P35-1 Effective immune-based treatment of extraskeletal myxoid chondrosarcoma guided by next-generation gene profiling

Chordoid meningioma, World Health Organization grade II, is an uncommon variant of meningioma with a propensity for aggressive behavior and increased likelihood of recurrence. As such, recognition of this entity is important in cases that show similar morphologic overlap with other chondroid/myxoid neoplasms that can arise within or near the central nervous system. A formal comparison of the immunohistochemical features of chordoid meningioma versus tumors with significant histologic overlap has not been previously reported. In this study, immunohistochemical staining was performed with antibodies against D2-40, S100, pankeratin, epithelial membrane antigen (EMA), brachyury, and glial fibrillary acidic protein (GFAP) in 4 cases of chordoid glioma, 6 skeletal myxoid chondrosarcomas, 10 chordoid meningiomas, 16 extraskeletal myxoid chondrosarcoma, 18 chordomas, 22 low-grade chondrosarcomas, and 27 enchondromas. Staining extent and intensity were evaluated semiquantitatively and mean values for each parameter were calculated. Immunostaining with D2-40 showed positivity in 100% of skeletal myxoid chondrosarcomas, 96% of enchondromas, 95% of low-grade chondrosarcomas, 80% of chordoid meningiomas, and 75% of chordoid gliomas. Staining with S100 demonstrated diffuse, strong positivity in all (100%) chordoid gliomas, skeletal myxoid chondrosarcomas, low-grade chondrosarcomas, and enchondromas, 94% of chordomas, and 81% of extraskeletal myxoid chondrosarcomas, with focal, moderate staining in 40% of chordoid meningiomas. Pankeratin highlighted 100% of chordoid gliomas and chordomas, 38% of extraskeletal myxoid chondrosarcomas, and 20% of chordoid meningiomas. EMA staining was positive in 100% of chordoid gliomas, 94% of chordomas, 90% of chordoid meningiomas, and 25% of extraskeletal myxoid chondrosarcomas. Brachyury was positive only in the chordomas (100%), whereas GFAP was positive only in the chordoid gliomas (100%). EMA was the most effective antibody for differentiating chordoid meningioma from skeletal myxoid chondrosarcoma, low-grade chondrosarcoma, and enchondroma, whereas D2-40 was the most effective antibody for differentiating chordoid meningioma from extraskeletal myxoid chondrosarcoma and chordoma. Our findings demonstrate that in conjunction with clinical and radiographic findings, immunohistochemical evaluation with a panel of D2-40, EMA, brachyury, and GFAP is most useful in distinguishing chordoid meningioma from chordoid glioma, skeletal myxoid chondrosarcoma, extraskeletal myxoid chondrosarcoma, chordoma, low-grade chondrosarcoma, and enchondroma. A lack of strong, diffuse S100 reactivity may also be useful in excluding chordoid meningioma. Among the neoplasms evaluated, brachyury and GFAP proved to be both sensitive and specific markers for chordoma and chordoid glioma, respectively. Of note, this study is the first to characterize the D2-40 immunoprofile in extraskeletal myxoid chondrosarcoma, results that could be of utility in differential diagnostic assessment.

Background: Extraskeletal myxoid chondrosarcomas (EMCs) are rare mesenchymal neoplasms comprising approx. 3% of all soft tissue tumors. EMCs arise mainly from the deep soft tissues of the extremities, accompanied with high rates of recurrence and metastases. The molecular hallmarks of EMCs are various cytogenetic NR4A3 rearrangements, generating chimeric -NR4A3 proteins. The most common reciprocal translocation t(9;22)(q22;q12), results in a fusion of the EWS RNA-binding protein 1 gene (EWSR1) to the nuclear receptor subfamily 4, group A, member 3 gene (NR4A3 or TEC; approximately 75% of cases). Further cytogenetic t(9;17)(q22;q11) rearrangements involve TAF15 RNA polymerase II, TATA box binding protein (TBP)-associated factor (TAF15; approximately 15% of cases). The less frequent reciprocal translocations t(9;15)(q22;q21) and t(9;3)(q22;q12), result in transcription factor 12 (TCF12)-NR4A3 and TRK-fused gene (TFG)-NR4A3 fusion proteins. Although the oncogenic -NR4A3 fusion transcripts seem to have a crucial role in EMC tumorigenesis and progression, the specific biological function and the mechanism of action remain to be defined. Methods: We characterized the cytogenetic rearrangements of 25 comprehensive EMC tumors by RT-PCR and/or fluorescence in situ hybridization (FISH). Next generation sequencing (NGS) was performed (Illumina MiSeq platform) to reveal additional genetic alterations besides the known chromosomal translocation. Therefore, a comprehensive cancer panel was designed, comprising 27 cancer-related genes known to be frequently mutated across various malignancies. Results: Overall, fusion transcripts were detected in 22 of 25 samples (88%). Sixteen were positive for the EWSR1-NR4A3 and six for the TAF15-NR4A3 fusion gene. The t(9;15) and t(9;3) translocations, resulting in TCF12-NR4A3 and TFG-NR4A3 fusion proteins were not identified in any EMC case. In Addition, several known oncogenic mutations were detected which have not been previously reported in EMC. Conclusions: The combination of RT-PCR and FISH on paraffin-embedded tissue is a sensitive and specific method for the molecular detection of the pathogenic translocations to be applied in the differential diagnosis of extraskeletal myxoid chondrosarcomas. Our results emphasize that cytogenetic NR4A3 rearrangements are the initiating events in the pathogenesis of EMC. Furthermore, our results indicate the occurrence of additional genetic aberrations providing a rational base for novel targeted therapeutic approaches. Citation Format: Marcel Trautmann, Magdalene Cyra, Ilka Isfort, Inga Grünewald, Konrad Steinestel, Sebastian Huss, Reinhard Büttner, Eva Wardelmann, Wolfgang Hartmann. Extraskeletal myxoid chondrosarcoma: a clinicopathologic and molecular study reveals novel genetic aberrations by targeted next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2703. doi:10.1158/1538-7445.AM2017-2703

