Primary Myxofibrosarcoma Research Articles

Clinical aggressiveness of myxofibrosarcomas associates with down-regulation of p12CDK2AP1: prognostic implication of a putative tumor suppressor that induces cell cycle arrest and apoptosis via mitochondrial pathway.

Attenuated endogenous protein levels of cyclin-dependent kinase 2 associated protein 1 (p12(CDK2AP1)) and its active homodimer p25(CDK2AP1) were found in myxofibrosarcoma-derived cell lines. Clinical and biological significances of this putative tumor suppressor in myxofibrosarcoma were studied. Plasmids carrying the CDK2AP1 gene and small hairpin RNA interference (shRNAi) targeting CDK2AP1 were transfected into NMFH-1 and/or OH931 cells to evaluate the effects on the CDK2, active caspase 3 (CASP3), cleaved-CASP8 and -CASP9 levels, cell cycle regulation, and/or apoptotic responses. Immunostaining of p12(CDK2AP1) was interpretable in 102 primary myxofibrosarcomas and correlated with clinicopathological variables, CDK2, Ki-67 and active CASP3 protein levels, and disease-specific survival. Exogenous expression of p12(CDK2AP1) in NMFH-1 and OH931 cells significantly induced G0/G1 cell cycle arrest and down-regulated CDK2 protein level. In NMFH-1 cells, these aspects were reversed by shRNAi targeting CDK2AP1 gene. Increased active CASP3 and cleaved-CASP9, but not -CASP8, were detected after CDK2AP1 overexpression, suggesting the cellular apoptosis were induced through the mitochondrial pathway. Immunostains of p12(CDK2AP1) were aberrantly decreased in 56.9 % of cases; positively and negatively correlated with protein levels of CDK2 (p = 0.023), Ki-67 (p = 0.001) and active CASP3 (p < 0.001), respectively. Following by high histological grades, p12(CDK2AP1) down-regulation was predictive of worse disease-specific survival in univariate (p = 0.003) and multivariate (p = 0.004) analyses. Through down-regulation of CDK2, high p12(CDK2AP1) level induced cell cycle arrest and the mitochondrial-dependent apoptotic pathway. Low p12(CDK2AP1) level represents a poor prognostic factor in patients with myxofibrosarcoma.

Low-grade myxofibrosarcoma following a metal implantation in femur: a case report

Myxofibrosarcoma is a myxoid variant of malignant fibrous histiocytoma that most commonly involves the extremities of elderly people. However, a primary myxofibrosarcoma with bone invasion in young adults is extremely rare. Herein, we report the case of a 31-year-old male with a gradually enlarging left thigh mass, who had a history of left femur fracture and received an open reduction and internal fixation with titanium alloy plates and screws 33 months previously. Imaging investigations revealed an irregularly shaped soft tissue mass around the left femur shaft and a partial bone defect in the middle one-third of the left femur. Pathological examination of the resected specimen showed a multi-nodular appearance, abundant myxoid matrix and elongated curvilinear capillaries. Immunohistochemical studies revealed that the tumor cells was positive for VIM and MDM2, and was negative for CK, MSA, SMA, DES, S-100 and CD34. Labeling index of Ki-67 was 25%. Based on the morphological finding and immunostaining, it was diagnosed as a low-grade myxofibrosarcoma. The clinical and imaging examinations did not reveal the evidence of a primary cancer elsewhere, and the patient had no personal or family history of malignancy. To our knowledge, this is the first case of a primary myxofibrosarcoma developed following a fracture and metal implantation in young adults.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1745984882113605

Very Rare Case of Large Obstructive Myxofibrosarcoma of the Right Ventricle Assessed with Multi-diagnostic Imaging Techniques

Primary myxofibrosarcoma of the heart is quite rare. We herein present the case of a 56-year-old man who presented with large obstructive myxofibrosarcoma of the right ventricle (RV), as assessed on multi-diagnostic imaging techniques (multidetector row computed tomography, magnetic resonance imaging and positron emission tomography). Most previous cases of cardiac myxofibrosarcoma have been reported in the left atrium and ventricle. In this report, we describe a very rare case of large obstructive myxofibrosarcoma of the RV.

