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Soft Tissue Sarcomas

Soft tissue sarcomas are malignant tumours that may arise in any of the mesodermal tissues (muscles, tendons, vessels that carry blood or lymph, joints, and fat). Sarcomas are a diverse range of tumours, they are named after the type of soft tissue cell they arise from. Types of soft tissue sarcomas include; alveolar soft-part sarcoma, angiosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma, malignant fibrous histiocytoma, hemangiopericytoma, mesenchymoma, schwannoma, peripheral neuroectodermal tumours, rhabdomyosarcoma, synovial sarcoma, and other types. In terms of treatment these different sub-types are usually treated in the same way using a uniform soft tissue protocol.

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Information for Patients and the Public
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Latest Research Publications
Childhood Soft Tissue Sarcoma
Uterine Sarcoma
Kaposi Sarcoma
Gastrointestinal Stromal Tumors

Information Patients and the Public (16 links)

Information for Health Professionals / Researchers (19 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Socoliuc C, Zurac S, Andrei R, Stăniceanu F
Multiple Histological Subtypes of Dermatofibrosarcoma Protuberans Occurring in the Same Tumor.
Rom J Intern Med. 2015 Jan-Mar; 53(1):79-88 [PubMed] Related Publications
Dermatofibrosarcoma protuberans (DFSP) represents a low-grade cutaneous sarcoma which may have different histological aspects, presenting as a fibrosarcomatous, pigmented, juvenile, myxoid, atrophic, sclerosing or myoid lesion. Some of these subtypes may occur isolated or in association with one of the others creating hybrid lesions. We present the case of a 66 years old woman having a 4 cm diameter tumor located on the abdominal wall. Histopathological examination of the resection specimen revealed areas of typical DFSP associated with fibrosarcomatous transformation, myoid and myxoid areas. Also, focally, pleomorphic tumor cells and foreign-body type multinucleated giant cells were observed. Immunostains revealed CD34 positivity in typical DFSP and myxoid areas with negative staining of some of the tumor cells in fibrosarcomatous areas and negative staining of myoid areas. Smooth muscle actin was positive in myoid areas. The nature of myoid fascicles in DFSP is a matter of debate, being uncertain whether these represent a type of tumor differentiation or a reactive myoid proliferation. In this particular case, finding the association of myoid cells with blood vessel walls sustains their reactive nature. We present the morphological aspects of the different areas of the tumor with emphasis on differential diagnostic problems and clinical implications.

Zhao S, Lu N, Chai Y, Yu X
Rapamycin inhibits tumor growth of human osteosarcomas.
J BUON. 2015 Mar-Apr; 20(2):588-94 [PubMed] Related Publications
PURPOSE: Treatment options for osteosarcoma are limited due to its resistance to chemotherapy and radiotherapy. Signaling through the mammalian target of rapamycin (mTOR) pathway contributes to cell proliferation and chemoresistance of many cancers. Rapamycin, as an inhibitor of mTOR, has been developed as potentially valuable therapeutic agent. In this report, we evaluated the effects of rapamycin on human osteosarcoma cells' growth in vitro and in vivo.
METHODS: Proliferation of osteosarcoma cells treated with rapamycin at different time periods was detected and changes in the cell cycle were measured by MTS and flow cytometry, respectively. Autophagy induced by rapamycin in osteosarcoma cells and the expression of cell cycle regulating proteins were detected by Western blotting. The effect of rapamycin on tumor growth in vivo was detected using mice xenograph models.
RESULTS: The proliferation of osteosarcoma cells was signif- icantly inhibited by rapamycin treatment in a concentration-dependent manner and the cell cycle progression was impaired with G1 arrest. Rapamycin induced autophagy, increased the expression of p27 and decreased the expression of Cyclin D1. In addition, rapamycin suppressed the tumor growth in mice xenograph models.
CONCLUSIONS: The potent antiproliferative activities of mTOR inhibitor rapamycin has been proven. Theses results strongly indicate that rapamycin may be a promising agent against osteosarcomas.

Rauh-Hain JA, Hariton E, Clemmer J, et al.
Incidence and effects on mortality of venous thromboembolism in elderly women with endometrial cancer.
Obstet Gynecol. 2015; 125(6):1362-70 [PubMed] Related Publications
OBJECTIVE: To describe the incidence of thromboembolic events (venous thromboembolism) before and after the diagnosis of epithelial endometrial cancer and to evaluate the effects of these events on survival.
METHODS: We used the National Cancer Institute's Surveillance, Epidemiology, and End Results cancer registries linked to Medicare claim files to identify patients with epithelial endometrial cancer diagnosed between 1992 and 2009. To identify venous thromboembolism events 3 months before diagnosis and up to 24 months after diagnosis, we used International Classification of Diseases, 9th Revision, and Healthcare Common Procedure Coding System codes.
RESULTS: A total of 23,122 patients were included; of them 1,873 (8.1%) developed a venous thromboembolism. Patients with low-grade (grades 1 and 2) endometrioid adenocarcinoma had a significantly lower rate of venous thromboembolism 3 months before and 6 months after the diagnosis of cancer (3.6%; 95% confidence interval [CI] 3.3-3.9%) compared with carcinosarcoma (9.2%; 95% CI 7.8-10.8%), clear cell (6.9%; 95% CI 4.8-9.7%), uterine serous cancer (8.1%; 95% CI 7.01-9.3%), and grade 3 endometrioid adenocarcinoma (6.1%; 95% CI 5.4-6.9%) (P<.001). On multivariate analysis during the same time period, most recent time periods of diagnosis, carcinosarcoma histology compared with lower grade endometrial cancer, higher stage, African American race, marital status, chemotherapy delivery, and lymph node dissection were associated with increased risk of venous thromboembolism. The median overall survival for women who experienced a venous thromboembolism 3 months before the diagnosis of endometrial cancer was 31 months (95% CI 20-48 months); in women diagnosed with venous thromboembolism 6 months after the cancer diagnosis was 37 months (95% CI 31-44), and in women who did not experienced a venous thromboembolism was 111 months (95% CI 109-114). After adjusting for prognostic factors, there was an association between venous thromboembolism diagnosed 3 months before endometrial cancer (hazard ratio 1.69, 95% CI 1.34-2.13) or 6 months after the diagnosis (hazard ratio 1.57, 95% CI 1.44-1.71) and lower survival.
CONCLUSION: Patients with uterine serous cancer, carcinosarcoma, clear cell carcinoma, and grade 3 endometrioid adenocarcinoma had a higher rate of venous thromboembolism than patients with low-grade endometrioid adenocarcinoma. A diagnosis of venous thromboembolism was associated with decreased survival in elderly patients with endometrial cancer.

