Extraskeletal Myxoid Chondrosarcoma Research Articles

Detection of EWSR1 gene rearrangement by fluorescence in situ hybridization in bone and soft tissue tumors: clinical application evaluation and atypical signal analysis

Objective: To investigate the clinical application of EWSR1 gene rearrangement by fluorescence in situ hybridization (FISH) in bone and soft tissue tumors and to analyze the cases with atypical signal pattern. Methods: The cases detected for EWSR1 gene rearrangement by FISH in Beijing Jishuitan Hospital, Capital Medical University from 2014 to 2021 were collected, and the value of detecting EWSR1 gene rearrangement for diagnosing bone and soft tissue tumors was analyzed. The cases with atypical positive signals were further analyzed by next generation sequencing (NGS). Results: FISH using EWSR1 break-apart probe kit was successfully performed in 97% (205/211) of cases, 6 cases failed. Four of the 6 failures were due to improper decalcification, 1 case due to signal overlap caused by thick slices, and 1 case due to signal amplification and disorder. EWSR1 gene rearrangements were positive in 122 cases (122/205, 59%), atypical positive signal in 8 cases (8/205, 4%), and negative in 75 cases (75/205, 37%). In cases testing positive, the percentage of positive cells ranged from 34% to 98%, with 120 cases (120/122, 98%) showing a positive cell percentage greater than 50%. Among the 205 successfully tested cases, 156 cases were histologically diagnosed as Ewing's sarcoma, of which 110 were positive (110/156, 71%), 7 were atypical positive (7/156, 4%), and 39 were negative (39/156, 25%). Nine cases were histologically diagnosed as clear cell sarcoma of soft tissue, of which 6 were positive (6/9), 1 was atypical positive (1/9), and 2 were negative (2/9). Five cases were histologically diagnosed as extraskeletal myxoid chondrosarcoma, of which 2 were positive (2/5) and 3 were negative (3/5). Three cases were histologically diagnosed as angiomatoid fibrous histiocytoma, of which 2 were positive (2/3) and 1 was negative (1/3). Two cases were histologically diagnosed as myoepithelioma of soft tissue, of which 1 was positive (1/2) and 1 was negative (1/2). One case was histologically diagnosed as olfactory neuroblastoma with a positive result. The 29 other tumor cases including osteosarcoma, synovial sarcoma, and malignant melanoma and others were all negative. Basing on histology as the standard for diagnosis and considering atypical positive cases as negative, comparing with the 29 cases of other tumors as control group, the sensitivity for diagnosing Ewing's sarcoma through the detection of EWSR1 gene rearrangement was 71%, and the specificity was 100%; the sensitivity for diagnosing clear cell sarcoma of soft tissue was 67%, and the specificity was 100%; the sensitivity for diagnosing extraskeletal myxoid chondrosarcoma was 40%, and the specificity was 100%; the sensitivity for diagnosing angiomatoid fibrous histiocytoma was 67%, and the specificity was 100%; the sensitivity for diagnosing myoepithelioma of soft tissue was 50%, and the specificity was 100%; the sensitivity for diagnosing olfactory neuroblastoma was 100%, and the specificity was 100%. Four of 8 cases with atypical positive signals analyzed by NGS showed EWSR1 rearrangement, including EWSR1::FLI1 in one case of Ewing sarcoma, EWSR1::NFATC2 in one case of EWSR1::NFATC2-rearranged sarcoma, EWSR1::ATF1 in one case of clear cell sarcoma of soft tissue and EWSR1::NR4A3 in one case of extraskeletal myxoid chondrosarcoma. Conclusions: Detection of EWSR1 rearrangement by FISH is of utmost significance in the diagnosis of bone and soft tissue tumors. Cases with atypical positive signals should be further scrutinized, correlating with their histomorphology and verifying by NGS if necessary.

Expanding the Spectrum of NR4A3 Fusion–Positive Gynecologic Leiomyosarcomas

Recurrent gene fusions have been observed in epithelioid and myxoid variants of uterine leiomyosarcoma. PGR::NR4A3 fusions were recently described in a subset of epithelioid leiomyosarcomas exhibiting rhabdoid morphology. In this study, we sought to expand the clinical, morphologic, immunohistochemical, and genetic features of gynecologic leiomyosarcomas harboring NR4A3 rearrangements with PGR and novel fusion partners. We identified 9 gynecologic leiomyosarcomas harboring PGR::NR4A3, CARMN::NR4A3, ACTB::NR4A3, and possible SLCO5A1::NR4A3 fusions by targeted RNA sequencing. Tumors frequently affected premenopausal women, involving the uterine corpus, uterine cervix, or pelvis. All were similarly characterized by lobules of monomorphic epithelioid and/or spindled cells arranged in sheets, cords, trabeculae, and micro- and macrocysts associated with abundant myxoid matrix and hemorrhage, creating labyrinth-like or pulmonary edema–like architecture. Myogenic differentiation with frequent estrogen receptor and progesterone receptor staining and no CD10 expression characterized all tumors. All cases showed high NR4A3 RNA expression levels and NOR1 (NR4A3) nuclear staining similar to salivary gland acinic cell carcinomas and a subset of extraskeletal myxoid chondrosarcomas harboring NR4A3 rearrangements. NOR1 (NR4A3) immunohistochemistry may serve as a useful diagnostic marker of NR4A3 fusion–positive gynecologic leiomyosarcomas.

