Spindle Cell Neoplasms Unique to the Sinonasal Tract.

The spindle cell neoplasms include sinonasal tract angiofibroma (STA), glomangiopericytoma (GPC), and biphenotypic sinonasal sarcoma (BSNS). These entities share some clinical, histomorphologic, immunohistochemical, and even molecular characteristics. Nevertheless, there are features that are unique to each tumor type. STA shows heavily collagenized and vascular stroma, with apparent relationship to underlying hormonal changes. GPC consistently exhibits monomorphic, ovoid cytologic appearance with the constant feature of Beta-catenin nuclear accumulation by IHC. Lastly, BSNS is a deceptively bland and neural-like neoplasm featuring consistent co-expression of S100 and smooth muscle markers with specific genetic rearrangements serving to uniquely characterize this entity.

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 TGFß 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.

[Research progress of intraspinal solitary fibrous tumor].

Objective: To review the research progress of intraspinal solitary fibrous tumor (SFT). Methods: The domestic and foreign researches on intraspinal SFT were extensively reviewed and analyzed from four aspects, including disease origin, pathological and radiological characteristics, diagnosis and differential diagnosis, and treatment and prognosis. Results: SFT is an interstitial fibroblastic tumor with a low probability of occurrence in the central nervous system, especially in the spinal canal. In 2016, the World Health Organization (WHO) used the joint diagnostic term "SFT/hemangiopericytoma" according to the pathological characteristics of mesenchymal fibroblasts, which can be divided into three levels according to specific characteristics. The diagnosis process of intraspinal SFT is complex and tedious. It has relatively variable imaging manifestations and specific pathological changes of NAB2-STAT6 fusion gene, which often requires differential diagnosis with neurinoma, meningioma, etc. The treatment of SFT is mainly resection, which can be assisted by radiotherapy to improve the prognosis. Conclusion: Intraspinal SFT is a rare disease. Surgery is still the main treatment. It is recommended to combine preoperative or postoperative radiotherapy. The efficacy of chemotherapy is still unclear. In the future, more studies are expected to establish a systematic diagnosis and treatment strategy for intraspinal SFT.

Adenofibromatous Solitary Fibrous Tumor: An Unusual Morphologic Variant Occurring in the Sinonasal Tract.

BACKGROUND: Solitary fibrous tumor can exhibit a broad morphologic spectrum, such as presence of epithelioid tumor cells, adipose cells and multinucleated giant cells. This report describes an unusual morphologic variant characterized by adenofibromatous features, all occurring in the sinonasal region. METHODS: Four cases of the adenofibromatous variant of solitary fibrous tumor were retrieved from the surgical pathology and consultation files in Queen Elizabeth Hospital, Hong Kong. Histologic examination, immunohistochemical study and reverse-transcription polymerase chain reaction (RT-PCR) were performed. RESULTS: The patients were adults who presented with an obstructive mass of the nasal septum, nasal cavity or nasolacrimal sac. Histologic examination showed a circumscribed biphasic tumor with intermingling of glandular structures and spindle cells, reminiscent of mammary fibroadenoma. Bland-looking spindle cells formed short, irregularly oriented fascicles, admixed with variable amount of collagen fibers. The glandular component comprised ducts and seromucinous acini with a lobular architecture, indicating that it represented exuberant hyperplasia of indigenous glands rather than part of the neoplastic process. Demonstration of CD34 and STAT6 immunoreactivity in the spindle cells and NAB2::STAT6 gene fusion by polymerase chain reaction supports the diagnosis of solitary fibrous tumor. CONCLUSION: This study reports four cases of sinonasal solitary fibrous tumor with adenofibromatous features, furthermore expanding the morphologic spectrum of this tumor.

[Fat-forming solitary fibrous tumor with NAB2/ STAT6 gene fusion. Case report of genial location and literature review]. / Tumor fibroso solitario variedad lipomatosa con fusión génica NAB2/STAT6. Estudio de un caso de localización geniana y revisión de la literatura.

The lipomatous variety solitary fibrous tumor is a soft tissue neoplasm composed of mature adipose tissue and hemangiopericytoma areas. A 53-year-old man consulted for facial asymmetry and maxillofacial magnetic resonance imaging showed a cystic lesion, 3 x 2 cm in size, in front of the anterior wall of the maxillary sinus. Histologically, there were dense spindle cells expressing CD34, CD99, Bcl-2, and STAT6, myxoid zones, hemangiopericytomatous blood vessels, and S100 positive adipocytes. NAB2/STAT6 gene fusion was revealed by RT-PCR. The main differential diagnosis was raised with the spindle cell lipoma and malignant variant of the lipomatous solitary fibrous tumor. STAT6 overexpression and NAB2/STAT6 gene fusion are specific for lipomatous solitary fibrous tumor and the presence of lipoblasts and atypical lipomatous tumor areas suggests malignancy. These tumors located in the head and neck region have a benign biological behavior.