Ghezelayagh T, Rauh-Hain JA, Growdon WB
Comparing mortality of vaginal sarcoma, squamous cell carcinoma, and adenocarcinoma in the surveillance, epidemiology, and end results database.
Obstet Gynecol. 2015; 125(6):1353-61 [PubMed] Related Publications
OBJECTIVE: To evaluate the mortality outcomes of vaginal sarcomas in a large cohort compared with vaginal squamous cell and adenocarcinomas.
METHODS: Women with primary invasive vaginal sarcomas, squamous cell carcinomas, and adenocarcinomas diagnosed between 1988 and 2010 were identified within the National Cancer Institute's Surveillance, Epidemiology, and End Results database. Parametric and nonparametric methods were used to compare the demographic and clinical characteristics of women among the three tumor types as well as between sarcoma histologic subtypes. Overall and cancer-specific mortality outcomes were examined using Kaplan-Meier and multivariable Cox proportional hazards models.
RESULTS: The final cohort consisted of 3,121 patients with vaginal squamous cell carcinoma, 720 patients with adenocarcinoma, and 221 patients with sarcoma. Compared with women with squamous cell carcinoma and adenocarcinoma, patients diagnosed with vaginal sarcomas tended to be younger, have larger tumors with less regional extension and lymph node positivity, and be treated primarily with surgery without radiation. In unadjusted analysis, 5-year mortality rates border 30% for all three histologies. After adjusting for other prognostic factors including use of radiation and surgery, patients with vaginal sarcomas had a 69% greater risk of cancer-related mortality compared with patients with squamous cell carcinoma (hazard ratio 1.69, 95% confidence interval 1.26-2.26). Although sarcoma histology failed to associate with mortality risk, age, tumor extension and metastasis, and surgery were poor prognostic factors.
CONCLUSION: Primary vaginal sarcomas are aggressive neoplasms with different presenting characteristics and increased adjusted risk of mortality compared with squamous cell and adenocarcinoma subtypes.

Mei J, Ni M, Jia GY, et al.
Intermittent internal fixation with a locking plate to preserve epiphyseal growth function during limb-salvage surgery in a child with osteosarcoma of the distal femur: a case report.
Medicine (Baltimore). 2015; 94(20):e830 [PubMed] Related Publications
Limb shortening is a problem associated with surgery for osteosarcoma of the lower extremity in adolescents, as the tumors frequently occur near the epiphysis. Herein we report the use of a less invasive stabilization system (LISS) and an intermittent fixation method to preserve the growth function of epiphysis in an 11-year-old patient with an osteosarcoma of the distal femur.The 11-year-old male presented with left knee enlargement and pain for 2 weeks, and magnetic resonance imaging (MRI) and biopsy were consistent with osteosarcoma of the left distal femur. After preoperative chemotherapy, en bloc tumor resection was performed with margins based on MRI findings preserving the epiphyseal growth plate, the tumor cavity was filled with inactivated bone and bone cement, and a LISS was used to stabilize the femur. Aggressive postoperative chemotherapy was given. Approximately 105 weeks after surgery radiography showed that the distal end of the plate had moved superior to the epiphysis along with bone growth. Locking screws were placed in the distal part of the LISS plate to stabilize the re-implanted bone, and external fixation was not needed.The patient was able to walk with the crutches 1 week postoperatively, and bear weight on the extremity 6 weeks postoperatively. At 6 years after surgery, the patient's height had increased 52 cm, shortening of the affected limb was only 1 cm, and the circumference of the affected limb was 2 cm smaller than that of the contralateral limb. There was no significant discomfort in the affected limb, and there was no gait abnormality. The patient could jump and run, and could participate in sports including basketball and badminton to the same degree as his peers.In summary, the novel method of bone reconstruction and fixation provided good results in a child with an osteosarcoma of the distal femur. This fixation method preserves the osteogenic function of the epiphysis and restored bone integrity simultaneously, and provides good functional recovery.

Bahk WJ, Mirra JM
Differential diagnostic value of "blue reticulated chondroid-like material" in aneurysmal bone cysts: a classic histopathologic analysis of 215 cases.
Am J Clin Pathol. 2015; 143(6):823-9 [PubMed] Related Publications
OBJECTIVES: Our classic histopathologic study of aneurysmal bone cyst (ABC) revealed that "blue reticulated chondroid-like material" (BRC) is characteristic of ABC.
METHODS: The light microscopic findings were retrospectively analyzed in 215 cases of ABC, including 101 primary and 114 secondary cases. In addition, 22 cases of telangiectatic osteosarcoma (TOS) were drawn from the same source and used as a control.
RESULTS: We found the presence of typical BRC in 24 (23.8%) of 101 cases of primary ABC and in six (5.3%) of 114 cases of secondary ABC, with an overall incidence of 30 (14%). None of the cases of TOS showed BRC. BRC was significantly more common in primary ABC than in secondary ABC (P < .05) and in patients 19 years or younger than in those 20 years or older (P < .05).
CONCLUSIONS: BRC appears to be a unique histopathologic feature of ABC, making it valuable to differentiate benign ABC from TOS. Simple H&E stain can be economically performed anywhere.

