NAB2-STAT6 Gene Fusion Research Articles

Intracranial Solitary Fibrous Tumor in a 25-Year-Old Woman

<p><strong>Introduction:</strong> Intracranial solitary fibrous tumors (ISFTs) are extremely rare spindle cell tumors originating from dendritic mesenchymal cells expressing CD34 antigens that are usually benign, although malignant transformation had been reported. The knowledge of natural course and prognostic factors of ISFTs is still limited and the tumor is easily misdiagnosed.</p><p><strong>Case Presentation:</strong> An intra-cranial extra-axial tumor tissue resection from a 25-year-old woman was evaluated in the Surgical Pathology Laboratory. Histologic findings (cellular spindle cell tumor with ‘patternless’ pattern, staghorn blood vessels and <5 mitoses per 10 hpf) and immunophenotype (positive for CD34, weakly and focally positive for STAT6) suggested a diagnosis of intracranial solitary fibrous tumor WHO Grade II.</p><p><strong>Discussion:</strong> ISFTs have very low incidence in the CNS and are difficult to distinguish radiologically from meningiomas, thus post operative pathological examination and immunohistochemistry markers evaluations are the mainstay for diagnosis. ISFT is associated with NAB2-STAT6 gene fusion and may exhibits a wide spectrum of histological features. STAT6 immunohistochemistry is considered as one of the most sensitive diagnostic methods, while the evaluation of CD34 expression can be used as alternative diagnostic method despite having lower sensitivity.</p>

Malignant solitary fibrous tumor of the kidney with IGF2 secretion and without hypoglycemia

BackgroundSolitary fibrous tumor (SFT) is a rare fibroblastic mesenchymal tumor that mostly involves the pleura and infrequently involves extra-pleural sites. De novo SFT of the kidney is uncommon, and malignant SFT is extremely rare.Case presentationWe report a case of a 51-year-old man with a large malignant SFT in the left kidney. Pathological examination confirmed the diagnosis of SFT based on typical morphology, nuclear STAT6 expression, and NAB2-STAT6 gene fusion. The malignant subtype was determined by a large tumor size (≥ 15 cm) and high mitotic counts (8/10 high-power fields). KRAS mutation was identified by DNA sequencing. Insulin-like growth factor 2 (IGF2) was diffusely and strongly expressed in tumor cells, however, hypoglycemia was not observed. Hyperglycemia and high adrenocorticotropic hormone (ACTH) concentration were observed one month after surgery. Hormone measurements revealed normal blood cortisol and aldosterone levels, and increased urinary free cortisol level. A pituitary microadenoma was identified using brain magnetic resonance imaging, which may be responsible for the promotion of hyperglycemia.ConclusionsWe report a case of renal malignant SFT with a KRAS mutation, which was previously unreported in SFT and may be associated with its malignant behavior. Additionally, we emphasize that malignant SFT commonly causes severe hypoglycemia due to the production of IGF2. However, this effect may be masked by the presence of other lesions that promote hyperglycemia. Therefore, when encountering a malignant SFT with diffuse and strong IGF2 expression and without hypoglycemia, other lesions promoting hyperglycemia need to be ruled out.

Exploring Solitary Fibrous Tumors at a Tertiary Cancer Center: Clinicopathological and Immunomorphologic Profile.

Background Solitary fibrous tumor (SFT) is a distinct fibroblastic tumor that can occur at any anatomical site and can manifest a variety of histopathological features. NAB2-STAT6 gene fusion has recently emerged as a sensitive and specific molecular marker and its surrogate on immunohistochemistry, STAT6 has also displayed considerable efficacy. Nevertheless, its histologic diversity can result in diagnostic challenges, especially when classic features are not apparent. Methods A retrospective study was conducted at a tertiary cancer centre in North India over 3 years to document the clinicopathologic and immunomorphologic profile of SFTs. Immunohistochemical analysis of BCORand p53 were gauged additionally and patients were stratified according to Modified Demicco and Salas criteria for risk of metastasis. Results Sixteen patients of SFT were identified, affecting middle-aged men and women equally. Though lung/pleura are known to be involved commonly, SFT affects other sites such as the kidney, brain, buccal mucosa, liver, and penis as well. The majority endured localized disease while a lesser number suffered locoregional/distant spread. Two patients revealed features of a malignant profile. Risk stratification according to the Modified Demicco and Salas criteria evinced comparable results. No discernible relationship however was highlighted between the immunohistochemical expression of BCOR, p53, and any significant SFT parameter. Conclusion Although SFTs are very rare substantially benign mesenchymal neoplasms, pathologists must be conversant with their histological diversity and be vigilant of their malignant attributes. The worth of STAT6 immunohistochemistry for precise diagnosis and long-term studies for delineating clinical behavior cannot be overemphasized.

