Spindle Cell Tumors of the Sinonasal Tract: A Diagnostic Update with Focus on Ancillary Workup.

Spindle cell neoplasms arising in the head and neck may be challenging to recognize due to their relative rarity. While underlying molecular alterations are increasingly elucidated, testing for these features may not be readily available. In most cases, combinations of key morphologic features and diagnostic immunohistochemical markers can be used to replace molecular diagnostics. Conversely, some molecular alterations and expression of their surrogate biomarkers are not specific for any one entity, and it is important to recognize these to avoid diagnostic pitfalls. In this review, we discuss both old and new spindle cell tumors of the sinonasal tract, with an emphasis on histologic features and clinically relevant immunohistochemical markers serving as surrogate markers for underlying genomic alterations.

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

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

Biphasic synovial sarcoma with myoepithelial features: a distinctive variant with a predilection for the foot.

Synovial sarcoma (SS) is a tumor known for its classic monophasic spindle cell or biphasic morphology. However, it exhibits a wide range of histologic variations, leading to diagnostic challenges. Here, we present four cases of molecularly confirmed, biphasic SS originating in the feet and displaying myoepithelial differentiation. The patients were two men and two women with an age range from 19 to 71 years (mean, 45 years). Each tumor showed foci with conventional spindle cell morphology. The epithelial components included areas with nests and cords of epithelioid cells set within a hyalinized and sclerotic stroma. The cytoplasm was clear to pale and eosinophilic. The nuclei were ovoid-round with fine chromatin and small to inconspicuous nucleoli. Mitotic figures were present (2-13 per 10 high-power fields; mean, 6.5). Immunohistochemical studies showed variable staining of the myoepithelial-like regions for low molecular weight keratins, EMA, p63, and S100 protein. Molecular studies confirmed the presence of SS18::SSX1/2 fusion in all four tumors. These cases highlight an unusual variant of synovial sarcoma with an apparent predilection for the distal lower extremity and suggest that differentiation of biphasic synovial sarcoma may be impacted by the anatomic site. Awareness of this variant is important to avoid misclassification and potential treatment and prognostic implications.

Integrative multi-omic cancer profiling reveals DNA methylation patterns associated with therapeutic vulnerability and cell-of-origin.

DNA methylation plays a critical role in establishing and maintaining cellular identity. However, it is frequently dysregulated during tumor development and is closely intertwined with other genetic alterations. Here, we leveraged multi-omic profiling of 687 tumors and matched non-involved adjacent tissues from the kidney, brain, pancreas, lung, head and neck, and endometrium to identify aberrant methylation associated with RNA and protein abundance changes and build a Pan-Cancer catalog. We uncovered lineage-specific epigenetic drivers including hypomethylated FGFR2 in endometrial cancer. We showed that hypermethylated STAT5A is associated with pervasive regulon downregulation and immune cell depletion, suggesting that epigenetic regulation of STAT5A expression constitutes a molecular switch for immunosuppression in squamous tumors. We further demonstrated that methylation subtype-enrichment information can explain cell-of-origin, intra-tumor heterogeneity, and tumor phenotypes. Overall, we identified cis-acting DNA methylation events that drive transcriptional and translational changes, shedding light on the tumor's epigenetic landscape and the role of its cell-of-origin.

Deep learning integrates histopathology and proteogenomics at a pan-cancer level.

We introduce a pioneering approach that integrates pathology imaging with transcriptomics and proteomics to identify predictive histology features associated with critical clinical outcomes in cancer. We utilize 2,755 H&E-stained histopathological slides from 657 patients across 6 cancer types from CPTAC. Our models effectively recapitulate distinctions readily made by human pathologists: tumor vs. normal (AUROC = 0.995) and tissue-of-origin (AUROC = 0.979). We further investigate predictive power on tasks not normally performed from H&E alone, including TP53 prediction and pathologic stage. Importantly, we describe predictive morphologies not previously utilized in a clinical setting. The incorporation of transcriptomics and proteomics identifies pathway-level signatures and cellular processes driving predictive histology features. Model generalizability and interpretability is confirmed using TCGA. We propose a classification system for these tasks, and suggest potential clinical applications for this integrated human and machine learning approach. A publicly available web-based platform implements these models.

Proteogenomic insights suggest druggable pathways in endometrial carcinoma.

