High-grade Undifferentiated Sarcoma Research Articles

Abstract 3009: ATRX loss blocks the differentiation of mesenchymal stem cells and promotes undifferentiated sarcoma development

Abstract Soft tissue sarcomas (STSs) are a collection of rare tumor types originated from the mesenchymal tissues. Among the over 70 histological subtypes of STS, undifferentiated sarcoma (US), which lacks any discernible morphological features of differentiated tissues, accounts for over 20% of all STSs and is correlated with high tumor grade and poor prognosis. Recent genomic profiling in US has identified p53 and ATRX among the most frequently mutated or deleted genes. ATRX is a SWI/SNF2 type of chromatin remodeling factor which functions in a histone variant H3.3-specific chaperone complex to orchestrates replication-independent nucleosome assembly at repetitive heterochromatic DNA regions including telomeres. Loss-of-function mutations occur frequently in many tumor types and is associated with the development of alternative lengthening of telomere (ALT). However, how loss of ATRX function may contribute to tumorigenesis is largely unknown. Here, we demonstrated that ATRX is required for the terminal differentiation of mouse mesenchymal stem cells (MSCs) into multiple lineages, such as adipocytes and osteocytes. Targeted deletion of Atrx in mouse MSCs, but not terminally differentiated mesenchymal lineage cells, accelerated sarcoma initiation induced by loss of p53 and significantly shortened the overall survival. Atrx-deficient tumors express high level of MSC markers such as CD44 and CD29 and exhibit pathological features highly reminiscent of human high-grade US. Transcriptomic analysis indicates that Atrx deficiency is associated with enhanced proliferation. Together, our data indicates that ATRX deficiency contributes to undifferentiated sarcoma development by inhibiting mesenchymal stem cell differentiation. Citation Format: Yiming Cai, Jun Yao, Dean N. Pan, Yanqiang Jin, James M. You, Wantong Yao, Haoqiang Ying. ATRX loss blocks the differentiation of mesenchymal stem cells and promotes undifferentiated sarcoma development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3009.

Outcomes after resection of primary cardiac sarcoma

ObjectiveTo evaluate the outcomes of surgical resection of malignant primary cardiovascular tumors. MethodsFrom 1983 to 2018, 32 patients underwent surgical resection of malignant primary cardiovascular sarcoma at Cleveland Clinic. Mean age was 48 ± 15 years, and 19 (59%) were women. Outcomes are compared between those with complete resection and those without, and in relation to primary location. ResultsThe most common histologic subtypes were angiosarcoma (n = 8 [25%]) and high-grade undifferentiated sarcoma (n = 7 [22%]). Fourteen (44%) involved the left heart, 9 (28%) the right heart, 8 (25%) the pulmonary arteries, and 1 (3%) the aorta. There was clinical evidence of isolated extracardiac metastases in 8 (25%). Six (19%) patients were deemed unresectable at surgery, undergoing biopsy and palliative debulking followed by referral for definitive chemotherapy and/or radiation. The remaining 26 (81%) patients underwent 31 tumor resections with curative intent. Seven (22%) patients had previously undergone a resection or biopsy at another institution. There were 10 second-time resections, 2 third-time resections, 1 fourth-time resection, and no operative mortalities. Median survival was 3 years, with estimated survival at 6 months and 1, 5, and 10 years of 90%, 73%, 31%, and 17%, respectively. Of the 8 (25%) who were considered disease-free following surgery, 4 experienced recurrences during follow-up. ConclusionsPrimary cardiac sarcoma continues to be a challenging disease with poor prognosis. Aggressive resection with curative intent, frequent surveillance for local and distant recurrence, and systemic and local multimodality treatment optimizes outcomes.

Incidence of NUT carcinoma in Western Australia from 1989 to 2014: a review of pediatric and adolescent cases from Perth Children\u2019s Hospital