Waxweiler TV, Rusthoven CG, Proper MS, et al.
Non-Rhabdomyosarcoma Soft Tissue Sarcomas in Children: A Surveillance, Epidemiology, and End Results Analysis Validating COG Risk Stratifications.
Int J Radiat Oncol Biol Phys. 2015; 92(2):339-48 [PubMed] Related Publications
PURPOSE: Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) are a heterogeneous group of sarcomas that encompass over 35 histologies. With an incidence of ∼500 cases per year in the United States in those <20 years of age, NRSTS are rare and therefore difficult to study in pediatric populations. We used the large Surveillance, Epidemiology, and End Results (SEER) database to validate the prognostic ability of the Children's Oncology Group (COG) risk classification system and to define patient, tumor, and treatment characteristics.
METHODS AND MATERIALS: From SEER data from 1988 to 2007, we identified patients ≤18 years of age with NRSTS. Data for age, sex, year of diagnosis, race, registry, histology, grade, primary size, primary site, stage, radiation therapy, and survival outcomes were analyzed. Patients with nonmetastatic grossly resected low-grade tumors of any size or high-grade tumors ≤5 cm were considered low risk. Cases of nonmetastatic tumors that were high grade, >5 cm, or unresectable were considered intermediate risk. Patients with nodal or distant metastases were considered high risk.
RESULTS: A total of 941 patients met the review criteria. On univariate analysis, black race, malignant peripheral nerve sheath (MPNST) histology, tumors >5 cm, nonextremity primary, lymph node involvement, radiation therapy, and higher risk group were associated with significantly worse overall survival (OS) and cancer-specific survival (CSS). On multivariate analysis, MPNST histology, chemotherapy-resistant histology, and higher risk group were significantly poor prognostic factors for OS and CSS. Compared to low-risk patients, intermediate patients showed poorer OS (hazard ratio [HR]: 6.08, 95% confidence interval [CI]: 3.53-10.47, P<.001) and CSS (HR: 6.27; 95% CI: 3.44-11.43, P<.001), and high-risk patients had the worst OS (HR: 13.35, 95% CI: 8.18-21.76, P<.001) and CSS (HR: 14.65, 95% CI: 8.49-25.28, P<.001).
CONCLUSIONS: The current COG risk group stratification for children with NRSTS has been validated with a large number of children in the SEER database.

El-Naggar AM, Veinotte CJ, Cheng H, et al.
Translational Activation of HIF1α by YB-1 Promotes Sarcoma Metastasis.
Cancer Cell. 2015; 27(5):682-97 [PubMed] Related Publications
Metastatic dissemination is the leading cause of death in cancer patients, which is particularly evident for high-risk sarcomas such as Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma. Previous research identified a crucial role for YB-1 in the epithelial-to-mesenchymal transition (EMT) and metastasis of epithelial malignancies. Based on clinical data and two distinct animal models, we now report that YB-1 is also a major metastatic driver in high-risk sarcomas. Our data establish YB-1 as a critical regulator of hypoxia-inducible factor 1α (HIF1α) expression in sarcoma cells. YB-1 enhances HIF1α protein expression by directly binding to and activating translation of HIF1A messages. This leads to HIF1α-mediated sarcoma cell invasion and enhanced metastatic capacity in vivo, highlighting a translationally regulated YB-1-HIF1α axis in sarcoma metastasis.

Que Y, Jiang F, Liu L, et al.
Clinical significance of preoperative serum high density lipoprotein cholesterol levels in soft tissue sarcoma.
Medicine (Baltimore). 2015; 94(18):e844 [PubMed] Related Publications
The prognostic value of lipid profile remains unclear in soft tissue sarcoma. The aim of the present study was to validate the prognostic value of preoperative plasma lipid profile (high density lipoprotein-cholesterol [HDL-C], low density lipoprotein-cholesterol [LDL-C], cholesterol, and triglycerides) levels on disease-free survival (DFS) and overall survival (OS) in soft tissue sarcoma (STS) patients undergoing extensive and radical surgical resection.The preoperative plasma lipid profile levels of 234 STS patients, who were operated on between 2000 with 2010, were retrospectively evaluated. Kaplan-Meier curves and multivariate Cox proportional models were calculated for DFS and OS.In univariate analysis, a decreased HDL-C level was significantly associated with decreased OS (hazard ratio [HR], 3.405; 95% confidence interval (CI), 1.445-8.021, P = 0.005) and remained significant in the multivariate analysis (HR, 5.615; 95% CI, 1.243-25.378, P = 0.025). Patients with HDL-C < 1.475 mmol/L showed a median OS of 71 months. In contrast, patients with HDL-C ≥1.475 mmol/L had a median OS of 101 months. In univariate analysis, a decreased HDL-C level was significantly associated with decreased DFS (HR, 2.085; 95% CI, 1.271-3.422, P = 0.004) and remained significant in the multivariate analysis (HR, 1.808; 95% CI, 1.118-2.924, P = 0.016). Patients with HDL-C <1.475 mmol/L presented with a median DFS of 47 months, whereas patients with HDL-C ≥1.475 mmol/L had a median DFS of 78 months. In univariate analysis and multivariate analyses regarding OS and DFS, there was no significant association between the groups in terms of LDL-C, CHO and TG.Our study investigated the potential prognostic utility of preoperative plasma HDL-C levels as an independent factor in STS patients who had undergone radical surgical resection.