We characterized a prospective endometrial carcinoma (EC) cohort containing 138 tumors and 20 enriched normal tissues using 10 different omics platforms. Targeted quantitation of two peptides can predict antigen processing and presentation machinery activity, and may inform patient selection for immunotherapy. Association analysis between MYC activity and metformin treatment in both patients and cell lines suggests a potential role for metformin treatment in non-diabetic patients with elevated MYC activity. PIK3R1 in-frame indels are associated with elevated AKT phosphorylation and increased sensitivity to AKT inhibitors. CTNNB1 hotspot mutations are concentrated near phosphorylation sites mediating pS45-induced degradation of ß-catenin, which may render Wnt-FZD antagonists ineffective. Deep learning accurately predicts EC subtypes and mutations from histopathology images, which may be useful for rapid diagnosis. Overall, this study identified molecular and imaging markers that can be further investigated to guide patient stratification for more precise treatment of EC.

VIM::KMT2A-rearranged sarcomas: A report of two new cases confirming an entity with distinct histologic features.

The recently described KMT2A-rearranged sarcomas are rare emerging entities where the KMT2A gene fuses with YAP1 and, less commonly, VIM, resulting in two distinct morphologies. Unlike the sclerosing epithelioid fibrosarcoma-like features that characterize tumors with KMT2A::YAP1 fusions, VIM::KMT2A-rearranged sarcomas are more uniformly cellular and lack the extensively sclerotic background seen in the former. Most tumors behave aggressively with metastases on presentation. Here, we describe the clinicopathologic and molecular findings in two additional cases of VIM::KMT2A rearranged sarcomas that arose in the deep soft tissues of adult males. Both tumors were composed of hypercellular fascicles of uniform spindle cells with pale eosinophilic cytoplasm and ovoid nuclei. The stroma had scant delicate collagen with occasional thin-walled ectatic blood vessels and perivascular hyalinization. Immunohistochemical studies showed an unspecific staining pattern with diffuse positivity for CD99 and BCL2 and variable staining for S100 protein. RNA-sequencing detected the presence of VIM::KMT2A gene fusion involving VIM exon 4 and KMT2A exon 2 in both cases. Sarcomas with VIM::KMT2A gene fusions seem to have sufficient morphologic features to warrant distinction from KMT2A-rearranged sarcomas with YAP1 partner. Without the benefit of molecular testing, these tumors pose a diagnostic challenge due to their lack of specific immunohistochemical profile and great morphologic overlap with other monomorphic spindle cell neoplasms.

GAB1::ABL1 fusions define a distinctive soft tissue neoplasm, with variable perineurial differentiation, and a predilection for children and young adults.

Although well known as a fusion partner in hematological malignancies, fusion genes involving the ABL proto-oncogene 1 (ABL1), mapping to chromosomal region 9q34.12, have only been anecdotally reported in five soft tissue tumors. These neoplasms have been variously reported as perineurioma, angiofibroma, and solitary fibrous tumor, and all have harbored a GAB1::ABL1 gene fusion; however, the nosology and clinicopathological characteristics of soft tissue tumors carrying this rare fusion have not been delineated. We herein describe eight tumors containing the GAB1::ABL1 fusion and review previously reported cases in a series to define their morphological spectrum, address immunohistochemical evidence for a line of differentiation, with special reference to the presence or absence of a perineurial immunophenotype, and gather insight into their behavior. The patients included four females and four males, aged 13-37 years (median, 24 years). Two cases each originated in the shoulder area, trunk, hands, and lower extremities, with a size range of 1.5-8 cm (median, 3.4 cm). Four tumors were deep and four superficial. All tumors were morphologically similar, being composed of bland fibroblast-like spindle to ovoid cells diffusely arranged in a paucivascular fibrous to fibromyxoid stroma with variable resemblance to soft tissue perineurioma. Mitotic activity was generally low (0-8 mitoses in 10 high-power fields [HPFs]; median, 1). All lesions had at least focally infiltrative margins, but they otherwise lacked pleomorphism and necrosis. Immunohistochemistry showed focal reactivity for CD34 (5/7), epithelial membrane antigen (EMA) (3/8), claudin1 (2/3), GLUT1 (4/6), and S100 (2/7); other markers, including MUC4 (0/7), desmin (0/9), and smooth muscle actin (SMA) (0/4), were negative. RNA sequencing revealed a GAB1::ABL1 fusion in all cases with exon 6 of GAB1 fused to exon 2 of ABL1. Treatments included various forms of surgical intervention in seven cases; one tumor was biopsied only. Limited follow-up was available for five patients. One tumor regrew rapidly within 1 month to 1.5 cm after an initial marginal excision and was re-excised with close margins. Four patients were disease-free at 1, 3, 14, and 25 months of follow-up. Metastases have not, to date, been observed. This series characterizes "GAB1::ABL1 fusion-positive spindle cell neoplasm" as a distinct entity, with overlapping features with soft tissue perineurioma and predilection for children and young adults.