BackgroundNUT carcinoma (NC), previously known as NUT midline carcinoma, is a rare and very aggressive cancer that occurs in both children and adults. NC is largely chemoresistant, with an overall survival of less than 7 months. Because the carcinoma is not restricted to a particular organ, diagnosis is often a challenge. In the absence of a clearly determined incidence for NC, we sought to study the diagnosis of patients in a well-defined population.MethodsWe systematically reviewed records of all patients that presented to the Oncology Department of the Princess Margaret Hospital for Children from 1989 to 2014. This institution in the geographically isolated state of Western Australia has a catchment population of around 2 million. We then identified all high grade undifferentiated sarcomas or carcinomas in the 0–16 year age group.ResultsOver 26 years, we found 14 patients of 16 years or younger with undifferentiated malignant tumors. Of these, five tumors were positive by immunohistochemistry for the NUT/NUTM1 (Nuclear Protein in Testis) protein and/or the translocation t(15;19). Three patients presented with thoracic tumors, one with a para-spinal tumor, and one had an upper airway nasopharyngeal carcinoma. In all five cases, there was an initial response to therapy and then progression. This 26-year survey was conducted in a geographically isolated state with a well-defined population, and we determined an estimated incidence of NC of around 0.41 per million child years (0–16 yrs. of age) at risk. From three patients it was feasible to derive cell lines for further genetic analyses and drug screening.ConclusionsFor the first time, the incidence of NC could be determined in a well-defined geographic area. The calculated rate of NC incidence is consistent with a history of under-recognition for this malignancy. These findings indicate that improved diagnostic detection of NC would enable better management and counselling of patients. Our findings emphasize the heterogeneity of NC, and they highlight the need to develop personalised therapy options, and to consider a diagnosis of NC in undifferentiated malignant tumors.

Clinicopathological findings of pediatric NTRK fusion mesenchymal tumors

BackgroundWhile ETV6- NTRK3 fusion is common in infantile fibrosarcoma, NTRK1/3 fusion in pediatric tumors is scarce and, consequently, not well known. Herein, we evaluated for the presence of NTRK1/3 fusion in pediatric mesenchymal tumors, clinicopathologically and immunophenotypically.MethodsWe reviewed nine NTRK fusion-positive pediatric sarcomas confirmed by fluorescence in situ hybridization and/or next-generation sequencing from Seoul National University Hospital between 2002 and 2020.ResultsOne case of TPR-NTRK1 fusion-positive intracranial, extra-axial, high-grade undifferentiated sarcoma (12-year-old boy), one case of LMNA-NTRK1 fusion-positive low-grade infantile fibrosarcoma of the forehead (3-year-old boy), one case of ETV6-NTRK3 fusion-positive inflammatory myofibroblastic tumor (IMT) (3-months-old girl), and six cases of ETV6-NTRK3 fusion-positive infantile fibrosarcoma (median age: 2.6 months, range: 1.6–5.6 months, M: F = 5:1) were reviewed. The Trk immunopositivity patterns were distinct, depending on what fusion genes were present. We observed nuclear positivity in TPR-NTRK1 fusion-positive sarcoma, nuclear membrane positivity in LMNA-NTRK1 fusion-positive sarcoma, and both cytoplasmic and nuclear positivity in ETV6-NTRK3 fusion-positive IMT and infantile fibrosarcomas. Also, the TPR-NTRK1 fusion-positive sarcoma showed robust positivity for CD34/nestin, and also showed high mitotic rate. The LMNA-NTRK1 fusion-positive sarcoma revealed CD34/S100 protein/nestin/CD10 coexpression, and a low mitotic rate. The IMT with ETV6-NTRK3 fusion expressed SMA. Six infantile fibrosarcomas with ETV6-NTRK3 fusion showed variable coexpression of nestin (6/6)/CD10 (4/5)/ S100 protein (3/6).ConclusionsAll cases of NTRK1 and NTRK3 fusion-positive pediatric tumors robustly expressed the Trk protein. A Trk immunopositive pattern and CD34/S100/nestin/CD10/SMA immunohistochemical expression may suggest the presence of NTRK fusion partner genes. LMNA-NTRK1 fusion sarcoma might be a low-grade subtype of infantile fibrosarcoma. Interestingly, more than half of the infantile fibrosarcoma cases were positive for S100 protein and CD10. The follow-up period of TPR-NTRK1 and LMNA-NTRK1 fusion-positive tumors are not enough to predict prognosis. However, ETV6-NTRK3 fusion-positive infantile fibrosarcomas showed an excellent prognosis with no evidence of disease for an average of 11.7 years, after gross total resection of the tumor.

Primary paediatric chest wall tumours necessitating surgical management.

Limited literature exists on oncological chest wall reconstruction in the paediatric population, with the field still largely undecided on the best surgical reconstructive techniques to employ. The use of biological grafts/meshes is gaining popularity in certain adult surgical procedures but their use in paediatric procedures is rarely reported in the literature. We present the outcomes of our institution's multidisciplinary approach to managing paediatric chest wall tumours as well as our experience with the use of biological grafts for chest wall reconstruction following oncological resections. Data were analysed retrospectively from eight paediatric patients who were treated for primary chest wall tumours between 2010 and 2018. The tumours comprised two lipoblastomas, three Ewing's sarcomas, an undifferentiated sarcoma with osteosarcomatous differentiation, a high grade undifferentiated sarcoma and a myofibroma. Seven of the eight patients underwent chest wall reconstruction with a biological graft. There were no postoperative mortalities and no evidence of recurrence in any of the patients in the series. No further chest wall operations were required and there were no postoperative infection related complications. We support the use of biological grafts for chest wall reconstruction after oncological resections and maintain that a multidisciplinary approach is essential for the management of paediatric chest wall tumours.