CHRNA6 RNA In Situ Hybridization Is a Useful Tool for the Diagnosis of Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is an uncommon mesenchymal neoplasm characteristically composed of uniform-appearing round to spindle-shaped cells with eosinophilic cytoplasm and abundant myxoid extracellular matrix. Although the majority of cases harbor a pathognomonic t(9;22) translocation that fuses EWSR1 with the orphan nuclear receptor NR4A3, there are less common variants that partner NR4A3 with TAF15, TCF12, or TFG. By immunohistochemistry, EMC has features of both cartilaginous and neuroendocrine differentiation, as evidenced by inconsistent expression of S100 protein and synaptophysin or INSM1, respectively, in a subset of cases. Given the limitations of available immunohistochemical stains for the diagnosis of EMC, we analyzed genome-wide gene expression microarray data to identify candidate biomarkers based on differential expression in EMC in comparison with other mesenchymal neoplasms. This analysis pointed to CHRNA6 as the gene with the highest relative expression in EMC (96-fold; P = 8.2 × 10−26) and the only gene with >50-fold increased expression in EMC compared with other tumors. Using RNA chromogenic in situ hybridization, we observed strong and diffuse expression of CHRNA6 in 25 cases of EMC, including both EWSR1-rearranged and TAF15-rearranged variants. All examined cases of histologic mimics were negative for CHRNA6 overexpression; however, limited CHRNA6 expression, not reaching a threshold of >5 puncta or 1 aggregate of chromogen in >25% of cells, was observed in 69 of 685 mimics (10.1%), spanning an array of mesenchymal tumors. Taken together, these findings suggest that, with careful interpretation and the use of appropriate thresholds, CHRNA6 RNA chromogenic in situ hybridization is a potentially useful ancillary histologic tool for the diagnosis of EMC.

Identification of Novel/Rare EWSR1 Fusion Partners in Undifferentiated Mesenchymal Neoplasms.

Recurrent gene fusions (GFs) in translocated sarcomas are recognized as major oncogenic drivers of the disease, as well as diagnostic markers whose identification is necessary for differential diagnosis. EWSR1 is a 'promiscuous' gene that can fuse with many different partner genes, defining different entities among a broad range of mesenchymal neoplasms. Molecular testing of EWSR1 translocation traditionally relies on FISH assays with break-apart probes, which are unable to identify the fusion partner. Therefore, other ancillary molecular diagnostic modalities are being increasingly adopted for accurate classification of these neoplasms. Herein, we report three cases with rare GFs involving EWSR1 in undifferentiated mesenchymal neoplasms with uncertain differential diagnoses, using targeted RNA-seq and confirming with RT-PCR and Sanger sequencing. Two GFs involved hormone nuclear receptors as 3' partners, NR4A2 and RORB, which have not been previously reported. NR4A2 may functionally replace NR4A3, the usual 3' partner in extraskeletal myxoid chondrosarcoma. The third GF, EWSR1::BEND2, has previously been reported in a subtype of astroblastoma and other rare entities, including a single case of a soft-tissue tumor that we discuss in this work. In conclusion, our findings indicate that the catalogue of mesenchymal neoplasm-bearing EWSR1 fusions continues to grow, underscoring the value of using molecular ancillary techniques with higher diagnostic abilities in the routine clinical setting.

18 F-FDG PET/CT Findings of Ovarian Myxoid Chondrosarcoma.

Ovarian myxoid chondrosarcoma is a rare and aggressive tumor. We present 18 F-FDG PET/CT findings of ovarian myxoid chondrosarcoma. The images not only demonstrated a pelvic mass with increased FDG uptake, but also a mass with increased FDG uptake in the right lower abdominal wall. Ovarian malignancy with abdominal wall metastases was suspected. An extraskeletal myxoid chondrosarcoma was diagnosed histopathologically after the mass excision.

