TSGCT and point to the potential difficulty of identifying fusion partners in tumor diagnostics using transcriptome sequencing when HERV or other repeat elements are involved.

Role of colony-stimulating factor 1 in the neoplastic process of tenosynovial giant cell tumor.

Tenosynovial giant cell tumors (TGCTs) are rare, locally aggressive, mesenchymal neoplasms, most often arising from the synovium of joints, bursae, or tendon sheaths. Surgical resection is the first-line treatment, but recurrence is common, with resulting impairments in patients' mobility and quality of life. Developing and optimizing the role of systemic pharmacologic therapies in TGCT management requires an understanding of the underlying disease mechanisms. The colony-stimulating factor 1 receptor (CSF1R) has emerged as having an important role in the neoplastic processes underlying TGCT. Lesions appear to contain CSF1-expressing neoplastic cells derived from the synovial lining surrounded by non-neoplastic macrophages that express the CSF1R, with lesion growth stimulated by both autocrine effects causing proliferation of the neoplastic cells themselves and by paracrine effects resulting in recruitment of CSF1 R-bearing macrophages. Other signaling pathways with evidence for involvement in TGCT pathogenesis include programmed death ligand-1, matrix metalloproteinases, and the Casitas B-cell lymphoma family of ubiquitin ligases. While growing understanding of the pathways leading to TGCT has resulted in the development of both regulatory approved and investigational therapies, more detail on underlying disease mechanisms still needs to be elucidated in order to improve the choice of individualized therapies and to enhance treatment outcomes.

A Rare Case of Diffuse-type Tenosynovial Giant Cell Tumor in a Teenager With Noonan Syndrome.

Noonan syndrome is a common autosomal dominant disorder associated with an increased risk of malignancy. We report a 16-year-old female with Noonan syndrome (KRAS gene variant, Q22R) and diffuse-type tenosynovial giant cell tumor, a proliferative disorder that has been rarely reported in this population. These tumors may represent a complication of the dysregulated RAS/MAPK signaling pathway that underlies Noonan syndrome. They lack typical clinical features, causing misdiagnosis and delays in management, which could lead to osseous invasion requiring more complicated surgical procedures. Increased awareness of this association will improve the clinical outcomes of patients with Noonan syndrome who develop diffuse-type tenosynovial giant cell tumors.

Detection of CSF1 rearrangements deleting the 3' UTR in tenosynovial giant cell tumors.

Tenosynovial giant cell tumors (TGCTs) are characterized by rearrangements of CSF1, thought to drive overexpression of macrophage colony-stimulating factor (CSF1), thereby promoting tumor growth and recruitment of non-neoplastic mononuclear and multinucleated inflammatory cells. While fusions to collagen promoters have been described, the mechanism of CSF1 overexpression has been unclear in a majority of cases. Two cohorts of TGCT were investigated for CSF1 rearrangements using fluorescence in situ hybridization (FISH) and either RNA-seq or DNA-seq with Sanger validation. The study comprised 39 patients, including 13 localized TGCT, 21 diffuse TGCT, and five of unspecified type. CSF1 rearrangements were identified by FISH in 30 cases: 13 translocations, 17 3' deletions. Sequencing confirmed CSF1 breakpoints in 28 cases; in all 28 the breakpoint was found to be downstream of exon 5, replacing or deleting a long 3' UTR containing known miRNA and AU-rich element negative regulatory sequences. We also confirmed the presence of CBL exon 8-9 mutations in six of 21 cases. In conclusion, TGCT in our large cohort were characterized by variable alterations, all of which led to truncation of the 3' end of CSF1, instead of the COL6A3-CSF1 fusions previously reported in some TGCTs. The diversity of fusion partners but consistent integrity of CSF1 functional domains encoded by exons 1-5 support a hypothesis that CSF1 overexpression results from transcription of a truncated form of CSF1 lacking 3' negative regulatory sequences. The presence of CBL mutations affecting the linker and RING finger domain suggests an alternative mechanism for increased CSF1/CSF1R signaling in some cases.