Potentially Curative Targeted Therapy for Undifferentiated High-Grade Sarcoma Developing After Malignant Transformation of a BRAF V600E-Mutated Ameloblastic Fibroma.

Potentially Curative Targeted Therapy for Undifferentiated High-Grade Sarcoma Developing After Malignant Transformation of a BRAF V600E-Mutated Ameloblastic Fibroma.

SARCOMA OF THE GREAT VESSELS MASQUERADING AS PULMONARY EMBOLISM

SESSION TITLE: Wednesday Medical Student/Resident Case Report Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: 10/23/2019 09:45 AM - 10:45 AM INTRODUCTION: Soft tissue sarcomas originating in the heart or great vessels are extremely rare and have a very poor prognosis. We present a case of a sarcoma of the great vessels originally identified as a pulmonary embolism. CASE PRESENTATION: A 74 year old male with a history of chronic obstructive pulmonary disease and sarcoidosis originally presented with hemoptysis, cough, and dyspnea on exertion. A computed tomography angiography of his chest was obtained and showed a 3 cm thrombus present in the right ventricular outflow tract extending into the proximal main pulmonary artery consistent with pulmonary embolism, along with two new centrally located masses in the right lung. Patient was subsequently admitted to the hospital and started on unfractionated heparin. Follow up echocardiogram failed to show right ventricular outflow tract obstruction along with normal bilateral ventricular function. Further imaging with cardiac magnetic resonance imaging showed a 2.5 x 16.6 cm solid mass lesion attached to the anterolateral aspect of the right ventricle prolapsing toward the pulmonic valve. Positron emission tomography–computed tomography did not show increased metabolic activity of this lesion although the right lung lesions were noted to have increased radiotracer uptake. Biopsy of one of the right lung lesions showed high-grade undifferentiated sarcoma of the great vessels with pulmonary metastasis. During his admission, the patient developed ongoing hemoptysis due to anticoagulation which was held on discharge. He was referred to a sarcoma specialist and was started on adriamycin and olaratumab after being deemed a non-surgical candidate. Following a poor response to chemotherapy he was started on local radiation. DISCUSSION: Soft tissue sarcomas originating in the heart or great vessels are very rare and only make up an estimated 1% of all sarcomas. Only a few cases are described in mainly case reports and case series. Given their rarity, they are often misidentified as pulmonary emboli given their location and clinical symptoms.. Mis-identification can lead to delay in treatment which is critical given the poor prognosis. Ideally the first step of treatment is referral to specialized sarcoma centers followed by surgical resection when possible as this is the only definitive therapy. However, in advanced disease, such as our patient, this is not feasible. Therefore, other treatment modalities such as chemotherapy and/or radiotherapy are used. Typically, these therapies are used for palliation or as a neo-adjuvant prior to possible resection. CONCLUSIONS: This case illustrates a very rare cause of primary cardiac tumor, its diagnosis, and management. Furthermore, when these tumors are located in or near the pulmonary artery, they are commonly misidentified as pulmonary embolism. Reference #1: Von Falck C, Meyer B, Fegbeutel C, Langer F, Bengel F, Wacker F, et al. Imaging features of primary sarcomas of the great vessels in CT, MRI and PET/CT: a single-center experience. BMC Med Imaging. 2013;13:25 Reference #2: Nicolas Girard, Jacques Cadranel, Elisabeth Brambilla, and Jean-François Cordier. Rare Primary Lung Tumors. Murray and Nadel's Textbook of Respiratory Medicine, 54, 965-980.e29 Reference #3: Mayer F, Aebert H, Rudert M, Konigsrainer A, Horger M, Kanz L, et al. Primary malignant sarcomas of the heart and great vessels in adult patients–a single-center experience. Oncologist 2007;12:1134–1142. DISCLOSURES: No relevant relationships by Johnathan Fagg, source=Web Response No relevant relationships by Thamer Sartawi, source=Web Response No relevant relationships by Taylor Stone, source=Web Response No relevant relationships by Tareq Zaza, source=Web Response

MRI examination of resected malignant bone tumor can be an option for assessment of the osseous surgical margin.