Myxofibrosarcoma with false-positive EWSR1 FISH

Abstract Introduction/Objective Myxofibrosarcoma is a common sarcoma in elderly patients. It comprises a spectrum of malignant fibroblastic neoplasms with variable myxoid stroma, pleomorphism, and a distinctive curvilinear vascular pattern. As soft tissue tumors frequently exhibit overlapping histologic features, immunohistochemical stains and fluorescent in situ hybridization (FISH) studies are utilized to determine accurate diagnosis. The purpose of this case is to report a false-positive EWSR1 FISH in a myxofibrosarcoma. Methods/Case Report A 54-year-old male presented with a mass in his left forearm that had been present for four months. The mass was as painless and had not grown larger since it was initially noticed. A resection of the mass was performed which revealed monotonous, spindled to focally epithelioid cell population in a myxoid background that bordered on chondroid in some foci. While this raised concern for a translocation-associated sarcoma, particularly extraskeletal myxoid chondrosarcoma, the scattered pleomorphism expected in a myxofibrosarcoma was still present. Immunohistochemistry revealed diffuse reactivity for CD34 and negativity for pancytokeratin, EMA, S100, SOX10, desmin, SMA, CD117, TLE1, and STAT6 stains. FISH for EWSR1 gene arrangement to exclude extraskeletal myxoid chondrosarcoma was positive. However, a follow-up NGS study was negative for gene rearrangement, indicating a false-positive FISH result. The diagnosis of myxofibrosarcoma, FNCLCC grade 1 or 3 was rendered. Results (if a Case Study enter NA) NA Conclusion EWSR1 gene rearrangements represent one of the most commonly involved genes in sarcoma. FISH has a reported sensitivity and specificity for this rearrangement of 100% and 87% respectively. This case highlights a false-positive FISH result in a soft tissue tumor and the importance of correlating results with histology and molecular genetics for accurate diagnosis to guide appropriate management for patients.

SMARCB1/INI1-deficient epithelioid and myxoid neoplasms in paratesticular region: Expanding the clinicopathologic and molecular spectrum

SMARCB1/INI1-deficient soft tissue tumors with epithelioid and myxoid features are diverse and mainly include soft tissue myoepithelial tumor, extraskeletal myxoid chondrosarcoma, and the recently described myoepithelioma-like tumor of the vulvar region and myxoepithelioid tumor with chordoid features. Because of their overlapping features, the accurate diagnosis and classification of these tumors are often challenging. Herein, we report two unique cases of SMARCB1/INI1-deficient soft tissue neoplasm with epithelioid and myxoid features occurring in male paratesticular region. The first case was a 52-year-old man presented with an intermittent painful left paratesticular mass for 1 year. The second case was a 41-year-old man presented with a painless paratesticular mass on the right side for 3 months. Both patients underwent an orchiectomy. After 6 and 26 months of follow-up, both were alive with no evidence of recurrence or metastasis. In both cases, the tumor was relatively well-demarcated and showed monomorphic round to epithelioid cells arranged in a nested, trabecular, reticular, and corded pattern, setting in a myxohyalinized and vascularized matrix. The tumor cells showed relatively uniform round nuclei with vesicular chromatin and variably prominent nucleoli. No rhabdoid cells were identified. Mitoses numbered 3 and 2 per 10 high-power fields. Tumor necrosis or lymphovascular invasion was absent. Immunohistochemically, both tumors expressed epithelial membrane antigen (focal), calponin (focal), and CD99. SMARCB1/INI1 expression was deficient in both cases. In addition, case 1 diffusely expressed pan-cytokeratin, and case 2 diffusely expressed CD34 and synaptophysin. Molecular genetically, case 1 showed SMARCB1 homozygous deletion as detected by fluorescence in-situ hybridization (FISH), and case 2 demonstrated SMARCB1 copy number deletions by next-generation sequencing and SMARCB1 monoallelic deletion by FISH. Both cases lacked EWSR1 rearrangements by FISH. The overall clinicopathologic profiles of the two cases made it difficult to classify them as one of the established categories of SMARCB1/INI1-deficient mesenchymal tumors. Our study further expands the clinicopathologic and molecular spectrum of SMARCB1/INI1-deficient epithelioid and myxoid neoplasms and highlights the challenges to diagnose these tumors.

Acute myeloid leukemia with monocytic differentiation (myeloid sarcoma) masquerading as bone-soft tissue malignancy

Abstract Introduction/Objective Myeloid sarcoma is an extramedullary solid neoplasm composed of myeloid precursors with or without maturation. This tumor usually occurs simultaneously or following the onset of acute leukemia. Rarely, it can be the first manifestation of acute myeloid leukemia. We report a case of this rare tumor presenting histologically as a bone sarcoma with features of extraskeletal myxoid chondrosarcoma and myoepithelial carcinoma Methods/Case Report A 76-year-old female was referred to our institution for evaluation of a right foot mass associated with pain and swelling. MRI showed a 2.4 x 1.5x 1.2 cm soft tissue mass along the lateral margin of proximal and mid diaphysis of first metatarsal. The clinical and radiologic differential diagnosis was primary bone-soft tissue malignancy, or infection. Histologically, the biopsies showed sheets and cords of cells in a myxoid background. Cytologically the cells were plasmacytoid, mononuclear, mitotically active with immature chromatin, prominent nucleoli, and moderate to abundant cytoplasm. This morphologic appearance elicited the differential diagnosis of extraskeletal myxoid chondrosarcoma, myoepithelial carcinoma, and plasmacytoma. An initial panel of immunohistochemical stains showed the lesional cells to be negative for S-100, SOX-10, pancytokeratin, desmin, p63, EMA, CAM5.2, and CD138 but positive for CD43. Additional immunohistochemistry showed diffuse reactivity for CD33, and lysozyme; CD163 was focally positive, and the cells were negative for CD20, CD3, CD30, CD99, MUM1, CD138, and CD34. A diagnosis of extramedullary acute myeloid leukemia with monocytic differentiation (myeloid sarcoma) was rendered. Subsequently, patient underwent bone marrow biopsy which showed involvement by acute myeloid leukemia with monocytic differentiation. Results (if a Case Study enter NA) NA Conclusion Myeloid sarcoma is a rare tumor and presentation as an isolated metatarsal mass is highly unusual and exceedingly rare. This can mislead clinicians, radiologists, and pathologists. Pathologists need to keep hematopoietic tumors in their differential diagnosis even when the anatomic sites as well as the morphology are not typical of hematopoietic malignancies.