Myopericytoma of the Parotid and Molecular Profiling: Report of a Rare Case and Review of the Literature.

Myopericytomas are uncommon tumors defined by their round to spindle shaped cells often arranged in a concentric pattern of perivascular growth. They are typically well-circumscribed, nodular, slow-growing lesions that occur in the soft tissue of the extremities. Here, we present a 30-year-old female with a 2.4 cm myopericytoma occurring in the deep lobe of the parotid gland. The diagnosis was made with detailed histopathologic and immunohistochemical findings and positive identification of the specific mutation for PDGFRß p.Asp666Lys by next generation sequencing (NGS). This is the first case report of a parotid myopericytoma with a genetic testing that shows a particular mutation that has been linked to myopericytomatosis.

Molecular description of meningeal solitary fibrous tumors/hemangiopericytomas compared to meningiomas: two completely separate entities.

INTRODUCTION: Meningeal solitary fibrous tumors (SFT), like all SFT, are defined by NAB2-STAT6 fusion and share clinicopathologic similarities with meningiomas, the most frequent meningeal tumors. Our aim is to establish the molecular identity of meningeal SFT and seek molecular prognostic factors. METHODS: RNA sequencing and whole exome sequencing were performed in STAT6-positive SFT and grade 2-3 meningiomas, and data concerning other soft tissues tumors was obtained from the local database. Uniform manifold approximation and projection, individual gene expression and Gene Set Enrichment Analysis were performed. RESULTS: RNA clustering shows that SFT share a common molecular signature, different from any other type of tumoral tissue. Meningeal SFT aggregate with other SFT, with no clinical or histological subgroup. Comparison of genes expressions suggests significant over-expressions of ZIC2, ZIC3, ZIC5, GABBR2, TP53 in CNS-SFT. The pathogenic TP53 c.743G>T variant, previously undescribed in SFT, was found in one sample of meningeal SFT during malignant progression. CONCLUSIONS: Meningeal SFT are molecular counterparts of extra-meningeal SFT, completely separate from meningiomas. They might develop from the same tissues and benefit from the same treatments as SFT.

NAB2-STAT6 Gene Fusions to Evaluate Primary/Metastasis of Hemangiopericytoma/Solitary Fibrous Tumors.

OBJECTIVES: Hemangiopericytomas (HPCs) and solitary fibrous tumors (SFTs) were considered two distinct entities, but a common gene fusion, NAB2-STAT6, has been identified in both. Although rare, HPCs and SFTs do metastasize, some many years later after resection. Given the extended disease-free interval, it can be difficult to determine with certainty if an HPC or SFT at a new anatomic location represents a second primary or metastatic disease. METHODS: RNA was extracted from formalin-fixed, paraffin-embedded tissue of two patients with multiple SFT/HPC samples. The fusion gene was amplified by reverse transcription polymerase chain reaction (RT-PCR) and a custom-designed Archer FusionPlex panel (94 target genes) and the Illumina NextSeq 550. RESULTS: We identified two patients with multiple resections for HPC/SFT during 26 years at our institution. The first patient had a history of HPC and almost 10 years later she was diagnosed with malignant SFT. The HPC and the SFT shared the same fusion breakpoint. The second patient had multiple lesions in the brain and bone/soft tissue over a 27-year span following a diagnosis of meningeal SFT. Three lesions from this patient shared the same fusion breakpoint. CONCLUSIONS: Our study demonstrated the same fusion breakpoints in primary and metastatic SFTs/HPCs at different time points using both RT-PCR and the Archer fusion panel.

Aberrant expression of thyroid transcription factor-1 in meningeal solitary fibrous tumor/hemangiopericytoma.