Bus MP, Bramer JA, Schaap GR, et al.
Hemicortical resection and inlay allograft reconstruction for primary bone tumors: a retrospective evaluation in the Netherlands and review of the literature.
J Bone Joint Surg Am. 2015; 97(9):738-50 [PubMed] Related Publications
BACKGROUND: Selected primary tumors of the long bones can be adequately treated with hemicortical resection, allowing for optimal function without compromising the oncological outcome. Allografts can be used to reconstruct the defect. As there is a lack of studies of larger populations with sufficient follow-up, little is known about the outcomes of these procedures.
METHODS: In this nationwide retrospective study, all patients treated with hemicortical resection and allograft reconstruction for a primary bone tumor from 1989 to 2012 were evaluated for (1) mechanical complications and infection, (2) oncological outcome, and (3) failure or allograft survival. The minimum duration of follow-up was twenty-four months.
RESULTS: The study included 111 patients with a median age of twenty-eight years (range, seven to seventy-three years). The predominant diagnoses were adamantinoma (n = 37; 33%) and parosteal osteosarcoma (n = 18; 16%). At the time of review, 104 patients (94%) were alive (median duration of follow-up, 6.7 years). Seven patients (6%) died, after a median of twenty-six months. Thirty-seven patients (33%) had non-oncological complications, with host bone fracture being the most common (n = 20, 18%); all healed uneventfully. Other complications included nonunion (n = 8; 7%), infection (n = 8; 7%), and allograft fracture (n = 3; 3%). Of ninety-seven patients with a malignant tumor, fifteen (15%) had residual or recurrent tumor and six (6%) had metastasis. The risk of complications and fractures increased with the extent of cortical resection.
CONCLUSIONS: Survival of hemicortical allografts is excellent. Host bone fracture is the predominant complication; however, none of these fractures necessitated allograft removal in our series. The extent of resection is the most important risk factor for complications. Hemicortical resection is not recommended for high-grade lesions; however, it may be superior to segmental resection for treatment of carefully selected tumors, provided that it is possible to obtain adequate margins.
LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Wang C, Luo Z, Chen J, et al.
Target therapy of unresectable or metastatic dermatofibrosarcoma protuberans with imatinib mesylate: an analysis on 22 Chinese patients.
Medicine (Baltimore). 2015; 94(17):e773 [PubMed] Related Publications
Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors.

Thway K, Fisher C
Angiomatoid fibrous histiocytoma: the current status of pathology and genetics.
Arch Pathol Lab Med. 2015; 139(5):674-82 [PubMed] Related Publications
CONTEXT: Angiomatoid fibrous histiocytoma (AFH) is a rare soft tissue neoplasm of intermediate biologic potential and uncertain differentiation, most often arising in the superficial extremities of children and young adults. While it has characteristic histologic features of nodular distributions of ovoid and spindle cells with blood-filled cystic cavities and a surrounding dense lymphoplasmacytic infiltrate, there is a significant morphologic spectrum, which coupled with its rarity and lack of specific immunoprofile can make diagnosis challenging. Angiomatoid fibrous histiocytoma is associated with 3 characteristic gene fusions, EWSR1-CREB1 and EWSR1-ATF1, which are also described in other neoplasms, and rarely FUS-ATF1. Angiomatoid fibrous histiocytoma is now recognized at an increasing number of sites and is known to display a variety of unusual histologic features.
OBJECTIVE: To review the current status of AFH, discussing putative etiology, histopathology with variant morphology and differential diagnosis, and current genetics, including overlap with other tumors harboring EWSR1-CREB1 and EWSR1-ATF1 fusions.
DATA SOURCES: Review of published literature, including case series, case reports, and review articles, in online medical databases.
CONCLUSIONS: The occurrence of AFH at several unusual anatomic sites and its spectrum of morphologic patterns can result in significant diagnostic difficulty, and correct diagnosis is particularly important because of its small risk of metastasis and death. This highlights the importance of diagnostic recognition, ancillary molecular genetic confirmation, and close clinical follow-up of patients with AFH. Further insight into the genetic and epigenetic changes arising secondary to the characteristic gene fusions of AFH will be integral to understanding its tumorigenic mechanisms.

Worhunsky DJ, Gupta M, Gholami S, et al.
Leiomyosarcoma: One disease or distinct biologic entities based on site of origin?
J Surg Oncol. 2015; 111(7):808-12 [PubMed] Related Publications
BACKGROUND: Leiomyosarcoma (LMS) can originate from the retroperitoneum, uterus, extremity, and trunk. It is unclear whether tumors of different origin represent discrete entities. We compared clinicopathologic features and outcomes following surgical resection of LMS stratified by site of origin.
METHODS: Patients with LMS undergoing resection at a single institution were retrospectively reviewed. Clinicopathologic variables were compared across sites. Survival was calculated using the Kaplan-Meier method and compared using log-rank and Cox regression analyses.
RESULTS: From 1983 to 2011, 138 patients underwent surgical resection for LMS. Retroperitoneal and uterine LMS were larger, higher grade, and more commonly associated with synchronous metastases. However, disease-specific survival, recurrence-free survival, and recurrence patterns were not significantly different across the four sites. Synchronous metastases (HR 3.20, P < 0.001), but not site of origin, size, grade, or margin status, were independently associated with worse DSS. A significant number of recurrences and disease-related deaths were noted beyond 5 years.
CONCLUSIONS: Although larger and higher grade, retroperitoneal and uterine LMS share similar survival and recurrence patterns with their trunk and extremity counterparts. LMS of various anatomic sites may not represent distinct disease processes based on clinical outcomes. The presence of metastatic disease remains the most important prognostic factor for LMS.