Extraskeletal Myxoid Chondrosarcoma of Floor of Mouth-A Rare Case Report and Review of Literature.

Chondrosarcomas are rare malignancies of the cartilage and myxoid chondrosarcoma is its variant which commonly occurs in soft tissue of extremities. Extraskeletal chondrosarcoma is a rare malignant neoplasm of bone or soft tissue origin and is characterized by the presence of spindle cells admixed with well differentiated cartilage or chondroid stroma. They are mostly radioresistant tumours and surgical resections with adequate margins is considered as the ideal treatment modality with adjuvant radiotherapy in high grade tumours and add on chemotherapy, in case of presence of poor prognostic factors. A 51-year-old diabetic, hypertensive female patient presented to our outpatient department with difficulty in chewing food for a duration of 6 months. On clinical examination, she had an ulceroproliferative growth involving right lower alveolus and floor of mouth. MRI face and neck with contrast showed a 4.1 × 2.9 × 4.5cm lesion involving right lower alveolus extending to floor of mouth. Biopsy showed features of extraskeletal myxoid chondrosarcoma. She was planned for upfront surgery (Right composite resection with modified radical neck dissection with free fibula flap). Patient was stable post-surgery and was discharged in stable condition. Final histopathology report was high grade myxoid chondrosarcoma. The case was presented in tumour board and the patient was planned for adjuvant radiotherapy. She has been on regular follow up for the past 2 years and shows no signs of recurrence. Extraskeletal myxoid chondrosarcoma of oral cavity is a rare entity and very few cases are reported. It is a malignant neoplasm which is diagnosed with the help of immunohistochemistry. Surgery is the ideal modality of treatment accompanied by adjuvant radiotherapy in cases of high-grade tumours.

Invasive urothelial carcinoma with chordoid features or abundant myxoid stroma: A reappraisal of morphologic spectrum and risk stratification based on molecular classification

Urothelial carcinoma (UC) with myxoid stroma or chordoid features is a rare diagnosis. We retrospectively collected data from 17 cases of diagnosed UC with myxoid stroma, mucin production, or chordoid features. We aimed to investigate the molecular subtypes of this neoplasm and to assess subtype correlations with clinical outcomes. Immunohistochemical (IHC) staining with a panel composed of markers for basal subtypes (CK5/6, CK14, and CD44) and luminal subtypes (GATA3, FOXA1, and CK20) was performed. Morphologically, all cases included an at least partial conventional UC component, with the first histologic pattern, named as “typical”, characterized by a small- or medium-sized tumor cell nest. The second histologic pattern, named as “chordoid”, was characterized by tumor cells with cording that mimic extra-skeletal myxoid chondrosarcoma or chordoma, and the third histologic pattern, named as “sarcomatoid”, was characterized by non-cohesive spindle tumor cells with a mucin-producing or myxoid stroma background. The “typical” cases showed [CK5/6- CK14- CD44-] [GATA3 + FOXA1 + CK20-] IHC results and was classified as lumina subtype. The “chordoid” cases showed [CK5/6 + CK14 + CD44-] [GATA3- FOXA1- CK20-] IHC results and was classified as basal subtype, and the “sarcomatoid” cases showed [CK5/6- CK14- CD44+] [GATA3- FOXA1- CK20-] IHC results and was “not classified”. All pT3 cases and all cases with lymph node (LN) metastasis belonged to the “sarcomatoid” pattern. All patients who had metastasis or died showed the “chordoid” or “sarcomatoid” morphology. Our findings suggest that UC with myxoid stroma/chordoid features shows characteristic expression of luminal and basal markers and different prognosis according to the morphologic pattern spectrum.