Human and machine: Better at pathology together?

Meaningful integration of artificial intelligence (AI) will transform the application of "big data" for patient care, diagnosis, and research. In this issue of Cancer Cell, Chen et al. describe a transparent system to integrate histopathology and molecular data to predict outcomes and identify novel biomarkers in cancer.

Retrospective observational studies in ultra-rare sarcomas: A consensus paper from the Connective Tissue Oncology Society (CTOS) community of experts on the minimum requirements for the evaluation of activity of systemic treatments.

BACKGROUND: In ultra-rare sarcomas (URS) the conduction of prospective, randomized trials is challenging. Data from retrospective observational studies (ROS) may represent the best evidence available. ROS implicit limitations led to poor acceptance by the scientific community and regulatory authorities. In this context, an expert panel from the Connective Tissue Oncology Society (CTOS), agreed on the need to establish a set of minimum requirements for conducting high-quality ROS on the activity of systemic therapies in URS. METHODS: Representatives from > 25 worldwide sarcoma reference centres met in November 2020 and identified a list of topics summarizing the main issues encountered in ROS on URS. An online survey on these topics was distributed to the panel; results were summarized by descriptive statistics and discussed during a second meeting (November 2021). RESULTS: Topics identified by the panel included the use of ROS results as external control data, the criteria for contributing centers selection, modalities for ensuring a correct pathological diagnosis and radiologic assessment, consistency of surveillance policies across centers, study end-points, risk of data duplication, results publication. Based on the answers to the survey (55 of 62 invited experts) and discussion the panel agreed on 18 statements summarizing principles of recommended practice. CONCLUSIONS: These recommendations will be disseminated by CTOS across the sarcoma community and incorporated in future ROS on URS, to maximize their quality and favor their use as control data when results from prospective studies are unavailable. These recommendations could help the optimal conduction of ROS also in other rare tumors.

Mesenchymal chondrosarcoma of the head and neck with HEY1::NCOA2 fusion: A clinicopathologic and molecular study of 13 cases with emphasis on diagnostic pitfalls.

BACKGROUND: Mesenchymal chondrosarcoma (MCS) is a rare translocation-associated sarcoma, driven by a canonical HEY1::NCOA2 fusion. The tumors typically have a biphasic phenotype of primitive small blue round cells intermixed with hyaline cartilage. The head and neck (HN) region is a common site for MCS, accounting for 12-45% of all cases reported. AIMS: We assembled a relatively large cohort of 13 molecularly confirmed HN MCS for a detailed clinicopathologic analysis. The underlying fusion events were determined using fluorescence in situ hybridization and/or targeted RNA sequencing. RESULTS: The median age of presentation was 19 years. Five MCSs (39%) had an intraosseous presentation (skull, maxilla, palate, and mandible), while the remaining eight cases occurred in the brain/meninges, orbit, and nasal cavity. Microscopically, HN MCSs were characterized by primitive round cells arranged in a distinctive nested architecture and a rich staghorn vasculature. A cartilaginous component of hyaline cartilage islands and/or single chondrocytes were present in 69% cases. A combined immunoprofile of CD99(+)/SATB2(+)/CD34(-)/STAT6(-) was typically noted. As this immunoprofile is non-specific, the referral diagnoses in cases lacking a cartilaginous component included Ewing sarcoma family and osteosarcoma. Among the seven patients with follow-up data, three developed distant metastasis and one died of disease. CONCLUSION: HN MCS may arise at intra- or extra-osseous sites. The HN MCS appears to have a more prolonged survival compared other MCS sites. Testing for HEY1::NCOA2 fusion is recommended in HN tumors with nested round cell morphology and staghorn vasculature that lack a distinctive cartilaginous component.

Xanthogranulomatous epithelial tumors and keratin-positive giant cell-rich soft tissue tumors: two aspects of a single entity with frequent HMGA2-NCOR2 fusions.