P-02 A case of solitary fibrous tumor originating from the adrenal gland presenting with hypoglycemia

Abstract Introduction Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm usually located in the pleura and associated with NAB2-STAT6 gene fusion. According to the World Health Organization (WHO) classification, although most SFTs are considered well benign, some SFTs have cytological atypia, hypercellularity, tumor necrosis, Ki-67 greater than 5%, high mitotic rate (>4 per high-power field (HPF)) and/or the presence of infiltrative surgical margins are considered malignant. SFT with severe hypoglycemia is called Doege-Potter syndrome which occurs with ectopic secretion of a prohormone of insulin-like growth factor 2 (IGF-2) from tumor tissue. We present a case who applied with severe hypoglycemia and was diagnosed with a solitary fibrous tumor thought to originate from the adrenal gland located in the right retroperitoneal region. Clinical Case A 61-year-old female patient was admitted to the hospital after hypoglycemia was detected in her application due to clouding of consciousness. While the patient's glucose level was 23 mg/dL, insulin:0.4 µIU/mL, C-peptide:<0.01 ng/mL, serum cortisole: 24,20 (µg/mL), growth hormone (GH): 13,20 ng/ mL and insulin-like growth factor I (IGF-1) 38 ng/mL were measured. Insulinoma was excluded and because of IGF-2 level could not be measured in our hospital, low serum insulin and IGF-1 levels suggested high serum IGF-2 levels. HbA1c, adrenal gland, and pituitary function tests were normal (Table 1). A mass lesion of approximately 145×133 mm in size, with heterogeneous contrast, containing cystic areas, was seen, which was thought to originate from the right adrenal gland in the upper abdomen tomography taken due to the presence of a palpable abdominal mass on physical examination (Figure 1). Urine catecholamines were found to be normal, and the plasma aldosterone concentration (PAC)/plasma renin activity (PRA) ratio was 2.56. The patient was operated under intravenous infusion of 10% dextrose due to persistent hypoglycemia. The immunohistochemical evaluation showed CD34, SOX-1 and STAT6 positivity and negativity for S-100, HMB45, straight muscle actin, desmin, caldesmon and melan A, thus confirming the diagnosis of a solitary fibrous tumor. After the operation, the patient's hypoglycemia disappeared. Since there are cases in the literature in which Doege-Potter syndrome was diagnosed without measuring IGF-2, we think that our patient had IGF-2-related hypoglycemia. Conclusion The development of hypoglycemia in Doege-Potter syndrome has been associated with the secretion of large amounts of IGF-2 by tumor tissue, resulting in decreased IGF-1 and Insulin-like growth factor-binding protein 3 (IGFBP-3) concentrations. In these patients, the tumor originates from mesenchymal tumors of low malignant potential. In our case, the Ki-67 proliferation index was around 2%, it was considered benign, and the patient's symptoms completely regressed after resection.Figure 1.CT images of the patientA mass in the right retroperitoneal area, associated with the adrenal gland and containing areas of necrosis, is seen on non-contrast (a) and contrast-enhanced (b) CT scans. Table 1.Laboratory workup

Establishment and characterization of a patient-derived solitary fibrous tumor/hemangiopericytoma cell line model.

Solitary fibrous tumor/Hemangiopericytoma (SFT/HPC) is a rare subtype of soft tissue sarcoma harboring NAB2-STAT6 gene fusions. Mechanistic studies and therapeutic development on SFT/HPC are impeded by scarcity and lack of system models. In this study, we established and characterized a novel SFT/HPC patient-derived cell line (PDC), SFT-S1, and screened for potential drug candidates that could be repurposed for the treatment of SFT/HPC. Immunohistochemistry profiles of the PDC was consistent with the patient's tumor sample (CD99+/CD34+/desmin-). RNA sequencing, followed by Sanger sequencing confirmed the pathognomonic NAB2exon3-STAT6exon18 fusion in both the PDC and the original tumor. Transcriptomic data showed strong enrichment for oncogenic pathways (epithelial-mesenchymal transition, FGF, EGR1 and TGFβ signaling pathways) in the tumor. Whole genome sequencing identified potentially pathogenic somatic variants such as MAGEA10 and ABCA2. Among a panel of 14 targeted agents screened, dasatinib was identified to be the most potent small molecule inhibitor against the PDC (IC50, 473 nM), followed by osimertinib (IC50, 730 nM) and sunitinib (IC50, 1765 nM). Methylation profiling of the tumor suggests that this specific variant of SFT/HPC could lead to genome-wide hypomethylation. In conclusion, we established a novel PDC model of SFT/HPC with comprehensive characterization of its genomic, epigenomic and transcriptomic landscape, which can facilitate future preclinical studies of SFT/HPC, such as in vitro drug screening and in vivo drug testing.