Extraskeletal myxoid chondrosarcoma of the gingival: a rare case report and review of the literature

BackgroundExtraskeletal myxoid chondrosarcoma (EMC) is a rare malignant tumor described in the head and neck region, especially in the gingival. We present one case arising in the gingival of right mandible, and briefly reviewed the related literature.Case presentationA 24-year-old male patient with a lesion of 3.5*2.0 cm in buccal gingival of right posterior mandible for 2 months. The tumor was composed of cartilaginous structures and myxoid matrix. Immunohistochemical(IHC) showed that the tumor cells to be positive for vimentin, focally positive for S-100, negative for calponin, SMA, SOX10. The Ki-67 labelling index was 80%. Fluorescent in situ Hybridization (FISH) was positive for NR4A3 rearrangement.ConclusionsDue to its unusual site and low incidence in the oral region, a combination of histological findings, immunohistochemistry, and molecular pathology as well as differential diagnosis with other diseases should be taken into consideration in the process of clinical diagnosis and treatment.

Whole genome sequencing for metastatic mutational burden in extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is an ultra-rare cancer that makes up less than 3% of all soft tissue sarcomas. It most often arises in the soft tissues of the proximal limbs and has a higher incidence in males. Though EMC has a good prognosis, it has an indolent course with high rates of local recurrence as well as metastasis to the lungs. EMC is characterized in 70% of cases by an EWS1-NR4A3 translocation, leading to constitutive expression of NR4A3. Structural variants (SVs) in EMC, especially large-scale genomic alterations, have not been well studied and studies are severely limited by sample size. In this study, we describe Whole Genome Sequencing (WGS) of a rare case of matched EMC primary tumor, lung metastasis, and pelvic metastasis to identify genomic alterations. We examined somatic variants, copy number variants (CNVs), and larger scale SVs such as translocations and breakend points. While the primary tumor and lung metastasis had similar somatic variations and CNVs, the pelvic metastasis had more unique SVs with especially increased mutational burden of SVs in chromosome 2. This suggests that different molecular drivers appear in more advanced, relapsing EMC compared with the primary tumor and early lung metastasis. Genomic studies such as ours may identify novel molecular complexities in rare cancers that may be leveraged for therapeutic strategies and precision medicine.

PRAME immunohistochemistry in soft tissue tumors and mimics: a study of 350 cases highlighting its imperfect specificity but potentially useful diagnostic applications.

Preferentially expressed antigen in melanoma (PRAME) immunohistochemistry is currently used in pathology for the assessment of melanocytic neoplasms; however, knowledge of its expression patterns in soft tissue tumors is limited. PRAME immunohistochemistry (clone QR005) was assessed on whole tissue sections of 350 soft-tissue tumors and mimics (> 50 histotypes). PRAME immunoreactivity was evaluated as follows: 0 "negative" (0% positive cells); 1+ (1-25% positive cells); 2+ (26-50% positive cells); 3+ (51-75% positive cells), and 4+ "diffuse" (> 75% positive cells). PRAME was expressed in 111 lesions (0 benign, 6 intermediate malignancy, and 105 malignant), including fibrosarcomatous dermatofibrosarcoma protuberans (2/4, 0 diffuse), NTRK-rearranged spindle cell neoplasm (2/4, 0 diffuse), atypical fibroxanthoma (1/7, 0 diffuse), Kaposi sarcoma (1/5, 0 diffuse), myxoid liposarcoma (11/11, 9 diffuse), synovial sarcoma (11/11, 6 diffuse), intimal sarcoma (7/7, 5 diffuse), biphenotypic sinonasal sarcoma (3/3, 1 diffuse), angiosarcoma (10/15, 6 diffuse), malignant peripheral nerve sheath tumor (9/12, 4 diffuse), pleomorphic rhabdomyosarcoma (2/3, 2 diffuse), alveolar rhabdomyosarcoma (2/6, 0 diffuse), embryonal rhabdomyosarcoma (7/7, 4 diffuse), undifferentiated pleomorphic sarcoma (2/12, 1 diffuse), leiomyosarcoma (2/15, 1 diffuse), clear cell sarcoma of soft tissue (1/10, 0 diffuse), low-grade fibromyxoid sarcoma (1/5, 0 diffuse), Ewing sarcoma (2/10, 1 diffuse), CIC-rearranged sarcoma (8/8, 4 diffuse), BCOR-sarcoma (2/5, 1 diffuse), melanoma (20/20, 14 diffuse), and thoracic SMARCA4-deficient undifferentiated tumor (5/5, all diffuse). All tested cases of spindle cell lipoma, dedifferentiated/pleomorphic liposarcoma, dermatofibrosarcoma protuberans, solitary fibrous tumor, inflammatory myofibroblastic tumor, myxoinflammatory fibroblastic sarcoma, nodular fasciitis, myxofibrosarcoma, epithelioid hemangioendothelioma, atypical vascular lesion, hemangioma, lymphangioma, vascular malformation, papillary endothelial hyperplasia, GIST, gastrointestinal clear-cell sarcoma, malignant melanotic nerve sheath tumor, neurofibroma, schwannoma, granular cell tumor, alveolar soft part sarcoma, epithelioid sarcoma, extraskeletal myxoid chondrosarcoma, myoepithelioma, ossifying fibromyxoid tumor, angiomatoid fibrous histiocytoma, PEComa, dermatofibroma, pleomorphic dermal sarcoma, and chordoma were negative. PRAME shows imperfect specificity in soft-tissue pathology but may serve as a diagnostic adjunct in selected differential diagnoses that show contrasting expression patterns.