Chow LT
Fibular giant cell-rich osteosarcoma virtually indistinguishable radiographically and histopathologically from giant cell tumor-analysis of subtle differentiating features.
APMIS. 2015; 123(6):530-9 [PubMed] Related Publications
Giant cell-rich osteosarcoma by its abundance of osteoclastic giant cells and paucity of tumor osteoid, leads to its easy confusion with giant cell tumor during biopsy interpretation. In this report, we describe a unique case of upper fibular metaphyseal giant cell-rich osteosarcoma in a 12-year-old boy; the radiographic and histopathologic features of the biopsy and initial resected tumor are virtually indistinguishable from conventional giant cell tumor. The tumor rapidly recurred 7 months after resection with metastasis to the groin lymph nodes, was resistant to first-line chemotherapy and pursued an aggressive course, developing disseminated metastasis to the lung, liver, pelvis, scapula and clavicle, and resulted in the death of the patient 21 months after initial presentation. The subtle features alerting one to the possibility of giant cell-rich osteosarcoma are retrospectively evaluated in comparison with cases of metaphyseal conventional giant cell tumors, four from our records and those from literature review. We conclude that the occurrence of a giant cell-rich lesion in the metaphysis of a skeletally immature individual merits careful assessment for the presence of periosteal reaction, permeative infiltrative margins, lacelike osteoid formation, high mitotic activity or Ki67 proliferative index, and extra-tumoral lymphovascular permeation, since the possibility of an aggressive lesion notably giant cell-rich osteosarcoma probably increases with the number of such features.

Mirabello L, Yeager M, Mai PL, et al.
Germline TP53 variants and susceptibility to osteosarcoma.
J Natl Cancer Inst. 2015; 107(7) [PubMed] Related Publications
The etiologic contribution of germline genetic variation to sporadic osteosarcoma is not well understood. Osteosarcoma is a sentinel cancer of Li-Fraumeni syndrome (LFS), in which approximately 70% of families meeting the classic criteria have germline TP53 mutations. We sequenced TP53 exons in 765 osteosarcoma cases. Data were analyzed with χ(2) tests, logistic regression, and Cox proportional hazards regression models. We observed a high frequency of young osteosarcoma cases (age <30 years) carrying a known LFS- or likely LFS-associated mutation (3.8%) or rare exonic variant (5.7%) with an overall frequency of 9.5%, compared with none in case patients age 30 years and older (P < .001). This high TP53 mutation prevalence in young osteosarcoma cases is statistically significantly greater than the previously reported prevalence of 3% (P = .0024). We identified a novel association between a TP53 rare variant and metastasis at diagnosis of osteosarcoma (rs1800372, odds ratio = 4.27, 95% confidence interval = 1.2 to 15.5, P = .026). Genetic susceptibility to young onset osteosarcoma is distinct from older adult onset osteosarcoma, with a high frequency of LFS-associated and rare exonic TP53 variants.

Jeong JY, Kim SY, Jeong DC, Kim KJ
A small Askin's tumor presenting with early onset of chest pain.
World J Surg Oncol. 2015; 13:112 [PubMed] Free Access to Full Article Related Publications
Most primitive neuroectodermal tumor of the chest wall destroy the rib, chest wall muscles, diaphragm, and lung or extend into the spinal compartment, resulting in a large-sized tumor and symptoms. In contrast, we recently encountered a rare case of Askin's tumor presenting with early-onset chest pain despite the small size. After resection of the tumor and adjuvant chemotherapy, the patient remains disease-free over 3 years of follow-up.

Niu G, Li B, Sun J, Sun L
miR-454 is down-regulated in osteosarcomas and suppresses cell proliferation and invasion by directly targeting c-Met.
Cell Prolif. 2015; 48(3):348-55 [PubMed] Related Publications
OBJECTIVES: Osteosarcoma is the most common primary bone malignancy of children and young adults. Increasing evidence has shown that microRNAs (miRNAs) are associated with cancer development, but, little is known concerning the role of miR-454 in osteosarcoma.
MATERIALS AND METHODS: qRT-PCR was performed to detect expression of miR-454 in osteosarcoma cell lines and tissues. To understand its role in osteosarcoma, we reintroduced expression of miR-454 in the MG-63 cell line by transfection with miR-454 mimics or inhibitors. CCK-8 assay and an invasion assay were used to detect the functional role of miR-454. Luciferase assay and western blot analysis were performed to detect the target gene of miR-454.
RESULTS: miR-454 was found to be down-regulated in osteosarcoma tissues and cell lines. Its over-expression inhibited tumour growth and invasion and its down-regulation promoted cell proliferation and invasion. Subsequent investigation revealed that c-Met was a direct and functional target of miR-454 in osteosarcoma. Overexpression of miR-454 impaired c-Met-induced cell proliferation and invasion. Finally, miR-454 was found to be inversely correlated to c-Met expression in human osteosarcoma tissues.
CONCLUSIONS: Reduced-expression of miR-454 in osteosarcoma cells promoted tumour growth by targeting c-Met, thus miR-454 may be a potential therapy target for this tumour.

He JY, Xi WH, Zhu LB, et al.
Knockdown of Aurora-B alters osteosarcoma cell malignant phenotype via decreasing phosphorylation of VCP and NF-κB signaling.
Tumour Biol. 2015; 36(5):3895-902 [PubMed] Related Publications
The aim of this study is to investigate the effects of inhibiting Aurora-B on osteosarcoma (OS) cell malignant phenotype, phosphorylation of valosin-containing protein (VCP), and the activity of NF-κB signaling in vitro. The expressions of Aurora-B and p-VCP proteins were detected by immunohistochemistry in 24 OS tissues, and the relationship between Aurora-B and p-VCP was investigated. The results showed that there was a positive correlation between Aurora-B and p-VCP proteins. The expression of Aurora-B in human OS cell lines U2-OS and HOS cells was inhibited by specific short hairpin RNA (shRNA) lentivirus (AURKB-shRNA lentivirus, Lv-shAURKB) which targeted Aurora-B. The results showed that the phosphorylation of VCP, the activity of NF-κB signaling pathway and the malignant phenotype of OS cells were all suppressed by knockdown of Aurora-B. It indicated that the inhibition of Aurora-B alters OS cells malignant phenotype by downregulating phosphorylation of VCP and activating of the NF-κB signaling pathway in vitro.