Massively parallel sequencing of tenosynovial giant cell tumors reveals novel CSF1 fusion transcripts and novel somatic CBL mutations.

Tenosynovial giant cell tumor (TSGCT) is a rare neoplasm. Although surgical resection is the widely accepted primary treatment for TSGCT, recurrences are frequent, and patients' joint function may be severely compromised. Previous studies reported that CSF1-COL6A3 fusion genes were identified in approximately 30% of TSGCTs. The aim of our study was to comprehensively clarify the genomic abnormalities in TSGCTs. We performed whole exome sequencing in combination with target sequence validation on 34 TSGCT samples. RNA sequencing was also performed on 18 samples. RNA sequencing revealed fusion transcripts involving CSF1, including novel CSF1-VCAM1, CSF1-FN1 and CSF1-CDH1 fusions, in 13/18 (72%) cases. These fusion genes were validated by chromogenic in situ hybridization. All CSF1 fusions resulted in the deletion of CSF1 exon 9, which was previously shown to be an important negative regulator of CSF1 expression. We also found that 12 (35%) of the 34 TSGCT samples harbored CBL missense mutations. All mutations were detected in exons 8 or 9, which encode the linker and RING finger domain. Among these mutations, C404Y, L380P and R420Q were recurrent. CBL-mutated cases showed higher JAK2 expression than wild-type CBL cases (p = 0.013). CSF1 fusion genes and CBL mutations were not mutually exclusive, and both alterations were detected in six of the 18 (33%) tumors. The frequent deletion of CSF1 exon 9 in the fusion transcripts suggested the importance of this event in the etiology of TSGCT. Our results may contribute to the development of new targeted therapies using JAK2 inhibitors for CBL-mutated TSGCT.

Malignant Tenosynovial Giant Cell Tumor: The True "Synovial Sarcoma?" A Clinicopathologic, Immunohistochemical, and Molecular Cytogenetic Study of 10 Cases, Supporting Origin from Synoviocytes.

We present our experience with ten well-characterized malignant tenosynovial giant cell tumors, including detailed immunohistochemical analysis of all cases and molecular cytogenetic study for CSF1 rearrangement in a subset. Cases occurred in 7 M and 3 F (mean age: 52 years; range: 26-72 years), and involved the ankle/foot (n = 1), finger/toe (n = 3), wrist (n = 1), pelvic region (n = 3), leg (n = 1), and thigh (n = 1). There were eight primary and two secondary malignant tenosynovial giant cell tumors. Histologically, all cases showed definite areas of typical tenosynovial giant cell tumor. The malignant areas varied in appearance. In some cases, isolated malignant-appearing large mononuclear cells with high nuclear grade and mitotic activity were identified within otherwise-typical tenosynovial giant cell tumor, as well as forming larger masses of similar-appearing malignant cells. Occasionally, these nodules of malignant large mononuclear cells showed transition to pleomorphic spindle cell sarcoma, with varying degrees of collagenization and myxoid change. One malignant tenosynovial giant cell tumor was composed of sheets of monotonous large mononuclear cells with high nuclear grade, growing in a hyalinized, osteoid-like matrix, with areas of heterologous osteocartilaginous differentiation. Mitotic activity ranged from 2 to 34 mitoses per 10 HPF (mean 18/10 HPF). Geographic necrosis was observed in four cases. The malignant-appearing large mononuclear cells were consistently positive for clusterin and negative for CD163, CD68, and CD11c. Desmin was positive in a small minority of these cells. Areas in malignant tenosynovial giant cell tumor resembling pleomorphic spindle cell sarcoma or osteo/chondrosarcoma showed loss of clusterin expression. RANKL immunohistochemistry was positive in the large mononuclear cells in eight cases. Two cases showed an unbalanced rearrangement of the CSF1 locus. Follow-up (nine patients; range 0.5-66 months; mean 20 months) showed three patients dead of disease, with three other living patients having lung and lymph node metastases; three patients were disease-free. We conclude that malignant tenosynovial giant cell tumors are highly aggressive sarcomas with significant potential for locally destructive growth, distant metastases, and death from disease. The morphologic and immunohistochemical features of these tumors and the presence of CSF1 rearrangements support origin of malignant tenosynovial giant cell tumor from synoviocytes.