Chondrosarcoma: The OSU experience.

e23505 Background: Chondrosarcomas (CSC) constitute a diverse group of malignant bone tumors whose optimal management remains controversial, and patients with advanced disease have a dismal prognosis. Methods: Patients evaluated at The Ohio State University between January 1, 2010, to March 7, 2022, were included in the analysis. Data includes demographics, pathology, next-generation sequencing results, treatment combinations and responses, survival, time to progression, and recurrence. Results: 147 patients were eligible for this retrospective study. 29 patients were censored as they received no treatment or were lost to follow-up, leaving 118 evaluable patients. 83 patients had Conventional CSC, 16 had Dedifferentiated CSC, 4 Mesenchymal/Clear cell CSC, and 15 Myxoid/Extraskeletal myxoid CSC. 108 of 118 were white (91.5%), and 60 of 118 were male (50.8%). The median age at diagnosis was 57, ranging from 21-84 years old. 107 (92.2%) patients in the dataset had localized disease (Stage 1 or 2) and had curative treatment intent. The median tumor size was 6.3 cm for all patients. The most common site of the tumor was in the lower extremities (36.4%), followed by thoracoabdominal in 46 patients (38.9%), skull base/head and Neck in 17 patients (14.4%), and upper extremities in 12 of 118 (10.2%). The Median survival time differed significantly by subtype: Conventional CSC 104.6 months, dedifferentiated CSC 25.9 months, mesenchymal + clear cell CSC 57.2 months, myxoid or extraskeletal myxoid CSC 108.3 months, Overall survival in the entire cohort was 90.6 months. Overall comparison among subtypes Chi-square 57.41, ( p = 0.0). No association was seen between anatomic subsite and overall survival (upper extremities 202.80 months, lower extremities 85.30 months, and Pelvis & Retroperitoneal & lower back & Chest/Abdomen Wall/Upper Back 82.3 months, p = 0.216). The grade was associated with overall survival: grade 1 median 202.80 months, grade II 80.87 months, and grade III 21.067 months (p = 0.000). 18 patients received chemotherapy, 116 received surgery, and 12 received radiation. Among the 18 patients that received chemotherapy ( 4 patients had localized disease and 14 had the metastatic disease), the most used systemic therapy was Pazopanib 10/18 (55%), which had the longest time to progression of 22.42 months. The median time to progression of the 18 patients that received chemotherapy was 9.71 months. Conclusions: CSC remains a clinical challenge due to its rarity and limited treatment options. While surgical resection remains the mainstay of treatment for localized disease, systemic therapy and radiation can have important roles in selected subsets of patients. Further refinement of these care paradigms will require a multi-institutional/consortium effort to create a data repository and develop clinical trials to improve outcomes for these patients.

TAF15::NR4A3 gene fusion identifies a morphologically distinct subset of extraskeletal myxoid chondrosarcoma mimicking myoepithelial tumors.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation predominantly arising in deep soft tissue. Its conventional morphologic appearance manifests as a relatively well-circumscribed, multilobular tumor composed of uniform short spindle-to-ovoid primitive mesenchymal cells with deeply eosinophilic cytoplasm arranged in anastomosing cords within abundant myxoid matrix. The genetic hallmark of EMC has long been considered to be pathognomonic gene rearrangements involving NR4A3, which when fused to TAF15, often have high-grade morphology with increased cellularity, moderate to severe cytologic atypia, and rhabdoid cytomorphology. Herein, we describe two cases of EMC with TAF15::NR4A3 fusion that appear morphologically distinct from both conventional and high-grade EMC. Both cases had an unusual biphasic appearance and showed diffuse positivity for p63, mimicking myoepithelial tumors. DNA methylation profiling demonstrated that both cases clearly cluster with EMC, indicating that they most likely represent morphologically distinct variants of EMC. The clinical significance and prognostic impact of this morphologic variance remains to be determined. Molecular testing, including DNA methylation profiling, can help to confirm the diagnosis and avoid confusion with mimics; it adds another layer of data to support expanding the morphologic spectrum of EMC.