Confirming the surgical osseous margin of a resected malignant bone tumor macroscopically before reconstruction with a prosthesis is ideal. However, making the cut-surface of the femur specimen during surgery is difficult because of the hard bone tissue. In order to resolve this problem, the possibility of intraoperative MRI was considered. MRI was performed at the surgical unit for five malignant femoral bone tumors that included two osteosarcomas and one undifferentiated high-grade sarcoma, and two metastatic tumors immediately after the tumor resection. The specimens were prepared in plastic containers with saline. The osseous surgical margins were confirmed to be those planned pre-operatively in all cases without metal-induced artifacts. The T1 weighted image (WI) was useful for evaluation of the osseous surgical margin, whereas the T2WI was useful for confirmation of extraosseous soft-tissue. The MRI was performed post-operatively as a preliminary evaluation of the technique. However, a limited sequence (i.e. coronal T1WI) with short examination time could be performed during surgery for the sole purpose of assessing the osseous margin. MRI examination of a resected malignant bone tumor specimen has not been reported, and can be an option for assessment of the osseous surgical margin.

A Rare Case of Undifferentiated High-Grade Sarcoma Masquerading as Thrombus Resulting in Acute Budd-Chiari Syndrome

We present a rare case of Budd-Chiari Syndrome (BCS) from a high-grade undifferentiated sarcoma that invaded and obstructed the inferior vena cava (IVC), hepatic veins and right atrium. There are just 6 cases of venous undifferentiated intimal sarcomas reported in the literature. A 56-year-old Caucasian female with hypertension presented to her primary doctor with 2 weeks of abdominal bloating, abdominal pain, 10-pound weight gain and lower extremity swelling. On exam she had mild ascites, tender hepatomegaly and lower extremity edema. Liver tests were unremarkable, but abdominal ultrasound revealed both mild ascites and both IVC and hepatic vein thrombosis. She was referred to the hospital and a CT revealed extensive thrombus within the entire IVC extending into the right atrium showing a separate 5.0 cm right atrial mass, as well as thrombus extending into the right gonadal vein and the renal veins bilaterally. Imaging showed moderate ascites as well as heterogeneous liver appearance presumably related to passive congestion. A 2-D echocardiogram revealed an ejection fraction of 50-55% with IVC thrombus extending into the right atrium creating a functional tricuspid stenosis from inflow obstruction. The patient was started on a heparin drip to prevent further clot burden and transferred to a tertiary care facility for further intervention. During open heart surgery the right atrial portion of the 5.0cm mass was excised and freed from the tricuspid valve. The portion of the mass coming from the IVC was adherent to the wall of the vessel and right atrium and unresectable. Frozen section immunostains of the tumor cells revealed negative epithelial differentiation (pancytokeratin), endothelial cell markers (CD34, CD117), nerve sheath differentiation (S100), and smooth muscle actin (SMA). Additional stains were negative for actin (HHF), desmin, CD99, EMA and CAM 5.2. The histology showed that there was cell neoplasm with pleomorphism - bizarre, enlarged nuclei, high nuclear-cytoplasmic ratio and abundant mitoses indicative of undifferentiated high-grade sarcoma. The patient was referred to an oncology center for chemotherapy and the patient is doing well. Without surgical intervention this could have been misdiagnosed and treated with long term anticoagulation. This unique BCS case stresses the importance of using different image modalities such as ultrasound and CT imaging to promptly diagnosis and assess the surgical approach.2429_A Figure 1. High-grade undifferentiated sarcoma extension into the inferior vena cava (IVC) and the right atrium showing a separate 5.0 cm right atrial mass, which caused a functional tricuspid stenosis from inflow obstruction.2429_B Figure 2. CT imaging shows a massive high-grade sarcoma tumor continuously present within the dilated inferior vena cava and tumor occupation extending into the right atrium. Thrombus extends into the right gonadal vein and the renal veins bilaterally. Moderate ascites and subcutaneous edema with small bilateral pleural effusions and heterogeneous appearance to the liver presumably related to passive congestion.2429_C Figure 3. Frozen section immunostains of the tumor cells revealed negative epithelial differentiation (pancytokeratin), endothelial cell markers (CD34, CD117), nerve sheath differentiation (S100), and smooth muscle actin (SMA). Additional stains were negative for actin (HHF), desmin, CD99, EMA and CAM 5.2. The histology showed that there was cell neoplasm with pleomorphism - bizarre, enlarged nuclei, high nuclear-cytoplasmic ratio and abundant mitoses indicative of undifferentiated high-grade sarcoma.