Does CSF1 overexpression or rearrangement influence biological behaviour in tenosynovial giant cell tumours of the knee?

AIMS: Localised- and diffuse-type tenosynovial giant cell tumours (TGCT) are regarded as different clinical and radiological TGCT types. However, genetically and histopathologically they seem indistinguishable. We aimed to correlate CSF1 expression and CSF1 rearrangement with the biological behaviour of different TGCT-types with clinical outcome (recurrence). METHODS AND RESULTS: Along a continuum of extremes, therapy-naive knee TGCT patients with >3-year follow-up, mean age 43 (range = 6-71) years and 56% females were selected. Nine localised (two recurrences), 16 diffuse-type (nine recurrences) and four synovitis as control were included. Rearrangement of the CSF1 locus was evaluated with split-apart fluorescence in-situ hybridisation (FISH) probes. Regions were selected to score after identifying CSF1-expressing regions, using mRNA ISH with the help of digital correlative microscopy. CSF1 rearrangement was considered positive in samples containing >2 split signals/100 nuclei. Irrespective of TGCT-subtype, all cases showed CSF1 expression and in 76% CSF1 rearrangement was detected. Quantification of CSF1-expressing cells was not informative, due to the extensive intratumour heterogeneity. Of the four synovitis cases, two also showed CSF1 expression without CSF1 rearrangement. No correlation between CSF1 expression or rearrangement with clinical subtype and local recurrence was detected. Both localised and diffuse TGCT cases showed a scattered distribution in the tissue of CSF1-expressing cells. CONCLUSION: In diagnosing TGCT, CSF1 mRNA-ISH, in combination with CSF1 split-apart FISH using digital correlative microscopy, is an auxiliary diagnostic tool to identify rarely occurring neoplastic cells. This combined approach allowed us to detect CSF1 rearrangement in 76% of the TGCT cases. Neither CSF1 expression nor presence of CSF1 rearrangement could be associated with the difference in biological behaviour of TGCT.

EWSR1-SMAD3 positive fibroblastic tumor.

We present a case of EWSR1-SMAD3 positive fibroblastic tumor that occurred in a 24-year-old man who presented with a recurrent tumor in the dorsum of his right foot. Magnetic resonance imaging (MRI) demonstrated a subcutaneous nodule located in the third metatarsophalangeal joint region, measuring 10 × 8 × 5 mm in size. Histological examination revealed a monomorphic spindle cell tumor composed of cellular fascicles of bland fibroblasts with hyalinization. Immunohistochemically, the tumor showed diffuse nuclear staining of ERG. Fluorescence in situ hybridization (FISH) assessment demonstrated an unbalanced rearrangement of the EWSR1 gene. Further next-generation sequencing (NGS) analysis identified EWSR1-SMAD3 gene fusion. Molecular detection may be helpful for identifying new entities, in particular to those that lack lineage-specific differentiation by conventional pathological examinations.

USP6 genetic rearrangements in cellular fibroma of tendon sheath.