Abstract 1067: MatchMiner: An open-source AI precision medicine trial matching platform

Abstract As the number of precision medicine (PM) trials and patient genomic data has grown, it has become challenging for clinicians and trial staff to identify PM trial options for patients. Several trial matching software platforms have been developed to match genomic data from patients with PM trials, but these existing platforms are proprietary and are not easily accessible for adoption by institutions. At Dana-Farber Cancer Institute (DFCI), we have addressed this challenge by developing our own open-source institutional trial matching software, MatchMiner. MatchMiner algorithmically matches patient genomic and clinical data with PM trial eligibility data. Trial eligibility data is manually curated into a human-readable markup language, called clinical trial markup language (CTML), for matching with patient genomic data. MatchMiner has 2 main modes of clinical use: (1) patient-centric, where clinicians search for trial matches for individual patients and (2) trial-centric, where trial staff identify patients that match their trial’s genomic eligibility. We recently described MatchMiner’s usage at DFCI and since our report, we have added 90 additional trial consents facilitated by MatchMiner (>250 trial consents, called MatchMiner consents [MMC]). Here, we describe new characteristics of our MMC including which user mode (patient-centric or trial-centric) was used to match the consent, genomic alterations and cancer types that matched to eligibility criteria, and whether the patient went onto trial. MMCs were mostly identified by patient-centric mode (70%), genomic alterations and cancer types among MMC were diverse (n=55 genes and n=20 cancer types), and 87% of MMC went on trial. Among MMCs, the most common altered genes leading to trial eligibility were ERBB2 and KRAS in breast cancer and lung cancer, which is consistent with the number of therapies targeting ERBB2 and KRAS. MMCs also included patients with rare cancer types, like extraskeletal myxoid chondrosarcoma, as well as rare genomic alterations, such as NTRK fusions. Thus, MatchMiner has been successful at facilitating PM trial matching for a broad range of genomic alterations and cancer types at DFCI. MatchMiner matches patients to trials as soon as their genomic report is available, however, many patients are not yet ready to enroll onto a trial because their cancer is responding to the standard of care or they are in a remission period. To address this problem, we are evaluating the use of artificial intelligence (AI) to identify patients that may be ready for a new treatment option. After trial matches have been generated by MatchMiner, radiology scan text from patients’ tumor scans is run through a natural language processing (NLP) model to identify patients who are more likely to be ready to enroll onto a trial. By using NLP to filter trial matches, we hope to improve MatchMiner’s efficiency of finding trial matches and provide more timely trial options for patients. Citation Format: Harry Klein, Tali Mazor, Matthew Galvin, Jason Hansel, Emily Mallaber, Pavel Trukhanov, Joyce Yu, James Lindsay, Kenneth Kehl, Michael Hassett, Ethan Cerami. MatchMiner: An open-source AI precision medicine trial matching platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1067.

Extraskeletal myxoid chondrosarcoma: A study of 17 cases focusing on the diagnostic utility of INSM1 expression and presenting rare morphological variants associated with non-EWSR1::NR4A3 fusions.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain lineage. Insulinoma-associated protein 1 (INSM1) has recently been described as a highly specific and sensitive immunohistochemical marker for EMC. The goal of this study was to evaluate the diagnostic significance of INSM1 immunohistochemistry in EMC. Furthermore, correlations between molecular and morphological findings were performed. Sixteen of 17 EMC cases were stained with the INSM1 antibody. Tumors with at least 5% INSM1-positive cells and any staining intensity were considered positive. Molecular testing was successfully performed in 12/17 cases. The immunohistochemical analysis detected 13 INSM1-positive (81%) and 3 INSM1-negative tumors (19%). The extent of the staining was classified as 1+ in 7 cases (44%), 2+ in 2 cases (13%), 3+ in 2 cases (13%) and 4+ in 2 cases (13%). Intensity of immunostaining was weak in 5 cases (31%), moderate in 2 cases (13%) and strong in 6 cases (38%). Molecular assays revealed 8 EWSR1::NR4A3 positive tumors (67%), 2 TAF15::NR4A3 positive tumors (17%), 1 TCF12::NR4A3 positive tumor (8%) and 1 NR4A3 positive tumor (8%) in which no other gene alteration was identified. Two of them, namely TCF12 positive and one TAF15 positive tumors, were highly cellular and partially associated with pseudopapillary architecture. Our study found that moderate/strong expression of INSM1 in more than 25% of tumor cells was present in only 31% of cases. Thus, the diagnostic utility of INSM1 is rather low. Two morphologically unique cases of non-EWSR1 rearranged EMC with an extremely rare pseudopapillary growth pattern are also reported.