Xanthogranulomatous epithelial tumor (XGET) and keratin-positive giant cell-rich soft tissue tumor with HMGA2-NCOR2 fusion (KPGCT) are two recently described neoplasms with both distinct and overlapping clinical and histopathologic features. We hypothesized that XGET and KPGCT may be related and represent a histologic spectrum of a single entity. To test this, we sought to characterize the clinical, radiographic, immunohistochemical, ultrastructural and molecular features of additional tumors with features of XGET and/or KPGCT, which we refer to descriptively as keratin-positive xanthogranulomatous/giant cell-rich tumors (KPXG/GCT). The archives were searched for potential cases of KPXG/GCT. Clinical and imaging features were noted. Slides were assessed for histologic and immunohistochemical findings. Ultrastructural and next generation RNA sequencing-based analysis were also performed. Nine cases were identified arising in seven women and two men [median age of 33 years (range: 12-87)]. Median tumor size was 4 cm (range: 2.4-14.0 cm) and tumors presented in the thigh (2), buttock (1), forearm (2), groin (1), cranial fossa (1), ilium (1), and tibia (1). Morphologically, tumors were most frequently characterized by a fibrous capsule, with associated lymphoid reaction, enclosing a polymorphous proliferation of histiocytes, giant cells (Touton and osteoclast-types), mixed inflammatory infiltrate, hemorrhage and hemosiderin deposition, which imparted a variably xanthogranulomatous to giant cell tumor-like appearance. One case clearly showed mononuclear cells with eosinophilic cytoplasm characteristic of XGET. All cases expressed keratin and 7 of 9 were found to harbor HMGA2-NCOR2 fusions including cases with xanthogranulomatous appearance. One patient developed local recurrence and multifocal pulmonary lesions, which were radiographically suspicious for metastases. Shared clinical, histologic and immunohistochemical features, and the shared presence of HMGA2-NCOR2 fusions supports interpretation of KPXG/GCT as a single entity which includes XGET and KPGCT. Given limited clinical follow-up to date and rare cases with apparently aggressive findings, we provisionally regard these tumors as having uncertain biologic potential.

Clear cell stromal tumour of the lung with YAP1::TFE3 fusion: four cases including a case with highly aggressive clinical course.

AIMS: Clear cell stromal tumour of the lung (CCST-L) is a rare, recently recognised neoplasm which has been found to express TFE3 and harbour YAP1::TFE3 fusions. Initial data suggested a benign process; however, a single reported case gave rise to distant metastases. We sought to describe the clinicopathological and molecular features of additional cases of CCST-L. METHODS AND RESULTS: Pathology and molecular archives were searched for cases of CCST-L or tumours with YAP1::TFE3 fusions. Clinical features were noted. Available slides, including immunohistochemical studies, were re-reviewed for diagnosis confirmation and assessment of pathological features. Results of molecular studies were also recorded. Four tumours were identified, all occurring in women (median age = 61 years, range = 24-69). Median tumour size was 4.4 cm (range = 1-9.5 cm); three tumours were unifocal and one was multifocal. Tumours were composed of epithelioid to spindled cells with eosinophilic to clear cytoplasm and grew in sheets, vague nests and short fascicles. Nuclear atypia was predominately mild; however, two cases showed scattered atypical cells. Mitotic activity was generally low, although one case showed a mitotic count of 6/2 mm2 . All tumours expressed TFE3 and harboured YAP1::TFE3 fusions. One case was unresectable and was treated with chemotherapy, and two underwent complete resection. One patient died of disease 7 months following diagnosis, while a second patient was alive with no evidence of disease after 43 months. Follow-up was not available for two cases. CONCLUSION: CCST-L expresses TFE3, harbours YAP1::TFE3 fusions and at least rare cases behave in an aggressive manner.

Toward Better Understanding and Management of Solitary Fibrous Tumor.

Solitary fibrous tumor (SFT) comprises a histologic spectrum of soft tissue neoplasms that are characterized by the unique NAB2-STAT6 gene fusion. Changes in diagnostic terminology and site-specific classification over the past few decades have resulted in a disjointed literature. Complete surgical excision with preservation of function remains the mainstay of treatment. New risk stratification systems including risk factors such as mitotic rate, age, tumor size, and presence of necrosis, among others, can be used to predict risk of recurrence or metastasis. Long-term follow-up after surgical resection is recommended. The clinical manifestations, diagnosis, management, and prognosis of SFT are reviewed here.