Objective To study the CT and MRI characteristics of myxoid soft tissue tumours. Methods Fifty-three myxoid soft tissue tumours pathologically confirmed were retrospectively studied. MR and CT scan were performed before operation. Noncontrast T1 and T2 weighted images, fat-suppressed T2 weighted images were obtained before contrast-enhanced scan with fat-suppressed T1 weighted sequence was underwent. Plain and contrast-enhanced CT was performed with tube potential of 120 kV, matrix 512×512, and automatic tube current modulation technique. Results There were 18 myxoid liposarcoma, 3 ganglioneuroma, 8 myxofibrosarcoma, 2 extraskeletal myxoid chondrosarcoma, 10 intramuscular myxoma, and 2 juxta-articular myxoma. Microscopic examination showed myxoid soft tissue tumours which were consisted of abundant myxoid stroma with tumour cells and blood vessels associated with fibrous bands. Low density in CT images, hypointensity in T1 weighted images, significantly hyperintense in T2 weighted images were their common manifestations in the area of abundance of extracellular myxiod matrix. Plain CT images demonstrated equidensite, T1 weighted images isointensity, and fat-suppressed T1 weighted images significant enhancement relatively in the areas of increased number of tumor cells. Hemorrhage, necrosis and capsule of the lesion were revealed in high grade malignant tumors. The septa can be identified in most of myxoid tumours of soft tissue. Conclusion CT and MRI can definitely show the image characteristics of myxiod soft tissue tumours, which can help make a qualitative diagnosis before operation. Key words: Soft tissue neoplasms; Tomography, X-ray computed; Magnetic resonance imaging

To summarize the diagnostic features of fine needle aspiration cytology (FNAC) of myxoid lesions in soft tissue, and to define the cytological criteria for differentiating benign lesions from sarcomas and between various myxoid lesions. FNAC data of 24 soft tissue myxoid lesions (14 benign lesions, 10 malignant lesions) from 1993 to 2006 from Kiang Wu Hospital, Macau were reviewed in correlation with the clinical course or the results of biopsy. Ganglion, myxoma, and myxoid nodular fasciitis were the most common benign myxoid lesions of the soft tissues, all of which had low cellularity and lack of marked cellular atypia in smears in common. Ganglion was characterized by the disappearance of or the gradual minimization of the nodule after aspiration and the lack of blood vessel in smears. Myxoid nodular fasciitis was characterized by a pleomorphic pattern of proliferative cells and the presence of ganglion cell-like cells. Myxoid liposarcoma, extraskeletal myxoid chondrosarcoma and myxofibrosarcoma were the most common myxoid sarcomas. Cytologically, they had high cellularity and various degrees of cellular atypia. Myxoid liposarcoma exhibited branching chicken-wire like capillary vessels and/or lipoblasts; myxofibrosarcoma were prominent in both pleomorphic and atypia of the cells. The data revealed that the diagnostic accuracy of FNAC was nearly 100% in differentiating benign and malignant myxoid lesions of the soft tissues. The coordinate rate to the histopathology diagnosis of the common myxoid lesions of the soft tissues was above 75% (benign 71.4% and malignancy 80% respectively). FNAC is an effective method in diagnosing myxoid lesions of soft tissue, in correlation with the clinical data and the accessory examinations. FNAC can provide an objective basis for the treatment of myxoid lesions and prevention of unnecessary surgical operations.