Primary meningeal sarcoma in children: a survey from the French Society of Pediatric Oncology (SFCE)

Objectives: To describe the outcome of primary meningeal sarcoma (PMS) in a pediatric population. Methods: We conducted a retrospective study on patients harbouring a PMS based on the French registry of paediatric tumours. Questionnaires were sent to all French paediatric oncologists. Data on patient characteristics and treatments were collected. Pathology and imaging were centrally reviewed. Results: Between August 1989 and May 2010, 12 patients from 6 French centres, aged 3 months to 14.5 years (mean: 3.3 years) were treated for a PMS. Mean follow-up was 12 years (range: 3 months to 24 years). Tumour locations were: frontal (3), parieto-occipital (2), parietal (1), temporal (1), occipital (1), thalamic (1), pontocerebellar angle (1), cerebellar tentorium (1), ambient cistern (1). No metastasis was observed. The first-line treatment was surgery in 10 cases, chemotherapy in 2. Resection was total in 6 cases, partial in 6. Central pathology review concluded to: high-grade undifferentiated sarcoma (8), chondrosarcoma (2), fibrosarcoma (1), myxoid desmoplastic tumour (1). Seven tumours were smaller than 5 cm in size. Eleven patients received 2 to 10 courses of chemotherapy (median: 5) but no response was observed. Four out of 6 patients for whom a total resection was performed were still alive at time of study, compared to 2 when only partial resection was possible. Four out of 6 patients who received radiotherapy are still alive, compared to 1 out of 4 patients without radiotherapy. The 5-year Event-Free Survival (EFS) and Overall Survival (OS) rates were 50%. The median EFS in case of total resection was 39 months versus 16 months in case of partial resection. Neither correlation was found between tumour size and location or between age at diagnosis and EFS/OS. Conclusions: We report the first multicentre case series describing clinical, radiological presentation and outcome of PMS in children. In this short series of very rare tumours, age and tumour size did not seem to be prognostic factors. Total resection and radiotherapy seem to be essential. The role of chemotherapy remains unclear.

Stem cell transcription factor SOX2 in synovial sarcoma and other soft tissue tumors

BackgroundSOX2 has gained considerable interest as a pluripotency inducing gene. Co-transfection of SOX2 together with NANOG, KLF4 and c-MYC into adult fibroblasts was able to generate pluripotent stem cells. SOX2 has been reported to be expressed in synovial sarcoma, a tumor being characterized by the SS18-SSX gene fusion forming part of the SWI/SNF chromatin remodeling complex that affects histone methylation. The role of SOX2 in this tumor type as well as other soft tissue tumor entities however is still poorly characterized. We analyzed SOX2 protein expression in soft tissue tumors. Alongside we tested Histone H3 expression (H3K27me3) in SOX2 positive cases to investigate this epigenetic mark and its correlation with the SOX2 status and clinicopathological parameters. MethodologyIn total, 60 samples of synovial sarcomas from the reference center for soft tissue tumors at the institute of pathology of the Jena University hospital were included into the study along with 343 other tissue tumors. Protein analysis was done by immunohistochemistry of tissue microarrays. All synovial sarcoma cases were confirmed by molecular testing using SS18 FISH break apart probes. ResultsSOX2 reactivity was detectable in 35 synovial sarcoma cases (58.3%) while 25 (41.7%) were negative. Only 13 cases of the other 343 soft tissue tumors, varying from nodular fasciitis to undifferentiated pleomorphic sarcoma, revealed a SOX2 expression, 12 out of these were undifferentiated high grade sarcoma. There was no obvious correlation with the clinicopathological data. H3K27me3 immunohistochemistry of the synovial sarcoma cases revealed a high statistically significant correlation between SOX2 and H3K27me3 expression (p < 0,0005, Chi square test). Similar to SOX2, there was no correlation between H3K27me3 expression and tumor grade. Six SOX2 positive synovial sarcoma cases were analyzed by FISH using a SOX2/CEN3 dual color FISH probe. None of these cases revealed an amplification of the SOX2 gene. ConclusionThe data confirms previous studies reporting SOX2 and H3K27me3 expression in synovial sarcoma and reveals that both biomarkers are related to each other. It strengthens the notion that the tumor type is driven by epigenetic processes similar to those that are operating in pluripotent stem cells. The relevance of these parameters in the pathway pathology of synovial sarcoma, i.e. the timing and dosing of SOX2 and H3K27me3 expression initiated by the SS18-SSX driver mutation together with the interplay of these events with other signaling pathways, cellular mechanisms and additional mutations in tumor progression, will require further studies.