Lau SK, Cykowski MD, Desai S, et al.
Primary rhabdomyosarcoma of the pineal gland.
Am J Clin Pathol. 2015; 143(5):728-33 [PubMed] Related Publications
OBJECTIVES: To report a case of primary rhabdomyosarcoma (RMS) of the pineal gland in an adult, as well as review the literature on this rare entity.
METHODS: The case is compared with previous reports of similar entities, with emphasis on this patient's characteristics and clinical presentation, investigations, and management.
RESULTS: Diagnosis of primary RMS of the pineal gland was based on the presence of strap cells and multinucleated myotube-like structures, as well as tumor cell expression of skeletal muscle markers consistent with myogenic differentiation. Multimodality treatment was initiated based on pediatric protocols. Unfortunately, the disease progressed on treatment, and the patient survived only 5 months from diagnosis.
CONCLUSIONS: Pineal RMS is a rare disease with poor prognosis. Optimal management is unknown but likely to involve aggressive multimodality therapy.

Demicco EG, Harms PW, Patel RM, et al.
Extensive survey of STAT6 expression in a large series of mesenchymal tumors.
Am J Clin Pathol. 2015; 143(5):672-82 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
OBJECTIVES: Expression of strong nuclear STAT6 is thought to be a specific marker for solitary fibrous tumors (SFTs). Little is known about subtle expression patterns in other mesenchymal lesions.
METHODS: We performed immunohistochemical studies against the C-terminus of STAT6 in tissue microarrays and whole sections, comprising 2366 mesenchymal lesions.
RESULTS: Strong nuclear STAT6 was expressed in 285 of 2,021 tumors, including 206 of 240 SFTs, 49 of 408 well-differentiated/dedifferentiated liposarcomas, eight of 65 unclassified sarcomas, and 14 of 184 desmoid tumors, among others. Expression in SFTs was predominately limited to the nucleus. Other positive tumors typically expressed both nuclear and cytoplasmic STAT6. Complete absence of STAT6 was most common in pleomorphic liposarcoma and alveolar soft part sarcoma (60% and 72% cases negative, respectively).
CONCLUSIONS: Strong nuclear STAT6 is largely specific for SFTs. Physiologic low-level cytoplasmic/nuclear expression is common in mesenchymal neoplasia and is of uncertain significance.

Weissferdt A, Kalhor N, Moran CA
Ewing sarcoma with extensive neural differentiation: a clinicopathologic, immunohistochemical, and molecular analysis of three cases.
Am J Clin Pathol. 2015; 143(5):659-64 [PubMed] Related Publications
OBJECTIVES: Three patients with Ewing sarcomas showing extensive neural differentiation are presented.
METHODS: The patients were two women and one man between the ages of 15 and 35 years. Anatomically, one tumor was in the lung, one in the testis, and one in the cervix uteri. The symptoms were determined by the location of the neoplasm and included respiratory symptoms, testicular pain, and pelvic manifestations, respectively. Complete surgical resection of the tumors was performed.
RESULTS: Histologically, all neoplasms showed similar characteristics-namely, a neoplastic cellular proliferation arranged in sheets and composed of small blue cells with round to oval nuclei and inconspicuous nucleoli typical for Ewing sarcoma. In addition, in two cases, there were areas characterized by the presence of neuropil, ganglion cells, and small cells most compatible with ganglioneuroblastoma, while in one tumor, the neural component was characterized by the presence of small cells with prominent perivascular pseudorosettes more closely resembling ependymoma. Immunohistochemical studies in all cases and molecular analysis in two tumors were in keeping with a diagnosis of Ewing sarcoma.
CONCLUSIONS: The recognition of such histologic variants is important in the diagnostic assessment of these tumors to avoid misinterpretation, especially in small biopsy specimens.

Di Luigi G, D'Alfonso A, Patacchiola F, et al.
Leiomyosarcoma: a rare malignant transformation of a uterine leiomyoma.
Eur J Gynaecol Oncol. 2015; 36(1):84-7 [PubMed] Related Publications
The malignant transformation of a uterine leiomyoma is still debated and, if it occurs, it is very rare. The case of a patient affected by one small leiomyoma is described. Diagnosis was made postoperatively on histopathological examination. The case reported here is meant to underline the need to keep all uterine myomas in check since the transition into leiomyosarcomas (LMSs) may occur with an evolution over a time period which has not been established so far. Specific receptors for luteinizing hormone/human chorionic gonadotropin (LH/hCG) have also been identified in the myometrium of several animal species, including humans. Conventional LMSs express estrogen receptors (ER), progesterone receptors (PR), and androgen receptors (AR) in 30-40% of cases. In comparison with other more common uterine malignancies, uterine LMSs bear some resemblance to type 2 endometrial carcinomas and high-grade serous carcinomas of ovary/fallopian tube origin, based on their genetic instability, frequent p53 abnormalities, aggressive behavior, and resistance to chemotherapy. It could be useful to understand with further researches if hormonal stimulation could be a contributing factor of uterine leiomyoma transformation into LMS. Until today the oncogenic mechanisms underlying the development of uterine LMSs remain elusive.

Kerimoglu OS, Pekin A, Yilmaz SA, et al.
Pyometra in elderly post-menopausal women: a sign of malignity.
Eur J Gynaecol Oncol. 2015; 36(1):59-61 [PubMed] Related Publications
PURPOSE: To describe the clinical and histopathological characteristics of 12 patients with pyometra and highlight the increased incidence of gynecological malignancy in these patients.
MATERIALS AND METHODS: The authors examined the medical records of 12 patients with pyometra, who were treated between 2009 and 2013.
RESULTS: All patients were post-menopausal, and their mean age was 70.83 ± 6.978 years (min = 61, max = 82). To remove purulent fluid via dilation and because of the probability of malignancy, three patients (25%) underwent cervical biopsy and endometrial curettage; the other nine patients (75%) underwent curettage alone, with suitable antibiotic therapy. Of the 12 patients, nine (75%) had gynecologic malignancy [(endometrial cancer, n = 5, 41.6%), (cervical cancer, n = 3, 25%), (uterine leiomyosarcoma, n = 1, 8.3%)]. In three (25%) patients, the cause of pyometra was benign pathologies, among which the most common were leiomyomas (n = 2, 66.6%).
CONCLUSION: Pyometra diagnosed during the post-menopausal period should be considered a complication caused by gynecological malignancy until proven otherwise.