BackgroundTrabectedin is reported to be particularly effective against translocation-related sarcoma. Recently, a randomized phase 2 study in patients with translocation-related sarcomas unresponsive or intolerable to standard chemotherapy was conducted, which showed clinical benefit of trabectedin compared with best supportive care (BSC). Extraskeletal myxoid chondrosarcoma (EMCS) and Mesenchymal chondrosarcoma (MCS) are very rare malignant soft tissue sarcomas, and are associated with translocations resulting in fusion genes. In addition, the previous in vivo data showed that trabectedin affect tumor necrosis and reduction in vascularization in a xenograft model of a human high-grade chondrosarcoma. The aim of the present analysis was to clarify the efficacy of trabectedin for EMCS and MCS subjects in the randomized phase 2 study.MethodsFive subjects with EMCS and MCS received trabectedin treatment in the randomized phase 2 study. Three MCS subjects were allocated to the BSC group. Objective response and progression-free survival (PFS) were assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by central radiology imaging review.ResultsThe median follow-up time of the randomized phase 2 study was 22.7 months, and one subject with MCS was still receiving trabectedin treatment at the final data cutoff. The median PFS was 12.5 months (95 % CI: 7.4–not reached) in the trabectedin group, while 1.0 months (95 % CI: 0.3–1.0 months) in MCS subjects of the BSC group. The six-month progression-free rate was 100 % in the trabectedin group. One subject with MCS showed partial response, and the others in the trabectedin group showed stable disease. Overall survival of EMCS and MCS subjects was 26.4 months (range, 10.4–26.4 months) in the trabectedin group. At the final data cutoff, two of five subjects were still alive.ConclusionsThis sub-analysis shows that trabectedin is effective for patients with EMCS and MCS compared with BSC. The efficacy results were better than previously reported data of TRS. These facts suggest that trabectedin become an important choice of treatment for patients with advanced EMCS or MCS who failed or were intolerable to standard chemotherapy.Trial registrationThe randomized phase 2 study is registered with the Japan Pharmaceutical Information Center, number JapicCTI-121850 (May 31, 2012).

Extraskeletal myxoid chondrosarcoma (EMC) is a rare tumour and usually occurs in the soft tissue of the extremities. Problems can occur when the site is unusual and the cellular differentiation is not distinct. Chest wall is an unusual site for EMC. When aspiration cytology of breast mass yields polygonal cells with no significant pleomorphism in a prominent myxoid/mucoid background, one should take into consideration the possibility of EMC of the anterior chest wall before diagnosing it as breast carcinoma, as both the entities have different treatment modalities. We present a case in which EMC of the anterior chest wall presented as a breast mass in a 55-year-old female patient; it was misdiagnosed as mucinous/myxoid carcinoma of the breast on fine-needle aspiration cytology, and subsequently, correct diagnosis was made on histopathological examination. This case has been highlighted for the unusual site of occurrence of EMC and its close similarity to breast carcinoma, both clinically and cytologically.

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

Extraskeletal myxoid chondrosarcoma (EMC) is a very rare sarcoma most often arising in the soft tissue. Rare EMC of the bone have been reported. EMC exhibits distinctive clinico-pathological and genetic features; however, despite the name, it lacks any feature of cartilaginous differentiation. EMC is characterized by the rearrangement of the NR4A3, which, in most cases (about 62-75%), is fused with EWSR1 and less frequently with other partners, including TAF15 (27%), TCF12 (4%), TFG, and FUS. We herein report the identification by whole-transcriptome sequencing of HSPA8 as a novel fusion partner of NR4A3 in a case of EMC. FISH analysis confirmed the presence of a genomic HSPA8-NR4A3 translocation in the vast majority of tumor cells. Our findings expand the spectrum of NR4A3 fusion partners involved in EMC pathobiology.

STRAIGHT TO THE LUNGS: UNUSUAL ETIOLOGY OF BILATERAL PULMONARY OPACITIES

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma with limited literature available on its cytological features. We report here one such case where a diagnosis of EMC was made based on fine needle aspiration cytology (FNAC). A 51 year-old male presented to our FNAC clinic with a slowly growing mass in the left thigh, which was subjected to fine needle aspiration biopsy. Radiological images showed no involvement of the underlying bone. Magnetic resonance imaging was suggestive of a malignant neoplasm. The FNA smears showed cell fragments and cords of monotonous cells embedded in abundant myxoid stroma. A diagnosis of a myxoid sarcoma favoring an EMC was made in this patient. Subsequent excision of the mass for histopathological examination confirmed this diagnosis. EMC has distinctive cytological features that are helpful in confidently making a diagnosis in the appropriate clinical setting.