Leiomyosarcoma: Current Clinical Management and Future Horizons.

Leiomyosarcomas are soft tissue tumors that are derived from smooth muscle mainly in the pelvis and retroperitoneum. Percutaneous biopsy is paramount to confirm diagnosis. Imaging is necessary to complete clinical staging. Multimodal treatment should be directed by expert sarcoma multidisciplinary teams that see a critical volume of these rare tumors. Surgery is the mainstay of curative intent treatment; however due to its high metastatic progression, there may be a benefit for neoadjuvant systemic treatment. Adjuvant systemic treatment has no proven disease-free survival, and its main role is in the palliative setting to potentially prolong overall survival.

ZFP64::NCOA3 gene fusion defines a novel subset of spindle cell rhabdomyosarcoma.

Spindle cell rhabdomyosarcoma represents a rare neoplasm characterized by monomorphic spindle cells with a fascicular architecture and variable skeletal muscle differentiation. Following incidental identification of a ZFP64::NCOA3 gene fusion in an unclassified spindle cell sarcoma resembling adult-type fibrosarcoma, we performed a retrospective archival review and identified four additional cases with a similar histology and identical gene fusion. All tumors arose in adult males (28-71 years). The neoplasms were found in the deep soft tissues, two were gluteal, and one each arose in the thigh, abdominal wall, and chest wall. Morphologically, the tumors were characterized by spindle cells with a distinctive herringbone pattern and variable collagenous to myxoid stroma. The nuclei were relatively monomorphic with variable mitotic activity. Three tumors had immunoreactivity for MyoD1, and four contained variable expression of desmin and smooth muscle actin. All cases tested for myogenin, CD34, S100, pankeratin, and epithelial membrane antigen were negative. Targeted RNA sequencing revealed a ZFP64::NCOA3 fusion product in all five tumors. Three patients developed distant metastases, and two ultimately succumbed to their disease within 2 years of initial diagnosis. This study suggests ZFP64::NCOA3 fusions define a novel subtype of rhabdomyosarcoma with a spindle cell morphology and aggressive clinical behavior. The potential for morphologic and immunohistochemical overlap with several other sarcoma types underscores the value of molecular testing as a diagnostic adjunct to ensure accurate classification and management of these neoplasms.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Soft Tissue Tumors.

The fifth (5th) edition of the World Health Organization (WHO) Classification of Head and Neck Tumors introduces a new chapter dedicated to soft tissue neoplasms commonly affecting the head and neck. While the diversity, rarity, and wide anatomic range of soft tissue tumors precludes a discussion of all entities that may be found in the head and neck, the addition of this new chapter to the head and neck "blue book" aims to provide a more comprehensive and uniform reference text, including updated diagnostic criteria, of mesenchymal tumor types frequently (or exclusively) arising at head and neck sites. Since publication of the previous edition in 2017, there have been numerous advances in our understanding of the pathogenesis of many soft tissue tumors which have facilitated refinements in tumor classification, identification of novel entities, development of diagnostic markers, and improved prognostication. This review will provide a focused discussion of the soft tissue tumors included in the 5th edition WHO Head and Neck classification, with an emphasis on updates.

Expanding the spectrum of mesenchymal neoplasms with NR1D1-rearrangement.

Undifferentiated mesenchymal neoplasms can be morphologically subclassified based on cell shape; epithelioid tumors may be diagnostically challenging, particularly since they can show morphologic and immunohistochemical overlap with epithelial neoplasms. Following the recent report of an NR1D1::MAML1 gene fusion in an undifferentiated pediatric neoplasm, we performed a retrospective archival review and identified four additional cases of undifferentiated mesenchymal neoplasms with NR1D1-rearrangement. All four tumors occurred in adult women. The tumors involved superficial and/or deep soft tissues of the extremities or abdomen. Morphologically, they showed a spectrum of overlapping features. In addition to epithelioid cells, two cases also had a prominent spindle cell component. Two cases also had admixed polygonal cells containing prominent cytoplasmic vacuoles with amorphous debris. The immunophenotype was nonspecific but all cases had at least focal keratin expression; this was extensive in two tumors. Targeted RNA-sequencing revealed two cases each with NR1D1::MAML1 and NR1D1::MAML2 gene fusions. One patient developed lung and liver metastases, and one patient required amputation due to multifocal disease and underlying bone involvement. This study confirms undifferentiated NR1D1-rearranged sarcoma represents a distinct mesenchymal neoplasm with an epithelioid morphology and potential for aggressive behavior. Further, we offer new insight into the spectrum of clinical, morphologic, immunohistochemical, and molecular findings possible in these rare neoplasms. An awareness of this entity is especially important given the potential for misclassification as a carcinoma.