Chitinase 3-like 1 induces cancer cell migration in solitary fibrous tumors

Solitary fibrous tumor (SFT) is a rare mesenchymal tumor that is diagnosed through the detection of the NAB2-STAT6 fusion gene. SFT rarely progresses to malignant tumors; however, metastasis is exhibited in approximately 20% of patients with SFT. In this study, we found that chitinase 3-like 1 (CHI3L1), which induces cancer cell migration, was upregulated in NIH-3T3 cells that were transfected with the NAB2-STAT6 fusion gene. Moreover, the expression levels of the migration markers MMP2 and MMP9 were increased and the p-Akt level was also upregulated. In addition, it was observed that when CHI3L1 siRNA was transfected into NAB2-STAT6-transfected cells, cell migration and proliferation were reduced. Therefore, this study demonstrated that CHI3L1 activates Akt signaling to induce cell migration.

Clinicopathological features of spinal solitary fibrous tumor

Objective: To investigate the clinicopathological, molecular genetic, immunohistochemical and prognostic features of spinal solitary fibrous tumor (SFT). Methods: The clinical data of 12 cases of spinal SFT in Beijing Tsinghua Changgung Hospital, Affiliated to Tsinghua University, diagnosed from January 2015 to December 2021 were collected and reclassified. The clinical data, histopathology, immunohistochemistry and molecular genetics were analyzed. Follow-up and related literature reviews were conducted. Results: Among the 12 patients, there were 5 males and 7 females; the age ranged from 31 to 73 years, with a median age of 50.5 years. All 12 cases were primary tumors, including 4 cases diagnosed at the first time and 8 recurrent cases. Among the 12 cases, 8 were WHO grade 1, 3 were WHO grade 2, and 1 was WHO grade 3. Microscopically, the spinal SFT appeared as a spindle cell tumor, the stroma was rich in many thin-walled blood vessels with various histological features such as cell morphology and necrosis according to the different tumor grade. All (12/12) of the cases expressed vimentin and STAT6 (diffuse and strong nuclear stain), 11 cases (11/12) expressed both CD34 and bcl-2, and 7 cases (7/12) expressed CD99. Next-generation sequencing showed that 12 (12/12) of the patients had NAB2-STAT6 gene fusion. The 12 patients were followed up for 6 to 80 months. There were no recurrences or metastases in the 4 first cases after operation. Among the 8 recurrent cases, 2 of the patients relapsed and 2 died. Conclusions: Spinal SFT is rare and has a high recurrence tendency. Many aspects need to be considered in the diagnosis process. STAT6 is a relatively specific marker for the diagnosis of this tumor. Complete surgical resection is the preferred treatment while postoperative radiotherapy is recommended to reduce tumor recurrence.