Systemic treatment in adult uterine sarcomas.

Uterine sarcomas (US) are rare mesenchymal tumours of the uterus and are divided mainly into uterine leiomyosarcoma (uLMS), low grade endometrial stromal sarcoma (LG-ESS), high grade endometrial stromal sarcoma (HG-ESS), adenosarcomas and high grade undifferentiated sarcoma (HGUS). US are often high-grade tumours with a high local recurrence rate and metastatic risk. We here discuss the current standard of care and knowledge of systemic therapy for adult uterine sarcomas, in particular uLMS, LG-ESS, HG-ESS and HGUS, in both the adjuvant as well as the metastatic setting.

Does fibroids surgery by endoscopy or laparotomy represent a malignancy threat?

The aim of this study was to 1) estimate the incidence of unsuspected uterine sarcoma in patients after myomectomies and hysterectomies for benign uterine fibroids; 2) to assess the incidence of uterine sarcomas among patient who had uterine fibroids or a suspicion of uterine sarcoma before undergoing the surgical procedures. Retrospective study in single center university hospital. Patient's records with uterine fibroids and uterine sarcoma from 2003 to 2015 collected. Data presented as mean and standard deviation for continuous variable and percentage for categorical variables. The exact Clopper-Pearson interval was used to calculate 95% confidence interval. The total number of women with uterine fibroids was 2269 and uterine sarcomas 7. Of these seven, four were uterine leiomyosarcomas (ULMS), one endometrial sarcoma (ESS), one high-grade undifferentiated uterine sarcoma (HGUS) and one embryonal rhabdomyosarcoma (ERMS). Six of these patients underwent direct open conventional cancer treatment. The mean age of the patients with ULMS was 73.7±3.9 years. Immunohistochemistry results indicated SMA(+), CD 10(+), desmin(+) and h-caldesmon(+). The two patients with HGUS and ERMS were also preoperatively diagnosed with suspected malignancy and operated upon according. However, only one woman 48 years old primarily diagnosed with benign uterine fibroids underwent a laparoscopic subtotal hysterectomy (LSH) procedure; however, the histological results detected an ESS. Immunohistochemistry showed CD10(+), desmin(+), smooth muscle actin (SMA)(-), Aktin(-) and 5% Ki67(+).Two weeks after the initial surgery, an open cervical stump resection with bilateral sapping-oophorectomy and an omentectomy was performed. The frequency of unsuspected ESS was 1/2269 among the women who underwent myomectomies and hysterectomies for the treatment of benign uterine fibroids. The total incidence of uterine sarcoma was 7/2275 among the patients who had presumed uterine fibroids or a suspicion of uterine sarcoma prior to undergoing the surgical procedures.

Frequency of uterine sarcomas in patients admitted for uterine fibroid surgery.

Objective:To estimate the frequency of unsuspected uterine sarcoma identified postoperatively in women undergoing surgery for presumed benign uterine fibroids at a single university hospital.Material and Methods:This was a retrospective single-center study; the records of all 2275 patients with uterine fibroids and uterine sarcomas from 2003 to 2015 were reviewed. Descriptive statistics were used to analyze demographic and clinical characteristics. To calculate confidence intervals (CIs), the Clopper-Pearson Exact method was applied.Results:Preoperatively, 2269 patients had presumed benign uterine fibroids, and six patients had suspected uterine sarcoma. Among the 2269 patients who underwent surgery for presumed uterine fibroids, endometrial stromal sarcoma was histopathologically revealed in only one patient [0.044%, 95% CI: (0.001-0.25)] after laparoscopic subtotal hysterectomy with morcellation. All six patients who were preoperatively diagnosed having uterine sarcoma underwent direct conventional cancer treatment. Histopathologic analyses confirmed four cases of uterine leiomyosarcoma, one high-grade undifferentiated uterine sarcoma, and one embryonal rhabdomyosarcoma. Altogether, seven women were diagnosed as having uterine sarcomas over this twelve-year period.Conclusion:In our institution, the frequency of unsuspected uterine sarcomas was 1/2269 (0.044%) among women who underwent myomectomies and hysterectomies to treat presumed benign uterine fibroids.