Jiang Y, Ludwig J, Janku F
Targeted therapies for advanced Ewing sarcoma family of tumors.
Cancer Treat Rev. 2015; 41(5):391-400 [PubMed] Article available free on PMC after 01/05/2016 Related Publications
The prognosis of adolescent and young adult patients battling metastatic Ewing sarcoma family of tumors (ESFT) remains less than 30% despite the development of systemic therapies. In the era of personalized medicine, novel molecular targets have been tested in preclinical or clinical settings in ESFT. In this review, we focus on early clinical and translational research that identified multiple molecular targets, including IGF-1R; mTOR; tyrosine kinase inhibitors; EWS-FLI1-related targets, and others. Overall, novel targeted therapies demonstrated modest efficacy; however pronounced and durable antineoplastic responses have been observed in small subsets of treated patients, for example with IGF-1R antibodies. Identifying outcome-predicting biomarkers and overcoming treatment resistance remain major challenges. Due to the rarity of ESFT, multi-institutional collaboration efforts of clinicians, basic and translational scientists are needed in order to understand biology of therapeutic response or resistance, which can lead to development of novel therapeutic methods and improved patient outcomes.

Zendah I, Habibech S, Kwas H, et al.
Primary sarcomatoid lung cancer: clinical and evolutive features: about five cases.
Tunis Med. 2014; 92(11):678-80 [PubMed] Related Publications
BACKGROUND: Primary sarcomatoid carcinoma of the lung are rare non small cell lung cancers (NSCLC) recently individualized by the World Health Organization. Their clinical, radiological and evolutive features are not well known but they seem to have bad prognosis with rapid progression and early metastases. Although they are felt to be chemo-refractory they must be treated as the other subtypes of NSCLC.
AIM: To evaluate clinical, radiological and evolutive features of primary sarcomatoid carcinoma of the lung.
METHODS: We report the cases of five patients presenting sarcomatoid carcinomas and assess their clinical and evolutive data.
RESULTS: One patient had stage IIB cancer underwent surgical resection and adjuvant chemotherapy, he is alive 18 months later; another had stage IIIB was treated by radio and chemotherapy and is alive 6 months later; and three other patients had stage IV in whom one had chemotherapy, the two others did not because of they had performance status. They died 1 to 3 months after the diagnosis.
CONCLUSION: Lung sarcomatoid carcinomas are of bad prognosis. Their treatment is nowadays not well established. Much more good studies are therefore needed.

Belfiore MP, Ronza FM, Della Volpe T, et al.
Long-term local disease control in a recurrent soft-tissue sarcoma of the thigh treated by radiofrequency ablation.
J Surg Oncol. 2015; 111(6):708-10 [PubMed] Related Publications
In 2008, we performed radiofrequency ablation (RFA) in an elderly patient with a large recurrent soft-tissue sarcoma of the thigh, previously treated with surgery and radiotherapy. After ablation, a marked shrinkage of tumor was obtained. Further local recurrences occurred during follow-up, all safely treated by RFA, with local control of the disease maintained until 6-year follow-up. RFA was safe, effective, and repeatable for soft-tissue sarcoma recurrences, and allowed long-term local control of the disease.

Cornejo KM, Deng A, Wu H, et al.
The utility of MYC and FLT4 in the diagnosis and treatment of postradiation atypical vascular lesion and angiosarcoma of the breast.
Hum Pathol. 2015; 46(6):868-75 [PubMed] Related Publications
Atypical vascular lesions (AVLs) and angiosarcomas (ASs) are well-recognized complications of radiotherapy for breast cancer. Early diagnosis may be challenging, particularly on small biopsies, and the treatment options are limited. Recently, MYC and sometimes FLT4 gene amplification has been reported in AS, but not in AVL, and FLT4 may be a target for therapy. We evaluated the MYC/FLT4 status in AVL and AS by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), determined its utility in differentiating these 2 entities in small biopsies, and ascertained the value of FLT4 as a potential marker for targeted therapy. Thirty-five vascular neoplasms were reviewed from 21 breast cancer patients who received radiotherapy (AVL, n = 18; AS, n = 17). MYC expression by IHC and/or gene amplification by FISH were identified in 13 (77%) of 17 ASs, but none of the AVL cases. Four patients had biopsies with follow-up excisions, of which 1 showed the morphology of an AVL on biopsy and AS on excision, both positive for MYC. Of 17 ASs, 3 (18%) showed strong and diffuse 3+ cytoplasmic FLT4 staining by IHC and FLT4 gene amplification by FISH. All 3 cases were coamplified for the MYC gene. Focal and weak FLT4 cytoplasmic immunoreactivity was present in 2 (12%) of 17 AVL cases and 12 (70%) of 17 AS cases. Although MYC is a valuable ancillary tool in distinguishing AS from AVL, FLT4 IHC may be used to screen for patients with FLT4 gene amplification who might benefit from targeted therapy, as only diffuse strong FLT4 immunoreactivity correlated with FLT4 gene amplification.