Solitary fibrous tumor: A rare lesion with an unusual paravertebral presentation

BackgroundSolitary fibrous tumor (SFT) is a rare spindle-cell neoplasm [1]. Although typically originating from pleura, head and neck presentation accounts for about 6–18 % and very few cases have been described in paravertebral and posterior neck spaces [2]. Both computed tomography (CT) scans and magnetic resonance imaging (MRI) help in differential diagnosis of such lesion [3]. However, only histological and immunohistochemical studies give a conclusive diagnosis: CD34, BCL-2, and in particular STAT6 stainings are strongly orientative [4]. Radical surgery with free margin excision is the first treatment option, rarely requiring adjuvant therapy [2]. Prognosis is typically good and strictly related to histological risk assessment [5]. Rare cases of local recurrence and distant metastasis have been described in literature [2]. ObjectiveThe purpose of this video is to describe the operative technique of a transcervical removal of a rare case of right paravertebral SFT. We present the diagnostic flowchart, management strategies, surgical technique and we provide anatomical dissection parallelism, which might be of interest to the readers. Materials and methodsA 59-years-old man with a one-year right cervical asymptomatic swelling was referred to our department. A contrasted MRI documented an expansive 6.5 cm capsulated lesion in the deep posterior neck spaces with diffuse contrast enhancement and inhomogeneous appearance. A core needle biopsy was performed, and the results from the initial immunohistochemical panel were not univocal showing positivity for cytokeratins AE1/AE3, PAX8, and no reactivity for CD34. A second immunohistochemical panel was then performed, displaying diffuse nuclear positivity for STAT6, which is a surrogate marker for the NAB2-STAT6 gene fusion, a specific driver mutation of SFT. Therefore, a radical excision was performed via transcervical approach (Video 1). No post-operative complications neither cranio-cervical neurological deficit occurred. ResultsIn comparison to pre-operative histopathologic study, the definitive histological examination of the whole mass revealed a more classical morphology of SFT. It was classified as an intermediate risk SFT [5]. A complete free margin excision was confirmed. After a multidisciplinary discussion, no adjuvant therapies were suggested. A six- and twelve-months radiological follow-up with MRI showed no evidence of disease. ConclusionSFT may represent a misdiagnosed entity in head and neck spaces and a correct diagnosis through immunohistochemistry is mandatory. Radical excision with free surgical margins should be pursued as adequate goal. Since SFTs show variable risk of metastatic disease, adjuvant radiotherapy should be contemplated in high-risk diseases and a clinico-radiological follow-up with MRI is required.

A review of solitary fibrous tumours of the orbit and ocular adnexa.

Solitary fibrous tumour (SFT) is an uncommon spindle cell tumour of mesenchymal origin characterised by NAB2-STAT6 gene fusion. Although it was first described in the pleura, it can occur in connective tissue in any part of the body, but rarely presents in the orbit and ocular adnexa. SFT, which is part of the same disease spectrum as other fibroblastic tumours such as giant cell angiofibroma, haemangiopericytoma and fibrous histiocytoma, usually presents as a painless, slow-growing mass in any age group and generally follows a benign course, with a good prognosis after complete excision. However, malignant forms rarely occur. Even for benign tumours a more aggressive clinical behaviour is possible, with relentless infiltrative local growth, frequent recurrence following surgery, and malignant transformation with the potential for metastatic spread. Careful long-term follow-up is essential. The published literature on SFTs of the orbit and ocular adnexa is reviewed, and the aetiology, clinical presentation, epidemiology, radiological features, histopathology, immunohistochemistry, risk stratification, clinical management, and prognosis are discussed, reflecting on our own experience.

Malignant solitary fibrous tumors: a clinicopathological and molecular genetic analysis

Objective: To explore the clinicopathological features, immunophenotype and molecular genetic characteristics of malignant solitary fibrous tumor (MSFT). Methods: Seven cases of MSFT were collected from the First Affiliated Hospital of Zhengzhou University from July 2018 to December 2020. Immunohistochemistry, RNA-based NGS and DNA-based NGS were performed. Results Among the 7 patients, there were 5 males and 2 females with a median age of 53 years (37-69 years). Two tumors located at skull base, and one in the tentorium of cerebellum, parietal occipital region, occipital area, chest and buttock respectively. The maximum diameter of the tumor was 2.5-20.0 cm. Microscopically, typical hemangiopericomatoid structures were noted; the tumor was cellular, fusiform or oval, very pleomorphic, with necrosis and high mitotic figures (>4/10 HPF). In some cases, classical solitary fibrous tumor morphology and dedifferentiated region were observed. Immunohistochemically, the tumor was positive for CD34 (6/7), STAT6 (7/7), bcl-2 (7/7), but negative for S-100 (7/7); CKpan or EMA was positive to varying degrees; mutated p53 was noted (3/7); Ki-67 positive index was more than 10%. NAB2-STAT6 gene fusion was typically detected in all the 7 cases. In 4 cases, ZNF415-FGFR1, COPG1-MET, IPO11-LRRC70_ncRNA-PLAG1 and Clorf198-CD274 (PD-L1) gene fusions were also detected. NOTCH1 mutation was found in 7 cases and TP53 mutation in 4 cases. TERT promoter mutations were not detected in all the cases. Conclusions: MSFT is rare and needs to be differentiated from many other spindle cell tumors. Especially when tumors express epithelial markers, they are easily misdiagnosed as sarcomatoid carcinoma and synovial sarcoma, etc. Immunohistochemistry and molecular detection of NAB2-STAT6 gene fusion have important diagnostic values. NOTCH1 and TP53 mutations may be associated with the progression of MSFT. Some patients have FGFR1 gene fusion and MET gene fusion, which may be potential therapeutic targets.