Meningeal solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) were categorized as the same entity in the World Health Organization (WHO) 2016 classification of tumors of the central nervous system (CNS). Although NAB2-STAT6 fusion protein can be used to distinguish most of SFT/HPC from the other sarcomas, additional biomarkers were requested to separate meningeal SFT/HPC from meningioma and the molecular pathological difference between meningeal SFT/HPC and extra-CNS SFT/HPC still remains unclear. In this study, we evaluated the expression of TTF-1 in 67 meningeal SFT/HPC, 62 extra-CNS SFT/HPC and 201 meningiomas samples with immunohistochemistry (IHC) assays. The results showed that TTF-1 was detected in 23 of 67 (34.3%) meningeal SFT/HPC, 3 retroperitoneum SFT/HPC and none of meningiomas. Meanwhile, the copy number variation and mRNA expression of TTF-1 were measured by real-time quantitative PCR (qPCR) in meningeal SFT/HPC. These results demonstrated that TTF-1 protein expression level was significantly correlated with its transcription level, but independently related to the gene copy number variant. In conclusion, our study suggested that a large proportion of meningeal SFT/HPC was positive to TTF-1, while very few extra CNS SFT/HPC cases and no meningiomas were stained. So TTF-1 has value as an auxiliary diagnostic marker for meningeal SFT/HPC.

Nasal hemangiopericytoma presenting with oncogenic osteomalasia: A case report and literature review.

Sinonasal type hemangiopericytoma is a rare soft tissue tumor. Oncogenic osteomalacia (tumor-induced osteomalacia) is a rare syndrome that develops especially due to benign mesenchymal tumors. Nonspecific general bone pain and weakness delay the diagnosis and treatment of oncogenic osteomalacia, and it is difficult to determine the localization of the primary tumor causing oncogenic osteomalacia. A 43-year-old male patient with nasal hemangiopericytoma with symptoms of oncogenic osteomalacia is presented. The patient had musculoskeletal complaints at first and was diagnosed with lumbar disc herniation and surgery was performed. When his complaints recurred 1 year later, he was re-evaluated and diagnosed with hypophosphatemic osteomalacia. Despite the various treatments he received, his complaints did not decrease but increased, so a detailed examination was decided. When the positive PHEX mutation and very high fibroblast growth factor 23 level were detected, PET-CT imaging was performed with a pre-diagnosis of possible oncogenic osteomalacia, but no finding was found. Then he was evaluated with Ga-68 DOTATATE, and the soft tissue mass filling the right ethmoidal sinus was detected. Due to the relation of the mass with surrounding structures, it was considered unsuitable for total excision and incomplete surgical excision was performed. Pathologic evaluation revealed sinonasal type hemangiopericytoma (glomangiopericytoma). A significant remission in the patient's complaints was observed after the operation. Young patients with osteomalacia with unknown causes should be evaluated for malignancy, and screening and further examinations should be performed.

Solitary Fibrous Tumor of the Vulva: Case Report of a Rare Entity and Review of Literature.

Solitary fibrous tumor (SFT) is an uncommon mesenchymal tumor of fibroblastic origin, which shows a prominent hemangiopericytoma-like branching pattern. It may be found at any location and can rarely involve the female genital tract with the vulva being the most common site of involvement. This is a case report of vulvar SFT in a 47-yr-old female who presented with a slow growing vulvar mass for 3 yr. Histologic examination showed a neoplasm composed of ovoid to spindle shaped cells with hypocellular and hypercellular areas in a collagenous background. Prominent hemangiopericytoma-like vessels were identified. Immunohistochemistry showed positive staining of the tumor cells for CD34, STAT6, ER, PR, and vimentin. Immunoshistochemical staining for desmin, SMA, and S100 was negative. The majority of SFTs have a NAB2-STAT6 gene fusion on chromosome 12, resulting in nuclear STAT6 overexpression, which is a sensitive and specific immunohistochemical marker for its diagnosis. Only 25 cases of vulvar SFT have been reported in the English literature and it should be considered in the differential diagnosis of spindle cell lesions at this site.

[What's new in the management of meningeal solitary fibrous tumor/hemangiopericytoma?] / Quoi de neuf dans la prise en charge des tumeurs fibreuses solitaires/hémangiopéricytomes des méninges ?

Meningeal fibrous solitary tumors/hemangiopericytoma are rare and aggressive mesenchymal neoplasms considered as sarcomas. They represent less than 1% of intracranial tumors and derive from the pericytes of Zimmerman which permit capillary contraction. They tend to occur more often in males in the fifth decade. They are often revealed by intracranial hypertension. Some scannographic and MRI characteristics permit to distinguish meningeal fibrous solitary tumor/hemangiopericytoma from other meningeal tumors. Meningeal hemangiopericytoma and fibrous solitary tumors were considered as different entities until 2016. Following the discovery of an identical genetic event, the locus 12q13 chromosome inversion leading to a NAB2-STAT6 fusion with nuclear immunoreactivity for STAT6 protein, the 2016 WHO classification defines these tumors as a single entity. Meningeal fibrous solitary tumors/hemangiopericytoma have a high recurrence rate. Long-term recurrences may occur. Local relapses are more frequent than extracranial metastasis. A multimodal management is recommended to treat a localized disease. It involves a complete resection followed by adjuvant radiotherapy. When local recurrences occur, surgery or stereotactic radiosurgery permit sometimes a local control. Metastatic disease has a poor prognostic and a weak chimiosensitivity. Targeted therapies, like pazopanib, are a hopeful option.