Fibroma of tendon sheath is a benign (myo)fibroblastic neoplasm of the tenosynovial soft tissues, typically affecting the distal extremities. It is classically described as a paucicellular, densely collagenized tumor; however, cellular variants have been described. A subset of cellular fibromas of tendon sheath shares similar histological features with nodular fasciitis. As nodular fasciitis very frequently harbors rearrangement of ubiquitin-specific peptidase 6 (USP6), we hypothesized that cellular fibromas of tendon sheath with nodular fasciitis-like features may also contain USP6 rearrangements. Cases of fibroma of tendon sheath (n=19), including cellular (n=9) and classic (n=10) variants, were evaluated for USP6 rearrangement by fluorescence in situ hybridization studies. A subset of cases was tested for MYH9 rearrangements and MYH9-USP6 and CDH11-USP6 fusion products. Classic fibroma of tendon sheath occurred in 5 males and 5 females (median age 67 years, range 23-77 years) as soft tissue masses of the hand (n=4), finger (n=3), forearm (n=1) and foot (n=2). Cellular fibroma of tendon sheath occurred in 5 males and 4 females in a younger age group (median age 32 years, range 12-46 years) as small soft tissue masses of the finger (n=5), hand (n=3) and wrist (n=1). USP6 rearrangements were detected in 6/9 cellular fibromas of tendon sheath. Among cellular fibromas of tendon sheath with USP6 rearrangements, no MYH9 rearrangements were detected. By RT-PCR, neither the MYH9-USP6 or the CDH11-USP6 fusion products were detected in any case. Neither USP6 nor MYH9 rearrangement were detected in any classic fibroma of tendon sheath. We report for the first time the presence of USP6 rearrangements in a subset of cellular fibroma of tendon sheath. Based on the similar morphological and molecular genetic features, we suspect that a subset of cellular fibromas of tendon sheath are under-recognized examples of tenosynovial nodular fasciitis, driven by alternate USP6 fusion genes. Further investigation will delineate how these lesions should best be classified.

Tenosynovial giant cell tumor: case report and molecular investigation.

Tenosynovial giant cell tumor is a benign neoplasm arising from the synovium of joints, including the temporomandibular joint (TMJ). Despite its benign nature, these tumors may exhibit aggressive behavior. A 57-year-old woman with a swollen, hardened area in the left TMJ was referred to the university´s clinic. The diagnosis of tenosynovial giant cell tumor was made based on the presence of hyperplastic synovial lining containing mononuclear and giant cells, hemorrhagic areas, hemosiderin deposits, and calcification foci in the biopsy. A low condylectomy was performed, and histopathologic analysis of the surgical piece upheld the diagnosis. Due to histopathologic resemblance with other giant cell-rich lesions (giant cell granuloma of the jaws, brown tumor of hyperparathyroidism, and non-ossifying fibroma) for which signature mutations are known, mutational analysis of KRAS, FGFR1, and TRPV4 genes was conducted. The results revealed wild-type sequences for all the mutations tested, thereby supporting the diagnosis of tenosynovial giant cell tumor.

Novel CSF1R-positive tenosynovial giant cell tumor cell lines and their pexidartinib (PLX3397) and sotuletinib (BLZ945)-induced apoptosis.

Tenosynovial giant cell tumor (TGCT) is a mesenchymal tumor derived from the synovium of the tendon sheath and joints, most frequently in the large joints. The standard of care for TGCTs is surgical resection. A new targeting approach for treating TGCTs has emerged from studies on the role of the CSF1/CSF1 receptor (CSF1R) in controlling cell survival and proliferation during the pathogenesis of TGCTs. We established four novel cell lines isolated from the primary tumor tissues of patients with TGCTs. The cell lines were designated Si-TGCT-1, Si-TGCT-2, Si-TGCT-3, and Si-TGCT-4, and the TGCT cells were characterized by CSF1R and CD68. These TGCT cells were then checked for cell proliferation using an MTT assay and three-dimensional spheroid. The responses to pexidartinib (PLX3397) and sotuletinib (BLZ945) were evaluated by two-dimensional MTT assays. All cells were positive for α­smooth muscle actin (α­SMA), fibroblast activation protein (FAP), CSF1R, and CD68. Except for Si-TGCT-4, all TGCT cells had high CSF1R expressions. The cells exhibited continuous growth as three-dimensional spheroids formed. Treatment with pexidartinib and sotuletinib inhibited TGCT cell growth and induced cell apoptosis correlated with the CSF1R level. Only Si-TGCT-4 cells demonstrated resistance to the drugs. In addition, the BAX/BCL-2 ratio increased in cells treated with pexidartinib and sotuletinib. With the four novel TGCT cell lines, we have an excellent model for further in vitro and in vivo studies.