Ladra MM, Mandeville HC, Niemierko A, et al.
Local failure in parameningeal rhabdomyosarcoma correlates with poor response to induction chemotherapy.
Int J Radiat Oncol Biol Phys. 2015; 92(2):358-67 [PubMed] Related Publications
BACKGROUND: Local control remains a challenge in pediatric parameningeal rhabdomyosarcoma (PM-RMS), and survival after local failure (LF) is poor. Identifying patients with a high risk of LF is of great interest to clinicians. In this study, we examined whether tumor response to induction chemotherapy (CT) could predict LF in embryonal PM-RMS.
METHODS: We identified 24 patients with embryonal PM-RMS, age 2 to 18 years, with complete magnetic resonance imaging and gross residual disease after surgical resection. All patients received proton radiation therapy (RT), median dose 50.4 GyRBE (50.4-55.8 GyRBE). Tumor size was measured before initial CT and before RT.
RESULTS: With a median follow-up time of 4.1 years for survivors, LF was seen in 9 patients (37.5%). The median time from the initiation of CT to the start of RT was 4.8 weeks. Patients with LF had a similar initial (pre-CT) tumor volume compared with patients with local controlled (LC) (54 cm(3) vs 43 cm(3), P=.9) but a greater median volume before RT (pre-RT) (40 cm(3) vs 7 cm(3), P=.009) and a smaller median relative percent volume reduction (RPVR) in tumor size (0.4% vs 78%, P<.001). Older age (P=.05), larger pre-RT tumor volume (P=.03), and smaller RPVR (P=.003) were significantly associated with actuarial LF on univariate Cox analysis.
CONCLUSIONS: Poor response to induction CT appears to be associated with an increased risk of LF in pediatric embryonal PM-RMS.

Blay JY, Pápai Z, Tolcher AW, et al.
Ombrabulin plus cisplatin versus placebo plus cisplatin in patients with advanced soft-tissue sarcomas after failure of anthracycline and ifosfamide chemotherapy: a randomised, double-blind, placebo-controlled, phase 3 trial.
Lancet Oncol. 2015; 16(5):531-40 [PubMed] Related Publications
BACKGROUND: Ombrabulin (AVE8062) disrupts the vasculature of established tumours and has shown preclinical synergistic anti-tumour activity when combined with cisplatin. In this phase 3 trial, we aimed to assess the efficacy and safety of ombrabulin plus cisplatin compared with placebo plus cisplatin in patients with advanced soft-tissue sarcomas.
METHODS: We did this multinational, randomised, double-blind, placebo-controlled phase 3 study at 44 centres in ten countries. Patients aged 18 years and older with metastatic soft-tissue sarcomas, an Eastern Cooperative Oncology Group performance status of 0-2, and who had previously received treatment with anthracycline and ifosfamide were randomly assigned (1:1) to intravenous infusion of ombrabulin 25 mg/m(2) plus cisplatin 75 mg/m(2) or intravenous infusion of placebo plus cisplatin 75 mg/m(2) every 3 weeks. Patients were allocated to treatment using a permuted blocks randomisation scheme (block size of four) via an interactive voice-response system, and stratified by histological subtype. Patients, medical staff, study investigators, and individuals who handled and analysed the data were masked to treatment assignment. Our primary endpoint was median progression-free survival in the intention-to-treat population. Safety analyses were done on all randomised patients who received at least one dose of study drug. This trial is now closed, and is registered with ClinicalTrials.gov, number NCT00699517.
FINDINGS: Between June 13, 2008, and April 26, 2012, we randomly assigned 355 patients to ombrabulin plus cisplatin (n=176) or placebo plus cisplatin (n=179). Median duration of follow-up was 27·9 (IQR 20·9-33·2) in the placebo group and 30·5 months (20·7-37·6) in the ombrabulin group. Progression-free survival was slightly, but significantly, improved in the ombrabulin group compared with the placebo group (median 1·54 months [95% CI 1·45-2·69] vs 1·41 [1·38-1·58] months; hazard ratio 0·76 [95% CI 0·59-0·98]; p=0·0302). Grade 3 or 4 adverse events occurred more frequently in individuals in the ombrabulin group than in those in the placebo group and included neutropenia (34 [19%] in the ombrabulin group vs 14 [8%] in the placebo group) and thrombocytopenia (15 [8%] vs six [3%] for placebo). Adverse events leading to death occurred in 18 patients in the ombrabulin group and 10 patients in the placebo group.
INTERPRETATION: The combination of ombrabulin and cisplatin significantly improved progression-free survival; however, it did not show a sufficient clinical benefit in patients with advanced soft-tissue sarcomas to support its use as a therapeutic option. Predictive biomarkers are needed for the rational clinical development of tumour vascular-disrupting drugs for soft-tissue sarcomas.
FUNDING: Sanofi.

Laé M, Lebel A, Hamel-Viard F, et al.
Can c-myc amplification reliably discriminate postradiation from primary angiosarcoma of the breast?
Cancer Radiother. 2015; 19(3):168-74 [PubMed] Related Publications
PURPOSE: Breast angiosarcomas are rare vascular malignancies that arise secondary to irradiation or de novo as primary tumours. The aim of this study is to know whether c-myc amplification can reliably discriminate these two entities.
MATERIEL AND METHODS: Forty-seven patients treated for breast angiosarcomas were studied. Thirty-two patients were diagnosed with postradiation angiosarcomas after breast cancer treatment and 15 patients with primary angiosarcomas. Interphase fluorescence in situ hybridization (FISH) was performed by hybridization of probes covering C-MYC (chromosome 8q24.21) and CEP8 on tissue sections.
RESULTS: Amplification (5- to 20-fold) of the c-myc oncogene was found in all breast radiation-induced angiosarcomas (32 tumours) but in none of the 15 primary angiosarcomas except one (7%).
CONCLUSION: This study reinforces that there are true pathogenetic differences between the two types of breast angiosarcomas which are morphologically indistinguishable. These data point the pathways preferentially involved in the pathogenesis of post radiation angiosarcomas of the breast and may provide the basis for an additional targeted therapy.

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