A mesenchymal chondrosarcoma with aberrant nuclear expression of STAT6: a potential diagnostic pitfall

STAT6 is usually considered to be a very sensitive and specific immunomarker for diagnosis of solitary fibrous tumor (SFT), being a surrogate of the NAB2-STAT6 fusion gene identified in most cases of this tumor. STAT6 expression has also been reported in rare cases of other soft tissue tumors, such as low-grade fibromyxoid sarcoma, myxoid/round cell liposarcoma, dedifferentiated liposarcoma and deep fibrous histiocytoma. The aim of this study was to report, for the first time, a case of mesenchymal chondrosarcoma showing diffuse aberrant immunohistochemical expression of STAT6. Molecular biology, showing the HEY1-NCOA2 fusion gene, was crucial to rule out SFT.

Mesenchymal Neoplasms of the Prostate and Seminal Vesicles: Spectrum of Disease with Radiologic-Pathologic Correlation.

There is a wide spectrum of benign and malignant mesenchymal neoplasms of the prostate, which account for less than 1% of all prostatic tumors. These include distinctive tumors that arise from the specialized prostatic stroma and site-agnostic neoplasms such as smooth muscle tumors, fibrous or myofibroblastic neoplasms, neurogenic tumors, vascular tumors, and a plethora of sarcomas. Select tumors show classic sites of origin within the prostate. While stromal tumors of uncertain malignant potential (STUMPs) commonly involve the peripheral zone at the prostate base, leiomyomas typically originate from the central prostate toward the apex. Some "prostatic" neoplasms such as gastrointestinal stromal tumors, solitary fibrous tumor (SFT), paragangliomas, and neurogenic tumors arise primarily from periprostatic soft tissues. Most mesenchymal tumors of the prostate and seminal vesicles manifest as large tumors that cause nonspecific symptoms; prostate-specific antigen level is not typically elevated. Diverse mesenchymal neoplasms demonstrate characteristic histopathologic and immunocytochemical features and variable cross-sectional imaging findings. While leiomyoma and SFT typically display low signal intensity on T2-weighted images, synovial sarcomas commonly show hemorrhage. Diagnosis is difficult because of the rarity and lack of awareness of the tumors and the significant overlap in histopathologic features. Select tumors show characteristic genetic abnormalities that allow the diagnosis to be established. For example, more than 90% of SFTs are characterized by a unique NAB2-STAT6 gene fusion, and more than 95% of synovial sarcomas are associated with a distinctive SYT-SSX chimeric transcript. Accurate diagnosis is imperative for optimal management owing to markedly different tumor biology as well as attendant therapeutic and prognostic implications. While STUMPs commonly recur, sarcomas typically charter an aggressive course with poor prognosis. Online supplemental material is available for this article. ©RSNA, 2022.

Case Report: Molecular Characterization of Aggressive Malignant Retroperitoneal Solitary Fibrous Tumor: A Case Study

Solitary fibrous tumors (SFT) are mesenchymal neoplasms with a favorable prognosis usually originating from the visceral pleura. Rarely, they may occur at various extrapleural sites and show malignant behavior coupled with dedifferentiation. NAB2-STAT6 fusion gene and STAT6 nuclear expression are biomarkers for diagnosis of SFT in addition to CD34, Bcl-2, and CD99. Furthermore, several reports have shown specific NAB2-STAT6 fusion variants and loss of STAT6 protein expression are associated with malignancy. We report a rare case of retroperitoneal SFT which rapidly progressed to death within 35 days after admission. Autopsy found a primary tumor containing both benign and malignant histologies, with multiple metastatic sites similar to the malignant, dedifferentiated tumor. STAT6 was detected in the primary differentiated tumor but not in the primary dedifferentiated tumor or lung/liver metastases. However, the NAB2-STAT6 fusion gene (NAB2ex6/STAT6ex16 variant) was detected in the primary tumor and lung/liver metastases. Intriguingly, fusion gene expression at the transcriptional level was downregulated in the dedifferentiated tumors compared to the differentiated tumor. We further performed target DNA sequencing and found gene mutations in TP53, FLT3, and AR in the dedifferentiated tumors, with TP53 mutations especially found among them. We demonstrate that downregulation of NAB2-STAT6 fusion gene at the transcriptional level is associated with malignant SFT for the first time. Moreover, the present study supports the idea that TP53 mutations promote malignancy in SFTs.