Highlights of Morcellation and Sarcoma Incidence in German Patients Admitted for Uterine Fibroid Surgery [12B

INTRODUCTION: To assess the incidence and frequency of unsuspected cases of uterine sarcomas among patients undergoing surgery for benign uterine fibroids in Germany. METHODS: This was a retrospective single-center study at a university hospital. The records of patients with uterine fibroids and uterine sarcoma from 2003 to 2015 were reviewed. RESULTS: A total of 2,275 patients were included. Preoperatively, 2,269 patients had presumed benign uterine fibroids, and 6 patients had suspected uterine sarcoma. Among the 2,269 patients who underwent surgery for presumed uterine fibroids, only one patient (0.044%, 95% CI: 0.001%-0.25%) histopathologically revealed endometrial stromal sarcoma (ESS) after laparoscopic subtotal hysterectomy (LSH) with morcellation(48 years old). Six patients were diagnosed with uterine sarcoma preoperatively and underwent a direct open conventional cancer treatment. Histopathological analyses confirmed four cases of uterine leiomyosarcoma (ULMS) mean age 73.7 ± 3.9, one high-grade undifferentiated uterine sarcoma (HGUS), and one embryonal rhabdomyosarcoma (ERMS). Altogether, seven of the 2,275 women (0.31%, 95% CI: 0.12%-0. 63%) were diagnosed with uterine sarcomas over this twelve-year period. CONCLUSION: The frequency of unsuspected uterine sarcoma was 1/2,269 (0.044%) among the women who underwent myomectomies and hysterectomies to treat presumed benign uterine fibroids. The total incidence of uterine sarcoma was 7/2,275 (0.31%) among the women who had presumed uterine fibroids or a suspected uterine sarcoma before undergoing the surgical procedures. Shall we continue with unprotected morcellation.

Transoral robotic surgery for the pediatric head and neck surgeries

Pediatric robotic surgery is a relatively new technology that has been shown to be safe and feasible for a number of pediatric procedures. Our literature analysis was performed using Pubmed database between January 2005 and December 2015, using key words: "robotic," "robotic surgery," "TORS," "pediatric," "children," "head and neck," and "da Vinci". We selected only publications in English. Eight published reports met the selection criteria. We totally found 41 patients, and the age range was between 2months and 19years. The cases are 16 only lingual tonsillectomy, nine base of tongue and lingual tonsillectomy, two malignant disease in the oropharynx (high-grade undifferentiated sarcoma and biphasic synovial sarcoma), one tongue base thyroglossal duct cyst, 11 laryngeal cleft cyst, one posterior glottic stenosis, and one congenital true vocal cord paralysis surgeries. One intraoperative complication was reported. No patient needed postoperative tracheotomy. Hospital duration time had a range of 1-16days. TORS is new for pediatric patients in head and neck areas, and there were few reports. It is becoming increasingly used in head and neck surgeries and those reports above are encouraging for pediatric robotic airway surgeries in otolaryngology in the future.

Abstract 5197: Patient-derived xenograft (PDX) models of soft tissue sarcoma (STS): a preclinical platform for early drug testing

Abstract Background: STS constitutes a rare and very heterogeneous family of mesenchymal tumors. The limited treatment options available for advanced STS underline the need for reliable preclinical models to test novel therapeutic strategies. Methods: A panel of patient-derived xenografts (PDX) was established by subcutaneous implantation of fresh, surgically resected tumor specimens in immunodeficient athymic nude NMRI mice. Once tumor growth was observed, pieces of tumor were re-transplanted to next generations of mice. At each passage tumor fragments were collected for histolopathological and molecular characterization. A model was considered established after observing stable histological and molecular features for at least two passages. To evaluate the stability of the genomic profile we performed low-coverage whole-genome sequencing on DNA isolated from tumors obtained from at least two passages. In addition RNA-seq was used to better characterize the mutational profile of the ex-mouse tumors. Results: Until now 139 STS samples from consenting patients treated at the University Hospitals, Leuven, Belgium, have been transplanted. Twenty six well-characterized, stable STS PDX models have been established, maintaining the histopathological and molecular features of the original tumor. Seventeen models, analyzed with low-coverage DNA sequencing, showed a stable genomic profile in at least two different tumor passages. At this point the panel includes models of gastrointestinal stromal tumor (6 models), myxofibrosarcoma (5), dedifferentiated liposarcoma (3), malignant peripheral nerve sheath tumor (3), synovial sarcoma (2), leiomyosarcoma (3) epithelioid haemangioendothelioma (1), mesenchymal chondrosarcoma (1) and undifferentiated high grade sarcoma (2). Some of these models have already been successfully used for in vivo testing of novel agents, including both targeted and cytotoxic (pro-)drugs, and results served as a rationale for at least four prospective clinical trials. In addition 22 other xenografts are still in early stages of engraftment, not yet fulfilling our criteria of an “established model”. Conclusion: Our panel of mesenchymal PDX models is characterized by stable histological and molecular features. These clinically well-annotated models can contribute to reliable preclinical studies for new anticancer treatments for STS. The availability of unique, rare STS xenografts also allows to study the biology of these diseases. The platform is made available to collaborators from academia and industry. Citation Format: Agnieszka Wozniak, Jasmien Cornillie, Yemarshet K. Gebreyohannes, Bram Boeckx, Haifu Li, Thomas Van Looy, Giuseppe Floris, Jasmien Wellens, Lise Vreys, Daphne Hompes, Marguerite Stas, Friedl Sinnaeve, Diether Lambrechts, Maria Debiec-Rychter, Raf Sciot, Patrick Schoffski. Patient-derived xenograft (PDX) models of soft tissue sarcoma (STS): a preclinical platform for early drug testing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5197.

