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Despite a wide spectrum of clinical presentations, including primary or secondary, most angiosarcomas are considered high grade. One exception is primary breast angiosarcoma, where historically, histologic grading has shown to predict outcome using the Rosen 3-tier system. However, more recent studies have challenged this concept suggesting that even in this specific clinical context angiosarcomas should be considered high grade. This study aimed to critically reevaluate the impact of histologic grade in a clinically uniform cohort managed at a single institution using a newly proposed grading system. Our study included 49 primary breast angiosarcomas diagnosed during 1994 to 2022 (median follow-up: 33 mo), classified as low grade (29%), intermediate grade (20%), and high grade (51%), based on mitotic count, extent of solid components, and necrosis. At last follow-up, 22% patients developed locoregional recurrences, 63% distant metastases, and 47% patients died of disease. As patients with low and intermediate-grade angiosarcomas had relatively similar outcomes, our cohort was further analyzed using a 2-tier system (low grade and high grade). Targeted-DNA next-generation sequencing (505 cancer gene panel) performed in 11 cases found KDR mutations in 78% and PIK3CA mutations in 44% of high-grade lesions. Histologic grade, by either 3-tier or 2-tier grading systems, had a strong impact on survival, with the 2-tier system being an independent predictor of disease-specific survival and overall survival. Based on 2-tier system, the 5-year overall survival was 38% for high-grade angiosarcoma and 74% for low-grade angiosarcoma. PIK3CA mutations alone or concurrent with KDR alterations were identified in angiosarcomas with worse prognosis.

Objective To characterize the results of surgery for gastrointestinal stromal tumor (GIST) in the pre and post-imatinib eras at a single institution and to identify current prognostic clinicopathologic factors. Background Imatinib has radically changed the management of GIST, yet the magnitude of impact on outcome across the spectrum of GIST presentation and relevance of historical prognostic factors are not well defined. Methods We retrospectively analyzed 1000 patients who underwent surgery for GIST at our institution from 1982 to 2016. Patients were stratified by presentation status as primary tumor only (PRIM), primary with synchronous metastasis (PRIM + MET), or metachronous recurrence/metastases (MET), and also imatinib era (before and after it became available). Cox proportional-hazard models and Kaplan-Meier methods were used to model and estimate overall survival (OS) and recurrence-free survival (RFS). Results OS was longer in the imatinib era compared with the pre-imatinib era in each presentation group, including in Miettinen high-risk primary tumors. Among PRIM patients from the pre-imatinib era, tumor site, size, and mitotic rate were independently associated with OS and RFS on multivariate analysis. PRIM patients in the imatinib era who received imatinib (neoadjuvant and/or adjuvant) had higher risk tumors, but after adjusting for treatment, only size >10 cm remained independently prognostic of RFS [hazard ratio (HR) 3.85, 95% confidence interval (CI) 2.00-7.40, P Conclusions Patients treated in the imatinib era had prolonged OS across all presentations. In the imatinib era, among site, size, and mitotic rate, high-risk features were associated with treatment with the drug, but only size >10 cm correlated with outcome. Imatinib should still be prescribed for patients with high-risk features.

To refine treatment recommendations for patients with metastatic gastrointestinal stromal tumors (GISTs) treated with tyrosine kinase inhibitors (TKIs) and surgery.Early reports suggested that patients with metastatic GIST responding to TKIs treated with surgery may have favorable outcomes. However, identification of prognostic factors was limited by small cohorts.Progression-free survival (PFS) and overall survival (OS) from time of surgery and from start of initial TKI was determined. Multivariate analysis was conducted on all patients undergoing GIST metastasectomy between 2001 and 2014 at 2 institutions.We performed 400 operations on 323 patients with metastatic GIST on TKIs. Radiographic response at time of surgery was classified as responsive disease (RD, n = 64, 16%), stable disease (SD, n = 100, 25%), unifocal progressive disease (UPD, n = 132, 33%), and multifocal progressive disease (MPD, n = 104, 26%). For patients on imatinib before surgery, radiographic response was predictive of PFS from time of surgery (RD 36 months, SD 30 months, UPD 11 months, MPD 6 months; P0.001) and from imatinib initiation (RD 71 months, SD 51 months, UPD 47 months, MPD 33 months; P0.001). Radiographic response was predictive of OS from time of surgery (RD not reached, SD 110 months, UPD 59 months, MPD 24 months; P0.001), and from imatinib initiation (RD not reached, SD 144 months, UPD 105 months, MPD 66 months; P = 0.005). Radiographic response was not predictive of PFS/OS for patients on sunitinib. Metastatic mitotic index ≥5/50 HPF, MPD, and R2 resection were prognostic of worse PFS/OS; primary mutation was not.Surgery in metastatic GIST patients in the absence of MPD on imatinib is associated with outcomes at least comparable with second-line sunitinib and may be considered in select patients.

CIC-DUX4 gene fusion, resulting from either a t(4;19) or t(10;19) translocation, is the most common genetic abnormality detected in EWSR1-negative small blue round cell tumors. Following their discovery it was debated if these tumors should be classified as variants of Ewing sarcoma (ie, atypical Ewing sarcoma) or as a stand-alone pathologic entity. As such the WHO classification temporarily grouped the CIC-rearranged tumors under undifferentiated sarcomas with round cell phenotype, until further clinical evidence was available. However, most studies reported so far include small series with limited follow-up information, which preclude a more definitive assessment. The present work investigates the clinicopathologic features of a large cohort of sarcomas with CIC gene rearrangement, to define their clinical presentation, morphologic spectrum, and outcome. Our study further examines the overall survival of the CIC-positive cohort compared with a control group of EWSR1-rearranged Ewing sarcoma matched for age and stage. The study cohort included 115 patients, with a mean age of 32 years and a slight male predominance. Most tumors occurred in the soft tissue (86%), predominantly deep-seated and equally divided among trunk and extremity, followed by visceral locations (12%) and rarely in the bone (3%). Microscopically, most tumors showed round to ovoid cytomorphology but half of the cases showed also focal areas of spindling and epithelioid/rhabdoid phenotype, with frequent myxoid stromal changes. Variable CD99 reactivity was seen in 84% cases, with a diffuse pattern only in 23% of cases, whereas nuclear WT1 was seen in 92%. A CIC-DUX4 fusion was detected in 57% of cases, with either DUX4 on 4q35 (35%) or on 10q26 in 25 (22%) cases. No FOXO4 gene rearrangements were present in 39 cases tested. Clinical follow-up was available in 57 patients, with a 5-year survival of 43%, which was significantly lower than the 77% 5-year survival in the control Ewing sarcoma group (P=0.002). Our findings show that CIC-DUX4 sarcomas occur most commonly in young adults within the somatic soft tissues, having a wide spectrum of morphology including round, epithelioid and spindle cells, and associated with an aggressive clinical course, with an inferior overall survival compared with Ewing sarcoma. The results support the classification of CIC-rearranged tumors as an independent molecular and clinical subset of small blue round cell tumors distinct from Ewing sarcoma.

INTRODUCTION AND OBJECTIVE:Testicular germ cell tumors (GCT) will rarely contain teratoma with secondary somatic malignancy (SSM). Little is known about the clinical implications of this finding in...