Multidisciplinary Intervention in Radiation-Associated Angiosarcoma of the Breast: Patterns of Recurrence and Response to Treatment.

BACKGROUND: Radiation-associated angiosarcoma (RAAS) of the breast is an aggressive malignancy affecting 1 in 1000 breast cancer patients. This study aimed to determine differences in treatments and outcomes for RAAS initially managed through a sarcoma multi-disciplinary team (SMDT) compared with an outside center (OC) and to describe outcomes after recurrence. METHODS: Patients with a diagnosis of breast RAAS between 2004 and 2019 were identified from our sarcoma database. Clinicopathologic characteristics, recurrence patterns, and factors predictive of survival were assessed. Differences in local recurrence-free survival (LRFS) and disease-specific survival (DSS) were estimated using Kaplan-Meier and compared using the log-rank test. RESULTS: Surgery was performed for 49 women with RAAS, who had a median age of 74 years (range 41-89 years). Primary management was performed by SMDT for 26 patients and by OC for 23 patients. Radical mastectomy and reconstruction were performed for 96% of the SMDT group versus 17% of the OC group (p = 0.00001). The proportion patients who received chemotherapy, radiation, or both was 42.3% in the SMDT group and 0% in the OC group. During a median follow-up period of 26 months, recurrence was experienced by 38% (10/26) of the SMDT cohort and 83% (19/23) of the OC cohort (p = 0.002). The 3-year LRFS was better in the SMDT cohort (59.3% vs 31.8%; p = 0.019). Of the 29 recurrences 16 received chemotherapy and 6 received radiation, surgery, or both. At the last follow-up visit, 20 patients were in first remission, 1 patient was in second remission, 8 patients were alive with disease, and 20 patients had died of disease. CONCLUSION: Initial treatment by SMDT was associated with more extensive surgery, multimodal treatments, and a better 3-year LRFS. Patients with breast RAAS likely benefit from early referral and treatment by an SMDT.

Soft tissue solitary fibrous tumors of the musculoskeletal system: spectrum of MRI appearances and characteristic imaging features.

OBJECTIVE: Solitary fibrous tumors (SFTs) uncommonly occur in the musculoskeletal system, with limited available data on their MRI appearance. This study was performed to assess the MRI features of SFTs in the musculoskeletal system (MSK-SFTs). MATERIALS AND METHODS: Pre-treatment MRI in 39 patients with pathologically proven SFTs in the trunk or extremities was evaluated. Patient demographics, clinical management and follow-up, and lesion histology were reviewed. MRI features including lesion location, size, morphology, signal characteristics, vascularity, and relationship to major neurovascular structures were assessed. RESULTS: MSK-SFTs most frequently occurred in the lower extremity (23/39 cases, 59%), deep to fascia (29/39, 74%), and intermuscular (22/29, 76%) in location. The majority of deep lesions were located along a major neurovascular bundle (20/29, 69%). Lesions had well-defined margins (39/39, 100%), multilobulated contours (27/39, 69%), and measured mean 6.9 ± 2.8 cm. The majority of lesions had slightly hyperintense T1 signal (34/39, 87%) and heterogenous intermediate-to-high T2/STIR signal (28/38, 74%). A "pseudo-cerebriform" internal architectural pattern on fluid-sensitive sequences, with internal lobulations and low signal bands/septations, was observed in 63% (24/38) of lesions. Lesions commonly demonstrated prominent intra-lesional (30/39, 75%) and peripheral juxta-lesional flow voids. Local invasion of surrounding structures was uncommon (3/39, 8%). Mitotically active lesions (p = 0.02) and lesions with tumor necrosis (p < 0.01) were larger in size. Tumor necrosis was associated with T1 heterogeneity (p = 0.04). Distant metastasis occurred in 10% (4/39) of patients, all in mitotically active lesions pre-operatively considered at least at intermediate risk of metastasis. CONCLUSION: MSK-SFTs commonly present as well-defined, hypervascular masses deep to fascia along major neurovascular bundles, with heterogeneous slightly hyperintense T1 signal, intermediate-to-high T2/STIR signal, and prominent macroscopic flow voids.