Interactions in CSF1-Driven Tenosynovial Giant Cell Tumors.

PURPOSE: A major component of cells in tenosynovial giant cell tumor (TGCT) consists of bystander macrophages responding to CSF1 that is overproduced by a small number of neoplastic cells with a chromosomal translocation involving the CSF1 gene. An autocrine loop was postulated where the neoplastic cells would be stimulated through CSF1R expressed on their surface. Here, we use single-cell RNA sequencing (scRNA-seq) to investigate cellular interactions in TGCT. EXPERIMENTAL DESIGN: A total of 18,788 single cells from three TGCT and two giant cell tumor of bone (GCTB) samples underwent scRNA-seq. The three TGCTs were additionally analyzed using long-read RNA sequencing. Immunofluorescence and IHC for a range of markers were used to validate and extend the scRNA-seq findings. RESULTS: Two recurrent neoplastic cell populations were identified in TGCT that are highly similar to nonneoplastic synoviocytes. We identified GFPT2 as a marker that highlights the neoplastic cells in TCGT. We show that the neoplastic cells themselves do not express CSF1R. We identified overlapping MAB features between the giant cells in TGCT and GCTB. CONCLUSIONS: The neoplastic cells in TGCT are highly similar to nonneoplastic synoviocytes. The lack of CSF1R on the neoplastic cells indicates they may be unaffected by current therapies. High expression of GFPT2 in the neoplastic cells is associated with activation of the YAP1/TAZ pathway. In addition, we identified expression of the platelet-derived growth factor receptor in the neoplastic cells. These findings suggest two additional pathways to target in this tumor.

Diagnostic utility of CSF1 immunohistochemistry in tenosynovial giant cell tumor for differentiating from giant cell-rich tumors and tumor-like lesions of bone and soft tissue.

BACKGROUND: Tenosynovial giant cell tumor (TSGCT) is a benign fibrohistiocytic tumor that affects the synovium of joints, bursa, and tendon sheaths and is categorized into localized TSGCT (LTSGCT) and diffuse TSGCT (DTSGCT). LTSGCT and DTSGCT are characterized by recurrent fusions involving the colony-stimulating factor 1 (CSF1) gene and its translocation partner collagen type VI alpha 3 chain. The fusion gene induces intratumoral overexpression of CSF1 mRNA and CSF1 protein. CSF1 expression is a characteristic finding of TSGCT and detection of CSF1 mRNA and CSF1 protein may be useful for the pathological diagnosis. Although there have been no effective anti-CSF1 antibodies to date, in situ hybridization (ISH) for CSF1 mRNA has been performed to detect CSF1 expression in TSGCT. We performed CSF1 immunohistochemistry (IHC) using anti-CSF1 antibody (clone 2D10) in cases of TSGCT, giant cell-rich tumor (GCRT), and GCRT-like lesion and verified its utility for the pathological diagnosis of TSGCT. METHODS: We performed CSF1 IHC in 110 cases including 44 LTSGCTs, 20 DTSGCTs, 1 malignant TSGCT (MTSGCT), 10 giant cell tumors of bone, 2 giant cell reparative granulomas, 3 aneurysmal bone cysts, 10 undifferentiated pleomorphic sarcomas, 10 leiomyosarcomas, and 10 myxofibrosarcomas. We performed fluorescence ISH (FISH) for CSF1 rearrangement to confirm CSF1 expression on IHC in TSGCTs. We considered the specimens to have CSF1 rearrangement if a split signal was observed in greater than 2% of the tumor cells. RESULTS: Overall, 50 of 65 TSGCT cases, including 35 of the 44 LTSGCTs and 15 of the 20 DTSGCTs, showed distinct scattered expression of CSF1 in the majority of mononuclear tumor cells. MTSGCT showed no CSF1 expression. Non-TSGCT cases were negative for CSF1. FISH revealed CSF1 rearrangement in 6 of 7 CSF1-positive cases on IHC. On the other hand, FISH detected no CSF1 rearrangement in all CSF1-negative cases on IHC. Thus, the results of IHC corresponded to those of FISH. CONCLUSION: We revealed characteristic CSF1 expression on IHC in cases of TSGCT, whereas the cases of non-TSGCT exhibited no CSF1 expression. CSF1 IHC may be useful for differentiating TSGCTs from histologically mimicking GCRTs and GCRT-like lesions.