A 28-year-old female with history of chest wall extraskeletal myxoid chondrosarcoma (EMC) presented to the emergency department complaining of two weeks of lightheadedness and fatigue. Laboratories showed hemoglobin of 7.6 g/dL and a positive hemoccult test. Upper and lower endoscopies were unremarkable, and the patient was discharged after blood transfusion. The next day she returned to the ED with left-sided weakness and perioral numbness. Brain CT scan revealed a 6 cm right frontal mass with midline shift and edema that required urgent craniotomy with resection of a hemorrhagic tumor. The patient continued dropping her hemoglobin, and CT scans showed a rounded 3 cm small bowel mass in the mid ileum. Repeat upper endoscopy revealed a 2 × 2 cm ulcerated mass in the fourth portion of the duodenum. The patient was taken to the operating room and was found to have two lesions; one in the distal duodenum and a second one in the mid ileum causing small bowel intussusception. Pathology was consistent with metastatic EMC grade 2/3, involving the bowel and mesenteric fat. Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft-tissue sarcoma with unique features that distinguishes, it from other sarcomas. It has been often described as a low-grade sarcoma although there are certain characteristics like high mitotic activity and the presence of focal regions of Ki67 staining above 25% that correlate with aggressive behavior of the tumor. This is the first case of EMC metastatic to the small bowel to be reported to the medical community.

Extraskeletal myxoid chondrosarcoma presenting in the head and neck is extremely rare. Histologic diagnosis is difficult and close co-operation among clinician, radiologist and pathologist is recommended. The tumour has a better prognosis than myxoid chondrosarcoma of the bone but surgical resection may be difficult due to its gelatinous nature. We present a case of extraskeletal myxoid chondrosarcoma originating in the left nasal cavity of a 35-year-old woman.

Patient: Female, 58Final Diagnosis: Extraskeletal myxoid chondrosarcoma with widespread metastasesSymptoms: —Medication: —Clinical Procedure: Left below knee amputationSpecialty: OncologyObjective:Rare diseaseBackground:Extraskeletal myxoid chondrosarcoma is a unique and distinct clinicopathological entity in terms of its origin, morphology, and biologic behavior. Despite being a slow-growing tumor, it has a high rate of local recurrences and history of metastases to uncommon sites like the mandible, liver, retroperitoneum, right ventricle, pancreas, and central nervous system. Here, we report a very unique case of extraskeletal myxoid chondrosarcoma that metastasized to the breast, which itself is a very rare site for metastases.Case Report:A 58-year-old woman presented with a large, firm, and tender soft-tissue mass (6.0×7.0 cm) underneath the sole of the left foot. A computerized tomography (CT) scan showed a heterogeneous lobulated mass in the plantar aspect of the forefoot, measuring 8.6×8.0×7.1 cm. Punch biopsies revealed histology consistent with extraskeletal myxoid chondrosarcoma. Metastatic work-up was negative. The mass was fully resected with left below-knee amputation. The histology of the resected mass was consistent with extraskeletal myxoid chondrosarcoma. A follow-up CT showed a new right breast nodule along with metastases to lung and bones. The results of the core needle biopsies of the right breast masses seen on mammogram were morphologically identical to extraskeletal myxoid chondrosarcoma.Conclusions:Although rare, metastases to the breast should be considered in the differential diagnosis of a breast mass. A close long-term follow-up is needed due to the unpredictable behavior of extraskeletal myxoid chondrosarcoma and the high frequency of local recurrences, metastases, and death due to disease.

Diagnostic Utility of Molecular Investigation in Extraskeletal Myxoid Chondrosarcoma

Introduction: Extra skeletal myxoid chondrosarcoma is a rare soft tissue tumor. It is a low-grade sarcoma, arising mainly in the deep tissues and musculature of the extremities, with a histological resemblance to its bony counterpart. It accounts for less than 3% of soft tissue sarcomas, and localizes mainly in the upper extremity, shoulder, neck, orbit but also intra-abdominally. It is a tumor with a high metastatic potential and an unfavorable long-term prognosis. Extra skeletal myxoid chondrosarcoma is a tumor occurring in middle-aged patients regardless of gender or race. Treatment is multimodal including surgery, radiation therapy and chemotherapy. Case presentation: A 37-year-old female patient consulted for a subcutaneous swelling on the sole of the left foot opposite the 5th toe; evolving for approximately six years. The clinical examination and the paraclinical work-up revealed a mass that encompassed the diaphysis of the 5th metatarsal with cortical lysis opposite. This mass arrived medially at the contact of the 4th metatarsal without cortical lysis. The extension work-up was unremarkable. The histological, immunohistochemical and molecular biology examination of the surgical biopsy concluded to an extra skeletal myxoid chondrosarcoma. Polychemotherapy with andriamycin and Ifosfamide, surgery and radiotherapy at a dose of 50Gy was performed. Conclusion: Rare tumor and of difficult diagnosis, the key of the diagnosis lies in molecular biology. Survival is often prolonged despite its local aggressiveness.