Primary solitary fibrous tumor of the thyroid gland: A review starting from a case report.

Primary solitary fibrous tumor (SFT) of the thyroid gland is a rare mesenchymal tumor with fibroblastic differentiation, ramified, thin-walled, enlarged (staghorn) vessels and specific NAB2-STAT6 gene fusion, which is more commonly found in pleura and peritoneum. This neoplasm can be located in a variety of anatomical sites outside pleura and peritoneum including bone, visceral organs and soft tissues, head and neck examples representing only 10-15% of the extra-pleural and extra-peritoneal tumors. Diagnosing this entity can be difficult, especially in thyroid gland, mainly because of the rarity of this neoplasm, but presence of characteristic microscopic features together with positivity for STAT6 and CD34 can confirm the diagnosis and exclude other differential diagnosis. Information about the diagnosis and treatment options of thyroid SFTs is limited but almost all primary thyroid SFTs have a good prognosis and indolent clinical course. Clinical surveillance is still necessary because some SFTs can be aggressive. Raising awareness regarding extra-pleural and extra-peritoneal location of this tumor in endocrine organs can help to better manage these patients. We report the case of a 34-year-old female with primary SFT of the thyroid gland. Additionally, we review the literature for the main clinical, paraclinical and pathological features of this neoplasm.

Determination of biological behavior of solitary fibrous tumors: correlation of expression of Ki-67, TPX2 and TERT mRNA subunit level and NAB2-STAT6 fusion compared to morphological aspects of SFTs.

We present a retrospective study of 65 cases of solitary fibrous tumors (SFTs) of several localizations including the most common site of origin in the pleura and lungs. SFTs are mesenchymal fibroblastic tumors with an unpredictable biological potential ranging from benign to malignant. We investigated morphologic characteristics, proliferation activity evaluated by immunohistochemical expression of Ki-67 antigen, and the existence of NAB2-STAT6 fusion gene together with Ki-67, TPX2, and TERT mRNA expression levels. The aim was to define relationships between proliferation activity and biological potential and progression of the disease. We measured Ki-67, TPX2, and TERT mRNA levels using quantitative real-time reverse transcription PCR (RQ-RT-PCR). We observed a significant association between increased Ki-67 and TERT mRNA levels and the SFTs with malignant potential. Also, we investigated the effect of TERT promoter mutation on telomerase activation and patient outcome in our SFT cohort. We verified that TERT promoter mutation was frequent (36.6%) and present in a majority of malignant SFTs and SFTs with uncertain biological behavior. TERT promoter mutation alone predicted the disease recurrence.

NOVEL USE OF EBUS-IFB TO DIAGNOSE SOLITARY FIBROUS TUMORS OF THE PLEURA

TOPIC: Procedures TYPE: Fellow Case Reports INTRODUCTION: Endobronchial ultrasound-guided intranodal forceps biopsy (EBUS-IFB) is a novel technique that allows higher yield sampling than fine-needle aspiration (FNA) [1]. We present a case of the EBUS-IFB technique utilized to diagnose a posterior mediastinal solitary fibrous tumor of the pleura. CASE PRESENTATION: A 50-year-old male with tobacco dependence and asbestos exposure presented intoxicated and complained of assault, prompting trauma evaluation. CT chest found an incidental 7.4 cm heterogeneously enhanced mass within the right upper posterior hemithorax abutting the mediastinum. The patient endorsed chronic back pain, cough, and weight loss. Our approach consisted of EBUS-FNA with a 19 gauge needle followed by EBUS-IFB. Immunohistochemistry demonstrated CD34, Vimentin, and signal transducer and activator of transcription 6 (STAT6) protein positive neoplastic cells with a final diagnosis of solitary fibrous tumors of the pleura. DISCUSSION: Solitary fibrous tumors are rare mesenchymal tumors (SFTP) with fibroblastic differentiation characterized by NAB2-STAT6 gene fusion on chromosome 12. NAB2-STAT6 fusion protein drives the nuclear entry of STAT6 protein, facilitating the discrimination between solitary fibrous tumors and histologically similar tumors. EBUS-FNA does not produce high yield results for SFTP [2]. In our case, small mini-forceps were passed into a targeted mass following EBUS-FNA needle puncture, and we obtained adequate tissue to make a successful diagnosis. To our knowledge, this is the first case EBUS-IFB applied to a posterior mediastinal SFTP. CONCLUSIONS: Our case demonstrates the novel use of EBUS-IFB to diagnose paraspinal SFTP. This technique provides a less invasive alternative from surgical biopsy to aid in the diagnosis of SFTP. REFERENCE #1: J Thorac Dis. 2019 Sep;11(9):4049-4058. REFERENCE #2: Curr Opin Pulm Med. 2012 Jul;18(4):339-46 DISCLOSURES: No relevant relationships by Kenneth D'Souza, source=Web Response No relevant relationships by Reiichiro Obata, source=Web Response no disclosure on file for Muhammad Perwaiz