Recurrence of Solitary Fibrous Tumor/Hemangiopericytoma Could Be Predicted by Ki-67 Regardless of Its Origin.

Since the discovery of the NAB2-STAT6 gene fusion in 2013, solitary fibrous tumor (SFT) and hemangiopericytoma (HPC) have been considered the same disease. STAT6 nuclear stain is approved as a highly sensitive and specific marker to diagnose SFT/HPC from other tumors with similar histology. As the next step, detection of fusion variants that may predict clinical malignancy of SFT/HPC has been attempted. However, no fusion variants with a clear relation to malignancy have been identified. In this study, the clinical and histological backgrounds of 23 Japanese patients diagnosed with SFT/HPC from 2000 to 2019 at Kochi University Hospital were examined to identify factors potentially related to recurrence. A significant relationship to recurrence was detected for mitosis ≥ 1/10 HPF (400×), necrosis, and Ki-67>5%. These findings indicate that a deliberate investigation of histological features such as mitosis and necrosis is crucial for the clinical observation of SFT/ HPC patients. In addition, Ki-67 was revealed to be a useful parameter to predict recurrence in SFT/HPC patients.

A dedifferentiated intracranial solitary fibrous tumor with osteosarcoma components: rapid tumor progression and lethal clinical course.

Solitary fibrous tumor/hemangiopericytoma is a mesenchymal tumor that originates from a common NAB2-STAT6 fusion gene and is known to very rarely demonstrate dedifferentiation in the pattern of local recurrence or distant metastasis. Here we describe for the first time a rare case of intracranial dedifferentiated solitary fibrous tumor/hemangiopericytoma with osteosarcoma components that developed in an 84-year-old man after frequent gamma knife radiosurgery over a 14-year period. We performed tumor-debulking and gamma knife radiosurgery, but unfortunately the patient died shortly after the development of dedifferentiation. There is no established treatment for dedifferentiated cases due to the rare histology and limited published data, and therefore further accumulation of histological and genetic profiles is necessary to develop novel target gene therapies.

Gene of the month: GLI-1.

The Glioma-associated homologue-1 (GLI-1) gene was first discovered to be amplified in glioblastoma multiforme. It encodes for a zinc-finger transcription factor in the Kruppel family of proteins and is important in the sonic hedgehog signalling pathway. GLI-1 also plays a role in several other pathways and is important for proliferation, migration, invasion, growth and angioinvasion, and cancer stem cell self-renewal in a variety of malignancies. GLI-1 is amplified in several malignancies, including an epithelioid, pericytomatous soft tissue neoplasm that can exhibit malignant behaviour. More recently, GLI-1 fusions with other partner genes have been found in three rare tumours: a pericytomatous tumour with a t(7;12) translocation, where it partners with Actin beta 1, and gastroblastoma and plexiform fibromyxoma, where the partner gene is metastasis-associated lung adenocarcinoma transcript 1, respectively.

Metastatic intracranial solitary fibrous tumors/hemangiopericytomas: description of two cases with radically different behaviors and review of the literature.

Solitary fibrous tumor/hemangiopericytoma with primary tumor location in the central nervous system accounts for less than 1% of all central nervous system tumors. Despite the relatively indolent clinical course, extracranial metastases are reported in 28% of cases. In recent years, NAB2-STAT6 gene fusion has been recognized as the pathognomonic molecular feature of solitary fibrous tumor/hemangiopericytoma and STAT6 immunohistochemistry has been shown to be a sensitive and specific surrogate for the identification of the gene fusion in these patients. Here we report two cases of patients who experienced occurrence of diffuse extracranial metastases several years after successful surgery for an intracranial solitary fibrous tumor/hemangiopericytoma. In the first patient, the metastases had maintained similar histological features to the primary tumor; in contrast, in the second case, a dedifferentiation occurred with loss of expression of CD34 and Bcl-2. These different histological features were associated with radically different behaviors. Whereas the first case experienced an indolent course of the disease, the second patient had a rapid disease progression and deterioration of clinical conditions. The molecular imaging findings in these two cases and the role of functional imaging for tumor detection, disease staging and monitoring in this rare cancer are also discussed. Recurrences and metastases maintained high expression of somatostatin receptors confirmed by somatostatin receptor imaging in the first case. In contrast, in the second patient, the abrupt transition into a highly aggressive form was associated with the absence of somatostatin receptors at 111In Pentetreotide scan and intense hypermetabolism at 18F-FDG PET.