Liposarcomatous differentiation in malignant phyllodes tumours is unassociated with MDM2 or CDK4 amplification.

Breast sarcomas are rare, usually occurring in the setting of malignant phyllodes tumour (MPT). Heterologous differentiation commonly resembles well-differentiated or pleomorphic liposarcoma. In extramammary sites, these subtypes have different biological behaviours and distinct genetic alterations: MDM2 and CDK4 amplification in well-differentiated liposarcoma, and polyploidy with complex structural rearrangements in pleomorphic liposarcoma. The aim of this study was to investigate foci resembling well-differentiated liposarcoma in MPT for MDM2 and CDK4 amplification. We evaluated the clinicopathological characteristics of MPTs received by the Vanderbilt Breast Consultation Service containing components resembling well-differentiated or pleomorphic liposarcoma. Cases with available tissue blocks were subjected to fluorescence in-situ hybridization with MDM2 and CDK4 probes. Thirty-eight MPTs with liposarcomatous components were available for review. The mean patient age was 49.8 years (range 26-84 years). In addition to well-differentiated liposarcoma, the following components were also present: high-grade undifferentiated sarcoma (n = 9; 23.7%), pleomorphic liposarcoma (n = 4; 10.5%), non-high-grade sarcoma not otherwise specified (n = 22; 57.9%), and malignant peripheral nerve sheath tumour-like (n = 2; 5.2%). Among 10 cases tested, none showed amplification of MDM2 or CDK4. This study examined molecular changes in the well-differentiated liposarcomatous components of MPT. Despite histological similarity to well-differentiated liposarcoma of soft tissues, liposarcomatous differentiation in MPT lacks the molecular phenotype characteristic of extramammary well-differentiated liposarcoma.

Myxofibrosarcoma Following Chemotherapy and Radiotherapy for Hodgkin's Lymphoma: Case Study and Review

Introduction: Although radiation-induced sarcomas are widely documented, most reports focus on pleomorphic malignant fibrous histiocytomas (high-grade undifferentiated pleomorphic sarcomas); few case studies involve myxofibrosarcomas. This paper reports on a grade II myxofibrosarcoma of the neck arising secondary to earlier chemotherapy and radiotherapy. Material and methods: A 61-year-old male received chemotherapy plus radiotherapy in 1983 for nodular sclerosing Hodgkin's lymphoma. Twenty-six years after completing treatment, the patient developed a grade II myxofibrosarcoma involving radiated soft tissue on the left side of the neck. Results: The tumor was removed. The tumor mass weighed 90 g and measured 6 × 5 × 4.5 cm and the histological examination revealed a grade-II superficial malignant myxoid spindle-cell tumor displaying a multinodular growth pattern. Immunohistochemical staining was positive for CD34 and negative for smooth muscle actin and desmin. Conclusions: Given the increasing use of adjuvant therapies, particularly in the early stages of cancer, patients should be closely monitored to ensure detection of radiation/chemotherapy-induced sarcomas.

Transformation of a Primitive Myxoid Mesenchymal Tumor of Infancy to an Undifferentiated Sarcoma

An 8-month-old girl underwent surgical resection of a cervical mass with histologic diagnosis of a primitive myxoid mesenchymal tumor of infancy (PMMTI). More than 5 years after the initial surgical intervention, the tumor recurred locally, with numerous distant metastases. The histologic morphology of this tumor was compatible with a diagnosis of an undifferentiated high-grade sarcoma. PMMTI is a recently described poorly differentiated fibroblastic soft-tissue tumor of infancy, of at least borderline biological behavior, characterized by local recurrence and a potential to metastasize. We present here the first case of a transformation of a PMMTI into an undifferentiated high-grade sarcoma.