Extraskeletal Myxoid Chondrosarcomas: The Uncommon Clinicopathologic Manifestations and Significance of TAF15::NR4A3 Fusion

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare sarcoma typically exhibiting myxoid/reticular histology and NR4A3 translocation. However, morphologic variants and the relevance of non–EWSR1::NR4A3 fusions remain underexplored. Three challenging pan-Trk–expressing cases, featuring cellular to solid histology, were subjected to RNA exome sequencing (RES), unveiling different NR4A3-associated fusions. Alongside RES-analyzed cases, fluorescence in situ hybridization was performed to confirm 58 EMCs, with 48 available for pan-Trk immunostaining and KIT sequencing. Except for 1 (2%) NR4A3-rearranged EMC without identifiable partners, 46 (79%), 9 (16%), and 2 (3%) cases harbored EWSR1::NR4A3, TAF15::NR4A3, and TCF12::NR4A3 fusions, respectively. Five EWSR1::NR4A3–positive EMCs occurred in the subcutis (3) and bone (2). Besides 43 classical cases, there were 8 cellular, 4 rhabdoid/anaplastic, 2 solid, and 1 mixed tumor-like variants. Tumor cells were oval/spindle to pleomorphic and formed loose myxoid/reticular to compact sheet-like or fascicular patterns, imparting broad diagnostic considerations. RES showed upregulation of NTRK2/3, KIT, and INSM1. Moderate-to-strong immunoreactivities of pan-Trk, CD117, and INSM1 were present in 35.4%, 52.6%, and 54.6% of EMCs, respectively. KIT p. E554K mutation was detected in 2/48 cases. TAF15::NR4A3 was significantly associated with size >10 cm (78%, P = .025). Size >10 cm, moderate-to-severe nuclear pleomorphism, metastasis at presentation, TAF15::NR4A3 fusion, and the administration of chemotherapy portended shorter univariate disease-specific survival, whereas only size >10 cm (P = .004) and metastasis at presentation (P = .032) remained prognostically independent. Conclusively, EMC may manifest superficial or osseous lesions harboring EWSR1::NR4A3, underrecognized solid or anaplastic histology, and pan-Trk expression, posing tremendous challenges. Most TAF15::NR4A3–positive cases were >10 cm in size, ie, a crucial independent prognosticator, whereas pathogenic KIT mutation rarely occurred.

Keratin-positive fibrotic extraskeletal myxoid chondrosarcoma: a close mimic of myoepithelial tumour.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare form of adult sarcoma with distinct histology and NR4A3 gene fusion. Immunohistochemically, EMCs are variably positive for S100 protein and neuroendocrine markers. Unlike histologically similar soft-tissue myoepithelial tumours, keratin expression is rare. Prompted by two recent EMC cases with diffuse keratin expression, we investigated the expression of epithelial markers in a molecularly confirmed cohort of EMC and identified two additional similar cases. Four keratin-positive EMCs occurred in one man and three women aged 46-59 years. All tumours displayed nonclassic histology with prominent stromal fibrosis, and keratin AE1/AE3 was expressed either diffusely (N=2) or focally (N=2). In one tumour, keratin expression was limited to the sclerotic area. All tumours coexpressed epithelial membrane antigen and two additionally expressed S100 protein or glial fibrillary acidic protein. All tumours harboured NR4A3 fusions, including TAF15::NR4A3 (N=1) and EWSR1::NR4A3 (N=3). Two cases were initially considered as most consistent with myoepithelial tumours based on widespread stromal fibrosis and keratin expression. DNA methylation analysis classified two tumours tested as EMCs. We identified a small subset of EMCs characterised by keratin expression and prominent stromal fibrosis. This histological pattern must be recognised in the differential diagnosis of myoepithelial tumours because misclassification may lead to the erroneous prediction of tumour behaviour and may alter patient management. NR4A3 genetic analysis should be considered even in the face of keratin expression and prominent stromal fibrosis.

Extraskeletal Myxoid Chondrosarcoma: Retrospective Case Series Examining Prognostic Factors, Treatment Approaches, and Oncologic Outcomes.

Extraskeletal myxoid chondrosarcoma (EMC) is an ultrarare soft tissue sarcoma, and a limited number of studies are published regarding its clinical course and efficacy of treatment. The goal of this retrospective case series is to explore patient characteristics, treatment approaches, and oncologic outcomes to help inform future EMC management. All patients with a diagnosis of EMC seen at the University of Michigan Sarcoma Center between 1998 and 2021 were identified. A chart review was performed to analyze demographics, tumor characteristics, treatments, and outcomes. Forty-four patients with EMC were identified. The median follow-up was 49.8 months. The median age at diagnosis was 57 (range: 25 to 79), and 35 patients (80%) were male. Thirty-four patients (77%) had locoregional disease at diagnosis, and 26 patients (59%) ultimately developed metastatic disease. After locoregional curative-intent surgery, 15 patients had documented recurrence, of which 11 were metastatic (73%). Five-year overall survival was 79% for all patients, 86% for locoregional disease, and 58% for metastatic disease; for locoregional disease, 5-year disease-free and metastasis-free survival post-surgery were 43% and 53%, respectively; 1-year progression-free survival for metastatic disease from the start of first-line systemic therapy was 43%. Older age was the only factor statistically associated with improved prognosis, although perioperative radiotherapy, lower histologic grade, and negative margins also had directional associations with outcomes. The data in this patient series are generally consistent with published literature on EMC and demonstrate a high recurrence rate, high propensity for metastasis, and high rate of progression of metastatic disease on systemic therapy.