"Hey! Whatever happened to hemangiopericytoma and fibrosarcoma?" An update on selected conceptual advances in soft tissue pathology which have occurred over the past 50 years.

Hemangiopericytoma and fibrosarcoma represented at one time two of the most common diagnoses in soft tissue pathology. Both terms are now largely extinct. This article will review the clinicopathologic, immunohistochemical and molecular genetic advances that have led to these changes, and review the pathologic features of a select group of soft tissue tumors previously classified as hemangiopericytoma or fibrosarcoma.

A DSTYK mutation activates ERK1/2 signaling to promote intraspinal dissemination in a case of solitary fibrous tumor/hemangiopericytoma.

Intracranial solitary fibrous tumors/hemangiopericytomas (SFT/HPCs) are vascular tumors that have a high rate of local recurrence and extracranial metastases. Intradural extramedullary spinal dissemination of intracranial SFT/HPC is extremely rare. There is a paucity of data available to elucidate the molecular mechanisms of intraspinal dissemination of intracranial SFT/HPC. Herein, we presented a case of intracranial SFT/HPC with intraspinal metastasis. The resected tumor specimens were enrolled in a clinical sequencing program, including whole-exome and transcriptome sequencing. By comparing genomic sequencing data of the intracranial tumors with intraspinal metastasis, we established the somatic mutational profiles of these tumors. Clonality analysis revealed a distinct subclonal structure in the intracranial tumor and its intraspinal metastasis, which might reflect the possibility of intratumoral clonal selection and evolution during the process of tumor dissemination. Through bioinformatics analysis and Sanger sequencing validation, a DSTYK mutation (Met296Ile) was identified as a candidate driver of intraspinal metastasis in this SFT/HPC case. Further, an intracranial tumor-derived SFT/HPC cell line, HPC3, was established to explore the mechanisms of the DSTYK mutation in promoting SFT/HPC metastasis. Based on the HPC3 cell model, we found that the DSTYK mutation promoted cell migration and invasion of HPC3 cells via activation of ERK1/2 signaling, which was inhibited by the MEK/ERK inhibitor AZD6244. The DSTYK mutation was also shown to upregulate the expression of two metastasis-related molecules: MMP2 and MMP9 in HPC3 cells; however, this effect was attenuated by AZD6244 treatment. Therefore, the DSTYK mutation may activate ERK1/2/MMP2/9 signaling to promote tumor cell metastasis in SFT/HPC. In conclusion, our study revealed the potential role of DSTYK mutation in the regulation of intraspinal metastasis of SFT/HPC, which might provide new biological insights into this rare disease.

Sinonasal glomangiopericytoma: A clinicopathologic study.

Sinonasal glomangiopericytoma (SNGP) is a neoplasm arising in the nasal cavity and paranasal sinuses that shows perivascular myoid differentiation. The diagnosis of SNGP may be diagnostically challenging due to a large number of potential mimics. In the present study, we sought to characterize the histological and molecular features of six cases of SNGP found in prior surgical pathology records over a 15-year period. The average age at diagnosis was 48.5 years (range: 31-78 years), and the male-to-female ratio was 1:1. Imaging studies in all six cases demonstrated avidly enhancing, lobulated soft tissue masses in the nasal cavity, extending into the sinuses and nasopharynx. Histologically, the tumors were unencapsulated and composed of a proliferation of closely packed, bland, and uniform spindle cells growing deep to an intact surface respiratory epithelium. The cells were separated by a distinctive vascular network ranging from capillaries to large vascular spaces. All cases demonstrated strong positivity for smooth muscle actin, cyclin D1, CD99, and ß-catenin (100%). Targeted sequencing revealed recurrent CTNNB1 missense mutations in all cases tested. Additionally, TLE1 was positive in all cases which has not been previously reported. No tested cases harbored SS18 translocations. We found that while no single marker resolves immunohistochemical overlap between SNGP and its histologic mimics, an extended immunohistochemical panel that includes ß-catenin, cyclin D1, STAT6, smooth muscle actin, pan-cytokeratin cocktails, S100, and SOX10 helps to support the diagnosis of SNGP in diagnostically challenging cases without the need for molecular studies.