A Comprehensive Review on Solitary Fibrous Tumor: New Insights for New Horizons.

Simple SummarySolitary fibrous tumor (SFT) is a malignant condition that exhibits different clinical behaviors ranging from low to high aggressive SFT, with dedifferentiated SFT (DD-SFT) being the fastest-growing subtype. Even when surgery alone provides curation rates above 60%, recurrences do occur in a fraction of patients where surgery is unable to provide disease control. Among the systemic therapeutic options, antiangiogenic compounds have shown higher efficacy than chemotherapy by indirect comparisons. Furthermore, rotating different antiangiogenics, at the progression time, has been shown to be effective. The exception is DD-SFT since it is resistant to antiangiogenics but can respond to chemotherapy. This comprehensive review also analyzes the underlying molecular components that play a key role in SFT origin and aggressiveness. The discovery in 2013 of anomalous fusion genes between NAB2 and STAT6 was determinant to increase the knowledge on the molecular drivers in SFT that could be potential targets for future therapies.Solitary fibrous tumor (SFT) is a rare mesenchymal, ubiquitous tumor, with an incidence of 1 new case/million people/year. In the 2020 WHO classification, risk stratification models were recommended as a better tool to determine prognosis in SFT, to the detriment of “typical” or “malignant” classic terms. The risk for metastasis is up to 35–45%, or even greater, in series with a longer follow-up. Over the last few decades, advances in immunohistochemistry and molecular diagnostics identified STAT6 nuclear protein expression and the NAB2–STAT6 fusion gene as more precise tools for SFT diagnosis. Recent evidence taken from retrospective series and from two prospective phase II clinical trials showed that antiangiogenics are active and their sequential use from first line should be considered, except for dedifferentiated SFT for which chemotherapy is the best option. Since the fusion transcript driver’s first description in 2013, new insights have been brought on key molecular events in SFT. This comprehensive review mainly focuses on the superior efficacy of antiangiogenics over chemotherapeutic agents in SFT, provides the current knowledge of key molecules that could co-drive the SFT behavior, and suggests new target candidates that deserve to be explored in preclinical and clinical research in SFT.

Lipomatous Solitary Fibrous Tumors Harbor Rare NAB2-STAT6 Fusion Variants and Show Up-Regulation of the Gene PPARG, Encoding for a Regulator of Adipocyte Differentiation

Solitary fibrous tumors (SFTs) harbor activating NAB2-STAT6 gene fusions. Different variants of the NAB2-STAT6 gene fusion have been associated with distinct clinicopathologic features. Lipomatous SFTs are a morphologic variant of SFTs, characterized by a fat-forming tumor component. Our aim was to evaluate NAB2-STAT6 fusion variants and to further study the molecular genetic features in a cohort of lipomatous SFTs. A hybrid-capture-based next-generation sequencing panel was employed to detect NAB2-STAT6 gene fusions at the RNA level. In addition, the RNA expression levels of 507 genes were evaluated using this panel, and were compared with a control cohort of nonlipomatous SFTs. Notably, 5 of 11 (45%) of lipomatous SFTs in the current series harbored the uncommon NAB2 exon 4-STAT6 exon 4 gene fusion variant, which is observed in only 0.9% to 1.4% of nonlipomatous SFTs. Furthermore, lipomatous SFTs displayed significant differences in gene expression compared with their nonlipomatous counterparts, including up-regulation of the gene peroxisome proliferator activated receptor-γ (PPARG). Peroxisome proliferator activated receptor-γ is a nuclear receptor regulating adipocyte differentiation, providing a possible explanation for the fat-forming component in lipomatous SFTs. In summary, the current study provides a possible molecular genetic basis for the distinct morphologic features of lipomatous SFTs.