t(1;2)-Positive Localized Tenosynovial Giant Cell Tumor With Bone Invasion.

BACKGROUND: Localized tenosynovial giant cell tumor (LTGCT) is one of the most common benign soft-tissue tumors of the foot. Although pressure erosion in the adjacent bone may be seen, intraosseous invasion of LTGCT is extremely rare. Recent molecular studies have identified the presence of pathognomonic translocation involving the colony stimulating factor 1 (CSF1) gene at 1p13. CASE REPORT: We present an unusual case of LTGCT mimicking a malignant tumor on imaging. The patient was a 16-year-old woman with no history of trauma who presented with a 2-year history of a slow-growing, painless mass in the left fourth toe. Physical examination revealed a 2-cm, elastic hard, immobile, nontender mass. Plain radiograph showed a lytic lesion with a partially sclerotic rim in the proximal phalanx of the fourth toe. Computed tomography demonstrated an expansile lesion with plantar cortical destruction. Magnetic resonance imaging revealed a nodular mass with intermediate signal intensity on T1-weighted sequences and heterogeneous high signal intensity on T2-weighted sequences. The mass had intense contrast enhancement. Complete excision of the mass was performed, and the bone defect was repaired with calcium phosphate cement. Cytogenetic analysis revealed a t(1;2)(p13;q37) translocation as the sole anomaly. Fluorescence in situ hybridization demonstrated the presence of CSF1 rearrangements. CONCLUSION: Although extremely rare, LTGCT should be considered in the differential diagnosis of an intraosseous lesion near small joints, especially when seen in the toe.

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.

ß-Arrestin2 Inhibits the Apoptosis and Facilitates the Proliferation of Fibroblast-like Synoviocytes in Diffuse-type Tenosynovial Giant Cell Tumor.

BACKGROUND/AIM: Diffuse-type tenosynovial giant cell tumor (TGCT) is a rare benign proliferative synovial neoplasm of uncertain etiology, and the efficacy of surgical resection is not satisfactory. Therefore, there is an urgent need to explore the pathogenesis and identify novel therapeutic targets for TGCT. MATERIALS AND METHODS: Synovial tissues were collected from patients with TGCT and osteoarthritis (OA). Differences of mRNA expression between TGCT and OA were explored using mRNA-seq. In addition, fibroblast-like synoviocytes (FLS) were treated with small interfering RNA (siRNA) or adenovirus in order to knockdown or overexpress ß-arrestin2 (Arrb2), respectively. FLS proliferation and apoptosis were evaluated using the MTT assay and the caspase 3 activity assay, respectively. RESULTS: The expression of Arrb2 in TGCT was significantly higher than that in OA. The overexpression of Arrb2 promoted the proliferation of FLS and inhibited its apoptosis, while knocking down Arrb2 had the opposite effect. Further studies showed that Arrb2 can activate the PI3K-Akt signaling pathway, leading to increased proliferation of TGCT. CONCLUSION: Arrb2 facilitates the proliferation and inhibits the apoptosis of TGCT FLS through activating the PI3K-Akt cell survival pathway, providing new insight into the molecular mechanism of TGCT.

Establishment and characterization of a novel cell line, NCC-TGCT1-C1, derived from a patient with tenosynovial giant cell tumor.

