Undifferentiated small round cell sarcoma with t(4;19)(q35;q13.1) CIC-DUX4 fusion: a novel highly aggressive soft tissue tumor with distinctive histopathology.

A subset of small round cell sarcomas remains difficult to classify. Among these, a rare tumor harboring a t(4;19)(q35;q13.1) with CIC-DUX4 fusion has been described. The aim of this study is to better understand its clinicopathologic features. Four cases of CIC-DUX4 sarcoma, all arising in adults (3 women, 1 man, aged 20 to 43 y), were identified using conventional cytogenetic, reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) methods. All 4 tumors demonstrated CIC-DUX4 fusion transcript by both RT-PCR and FISH and CIC rearrangement by FISH. Cytogenetic results from 2 tumors showed t(4;19)(q35;q13.1) occurring as part of a simple karyotype in 1 tumor and as part of a complex karyotype in the other, the latter from a postchemotherapy specimen. Both tumors harbored trisomy 8 and lacked any other known sarcoma-associated translocation. No EWS or SYT rearrangements were detected by RT-PCR or FISH. The tumors had small round cell morphology with a distinctive constellation of histologic features including extensive geographic necrosis, mild nuclear pleomorphism with coarse chromatin and prominent nucleoli, clear cell areas, and focal myxoid matrix. Only focal staining for CD99 was present in each tumor. Two had very focal cytokeratin staining. All tumors were negative for desmin, myogenin, TLE-1, and S100 protein, whereas nuclear INI-1 staining was retained. The tumors were highly aggressive, and all patients died of disseminated disease within 16.8 months. CIC-DUX4 sarcoma represents a novel translocation-associated sarcoma with distinctive histopathologic features and rapid disease progression.

Risk factors for local recurrence and metastasis in soft tissue sarcomas of the extremity.

OBJECTIVES: We reviewed our institution's experience in treating soft tissue sarcomas of the extremity to identify factors associated with local recurrence, metastasis, and overall survival, to identify patients who may benefit from intensification of therapy. METHODS: A retrospective analysis was performed for patients who underwent both limb-sparing surgery and external beam radiotherapy for extremity sarcoma. Those who had gross residual disease or who presented with recurrent or metastatic disease were excluded. The Kaplan-Meier product limit and multivariate Cox regression were used to estimate local failure-free probability, distant failure-free probability, and overall survival along with associations with patient, tumor, and treatment characteristics. RESULTS: One hundred eighty-eight patients were included in the analysis. Twenty-five (13%) and 46 (24%) experienced local and distant recurrence, respectively. Patients with high/intermediate-grade tumors [hazard ratio (HR)=5.63, 95% confidence interval (CI): 1.27-24.89, P=0.023] or with multifocally positive margins (HR=4.27, 95% CI: 1.20-15.24, P=0.026) were more likely to fail locally. Those with a preceding local recurrence (HR=8.58, 95% CI: 3.87-19.04, P<0.0001), high/intermediate-grade tumors (HR=5.68, 95% CI: 1.28-25.25, P=0.023), or no secondary reexcision (HR=2.5, 95% CI: 1.09-5.74, P=0.031) were more likely to develop metastasis. Patients with local recurrence (HR=3.6, 95% CI: 1.77-7.29, P<0.001), metastasis (HR=16.0, 95% CI: 7.93-32.31, P<0.0001), or without secondary reexcision (HR=3.2, 95% CI: 1.27-8.09, P=0.014) had decreased overall survival. CONCLUSIONS: Patients whose tumor grade or margin status put them at high risk for local failure should be considered for intensification of therapy. Those with a local recurrence should be considered for increased surveillance or systemic therapy, as local failure is associated with subsequent metastasis and decreased survival.

Dose--effect relationships for femoral fractures after multimodality limb-sparing therapy of soft-tissue sarcomas of the proximal lower extremity.

PURPOSE: We investigated the clinical and dosimetric predictors for radiation-associated femoral fractures in patients with proximal lower extremity soft tissue sarcomas (STS). METHODS AND MATERIALS: We examined 131 patients with proximal lower extremity STS who received limb-sparing surgery and external-beam radiation therapy between 1985 and 2006. Five (4%) patients sustained pathologic femoral fractures. Dosimetric analysis was limited to 4 fracture patients with full three-dimensional dose information, who were compared with 59 nonfracture patients. The mean doses and volumes of bone (V(d)) receiving specified doses (≥30 Gy, 45 Gy, 60 Gy) at the femoral body, femoral neck, intertrochanteric region, and subtrochanteric region were compared. Clinical predictive factors were also evaluated. RESULTS: Of 4 fracture patients in our dosimetric series, there were three femoral neck fractures with a mean dose of 57.6 ± 8.9 Gy, V30 of 14.5 ± 2.3 cc, V45 of 11.8 ± 1.1 cc, and V60 of 7.2 ± 2.2 cc at the femoral neck compared with 22.9 ± 20.8 Gy, 4.8 ± 5.6 cc, 2.5 ± 3.9 cc, and 0.8 ± 2.7 cc, respectively, for nonfracture patients (p < 0.03 for all). The femoral neck fracture rate was higher than at the subtrochanteric region despite lower mean doses at these subregions. All fracture sites received mean doses greater than 40 Gy. Also, with our policy of prophylactic femoral intramedullary nailing for high-risk patients, there was no significant difference in fracture rates between patients with and without periosteal excision. There were no significant differences in age, sex, tumor size, timing of radiation therapy, and use of chemotherapy between fracture and nonfracture patients. CONCLUSIONS: These dose-volume toxicity relationships provide RT optimization goals to guide future efforts for reducing pathologic fracture rates. Prophylactic femoral intramedullary nailing may also reduce fracture risk for susceptible patients.