Clinical and molecular implications of NAB2-STAT6 fusion variants in solitary fibrous tumour.

Solitary fibrous tumour (SFT) is a mesenchymal neoplasm characterised by pathognomonic NAB2-STAT6 gene fusions. The clinical implications and prognostic value of different fusion variants has not been clarified. In the current study, we explore the clinicopathological, prognostic and molecular differences between tumours with different fusions. Thirty-nine patients with localised, extrameningeal SFT were included, of whom 20 developed distant recurrence and 19 were without recurrence after long term follow-up. Capture-based RNA sequencing identified 12 breakpoint variants, which were categorised into two groups based on the STAT6 domain composition in the predicted chimeric proteins. Twenty-one of 34 (62%) sequenced tumours had fusions with most of the STAT6 domains intact and were classified as STAT6-Full. Thirteen tumours (38%) contained only the transactivation domain of STAT6 and were classified as STAT6-TAD. Tumours with STAT6-TAD fusions had a higher mitotic count (p=0.016) and were associated with inferior recurrence-free interval (p=0.004) and overall survival (p=0.012). Estimated 10-year recurrence-free survival was 25% for patients with STAT6-TAD tumours compared to 78% for the STAT6-Full group. Distinct transcriptional signatures between the fusion groups were identified, including higher expression of FGF2 in the STAT6-TAD group and IGF2, EGR2, PDGFRB, STAT6 and several extracellular matrix genes in STAT6-Full tumours. In summary, we demonstrate that NAB2-STAT6 fusion variants are associated with distinct clinicopathological and molecular characteristics and have prognostic significance in extrameningeal SFT.

Solitary Fibrous Tumor/Hemangiopericytoma Metastasizes Extracranially, Associated with Altered Expression of WNT5A and MMP9.

Simple SummaryMeningeal/intracranial solitary fibrous tumor/hemangiopericytoma (icSFT/HPC) have a poor clinical outcome with metastatic behavior compared to soft tissue/extracranial SFT/HPCs (exSFT/HPC), but the underlying genetic factors are unclear. This study showed that WNT signaling, including WNT5A, was elevated in exSFT/HPC and MMP9 expression was higher in icSFT/HPC at both the mRNA and protein levels. Expression of CLDN5, a marker of endothelial tight junctions, was decreased in icSFT/HPC. The metastatic behavior of icSFT/HPC may be due to dysregulated angiogenesis and increased permeability of the vasculature caused by an altered WNT signaling pathway. Along with the increased expression of MMP9 in individual tumor cells, the combination of these effects will increase the probability of distant metastasis. Although exSFT/HPC and icSFT/HPC share a key molecular event, i.e., NAB2-STAT6 fusion, SFT/HPC may exhibit different biological properties and clinical courses depending on tumor location.Solitary fibrous tumor/hemangiopericytoma (SFT/HPC) is a mesenchymal tumor originating from various soft tissues and meninges, which carries the NAB2-STAT6 fusion gene. Meningeal/intracranial SFT/HPCs (icSFT/HPC) have a poor clinical outcome with metastatic behavior compared to soft tissue/extracranial SFT/HPCs (exSFT/HPC), but the underlying genetic factors are unclear. Differentially expressed genes (DEGs) were analyzed by NanoString nCounter assay using RNA extracted from formalin-fixed paraffin-embedded (FFPE) tissue samples. Additionally, immunohistochemistry (IHC) was performed on 32 cases of exSFT/HPC, 18 cases of icSFT/HPC, and additional recurrent or metastatic cases to verify the findings. Pathway analysis revealed that the WNT signaling pathway was enriched in exSFT/HPC. Analysis of DEGs showed that expression of WNT5A was lower and that of MMP9 was higher in icSFT/HPC than in exSFT/HPC (p = 0.008 and p = 0.035, respectively). IHC showed that WNT5A and CD34 expression was high in exSFT/HPC (p < 0.001, both), while that of MMP9 was high in icSFT/HPC (p = 0.001). Expression of CLDN5 in tumoral vessels was locally decreased in icSFT/HPC (p < 0.001). The results suggested that decreased WNT5A expression, together with increased MMP9 expression, in icSFT/HPC, may affect vascular tightness and prompt tumor cells to metastasize extracranially.