Tenosynovial giant cell tumor (TGCT) is a mesenchymal tumor arising from the synovium of tendon sheath and joints, characterized by translocation t(1;2)(p13;q37). Clinical behaviors of TGCT range from favorable to locally aggressive and further research is required to lead the identification of novel therapeutic avenues for TGCT. Patient-derived cell lines are an indispensable tool for interrogating molecular mechanisms underlying the progression of disease. However, only one TGCT cell line is currently available from cell banks, and a paucity of adequate patient-derived cells hinders basic and translational research. This study aimed to establish a novel cell line of TGCT. To this end, a novel cell line, NCC-TGCT1-C1 was established from the primary tumor tissue of a 40-year-old female patient with TGCT. The cells exhibited translocation t(1;2)(p13;q37), generating COL6A3-CSF1 fusion gene. The cells were maintained as a monolayer culture through more than 30 passages over 12 months. The cells exhibited continuous growth and the ability for spheroid formation and invasion. When used in a high-throughput assay to evaluate the anti-proliferative effects of 164 anticancer drugs, the cells responded strongly to a kinase inhibitor such as gefitinib, and mitoxantrone. Our results indicate that the novel TGCT cell line, designated NCC-TGCT1-C1, was successfully established and could be used to study TGCT development and the effects of anticancer agents.

Giant Cell Tumor of Tendon Sheath With a t(1;1)(p13;p34) Chromosomal Translocation.

BACKGROUND: Giant cell tumor of tendon sheath (GCTTS) is a benign soft-tissue tumor that occurs predominantly in the fingers, with the capacity for local recurrence. The cytogenetic hallmark of GCTTS is the presence of 1p13 rearrangement. Several chromosomal segments have been recognized as translocation partners to 1p13. Herein, we describe a novel cytogenetic finding of GCTTS arising in the right thumb of a 71-year-old man. CASE REPORT: Physical examination revealed a 4-cm, elastic hard, immobile, nontender mass. Magnetic resonance imaging demonstrated a nodular mass with reduced signal intensity on both T1- and T2-weighted images. Contrast-enhanced fat-suppressed T1-weighted images showed intense heterogeneous enhancement of the mass. After a needle biopsy, complete excision was performed. Histologically, the tumor was composed of mononuclear cells admixed with multinucleated osteoclast-like giant cells, hemosiderin-laden macrophages, foamy cells, and inflammatory cells. Cytogenetic analysis revealed a reciprocal t(1;1)(p13;p34) translocation as the sole structural aberration. CONCLUSION: To the best of our knowledge, this is the first report of this tumor with t(1;1)(p13;p34).

Optimal Treatment for Tenosynovial Giant Cell Tumor of the Hand.

This review examines the following aspects of tenosynovial giant cell tumors (TSGCTs): the use of multiple names, the complex relationship between tumor growth pattern and location, the high rate of postoperative recurrence, local invasiveness, use of nonsurgical therapy with molecularly targeted drugs, and best current treatments. This tumor has been referred to by various names, but is now most frequently referred to as TSGCT. TSGCT is classified as localized and diffuse, in accordance with its growth characteristics. Most TSGCTs of the fingers are localized. TSGCT is likely a neoplastic process arising from synovial lining cells, in which tumor cells express the colony stimulating factor 1 (CSF1) gene. The postoperative recurrence rate of TSGCT is approximately 15%. The intrinsic characteristics of recurrence are not clear, and complete resection of the lesion is still the treatment mainstay. Moreover, TSGCT commonly grows out of a pseudocapsule. Therefore, to perform complete resection of TSGCT, surgery must be performed cautiously after appropriate preparation, by using anesthesia, a tourniquet, surgical loupe, and surgical microscopy. After accurate preoperative diagnosis, meticulous planning by surgeons is necessary. The lesion should be resected along with approximately 1-mm of healthy tissue at the adhesion site. In addition, because satellite lesions might be present near the tumor, careful dissection and observation of the color of surrounding tissue are important. International clinical trials of CSF1 receptor inhibitors for TSGCT treatment are ongoing.