An Analysis of Factors Related to Recurrence of Myxofibrosarcoma

Myxofibrosarcoma is clinically characterized by a high frequency of local recurrence after surgery. To improve the clinical outcome of patients with myxofibrosarcoma, it is imperative to control any postsurgical local recurrence. In this study, we performed a retrospective clinicopathologic analysis of 100 consecutive patients with myxofibrosarcoma to identify factors related to poor prognosis. All of the patients had been diagnosed, and had undergone surgery at the National Cancer Center Hospital between 1999 and 2008. At the initial visit to our hospital, 64 patients had primary myxofibrosarcoma, whereas 36 had undergone primary unplanned resection at other facilities. Of the 36 patients, 11 consulted our hospital before recurrence and 25 did so after recurrence. A histologically positive margin after surgery was evident in 28% of the cases overall. The estimated 5-year recurrence-free survival rate was 74.8%. Univariate analysis showed that primary unplanned resection at another facility (P = 0.0001) and a histologically positive margin (P = 0.0224) were significant predictors of local recurrence. When these two factors were subjected to multivariate analysis, only primary unplanned resection at another facility was significantly correlated with the estimated recurrence-free survival rate (P = 0.0011). Primary unplanned resection was also significantly related to the 5-year disease-free survival rate (P = 0.0401). Our findings indicate that primary unplanned resection at a non-referral hospital is the most important risk factor related to poor prognosis of myxofibrosarcoma. Accurate diagnosis and adequate initial surgery are most important factors for improving the clinical outcomes of myxofibrosarcoma.

A deeply seated brain metastasis from a primary myxofibrosarcoma: Case report

1. IntroductionMyxofibrosarcoma (MFS) is a common sarcoma type, affectingmainly elderlyindividualsandoftenoccurringinthesubcutaneoustissue of extremities, with trunk being a less common site of origin[1,2]. To our knowledge, only two reports of deeply seated intrace-rebral MFS manifestations have been published [3,4]. We report arare caseofclinicallyaggressiveMFSofthetrunkwithintracerebralmetastasis.2. Case reportWe report the case of a 73-year-old male presenting to his gen-eral practitioner with a palpable painful mass at the right lowerthoracic level.On magnetic resonance (MR)-imaging, a well-demarcated,contrast-enhancing lesion (6×4×7cm) harboring a central cys-tic component was found on the dorsolateral thoracic wall at theheight of the 12th rib. Open incisional biopsy of the lesion was

Primary Cardiac Myxofibrosarcoma: A Case Report and Review of the Literature

Aims and background Primary myxofibrosarcoma of the heart is a rare malignancy. To the best of our knowledge, no more than 17 cases have been reported since 1963. Methods and study design We report the case of a 42-year-old man who presented with dyspnea and palpitation of one month's duration. Echocardiography and enhanced computed tomography revealed a large tumor in the left atrium. Results The patient underwent palliative excision of the tumor and histopathological analysis revealed it to be a low-grade myxofibrosarcoma. The patient developed a bone metastasis two years later and is still alive 26 months after the cardiac surgery. Conclusions Primary cardiac myxofibrosarcoma involves predominantly the left atrium and the most common symptom induced by the tumor is dyspnea. Disease outcome is often disappointing despite aggressive postoperative radiotherapy and chemotherapy.

Recurrent Amplification at 7q21.2 Targets CDK6 Gene in Primary Myxofibrosarcomas and Identifies CDK6 Overexpression as an Independent Adverse Prognosticator

Myxofibrosarcoma is genetically complex and remains obscure in molecular determinants of clinical aggressiveness. Our prior study revealed recurrent gains of 7q in myxofibrosarcomas where MET and CDK6 genes displayed increased DNA copies. Previously, we demonstrated the implication of MET overexpression, prompting us to further elucidate the roles of CDK6 in myxofibrosarcomas. On tissue microarrays, CDK6 immunoexpression was assessable in 77 primary tumors, 55 of which were successfully quantified for CDK6 and MET genes by real-time PCR using genomic DNA extracted from laser-microdissected tumor cells. Gene status and protein expression of CDK6 were correlated with each other, clinicopathological variables, metastasis-free survival (MFS), and disease-specific survival (DSS). Protein overexpression and gene amplification of CDK6, which were detected in 21 of 77 (27.2 %) and 13 of 55 cases (23.6 %), respectively, were highly related to each other (p < .001) and associated with higher grades (overexpression, p = .004; amplification, p = .014). There was a strong correlation between CDK6 and MET gene copies (p < .001, r = 0.0714). Importantly, CDK6 protein overexpression (MFS, p = .0002; DSS, p = .0015) and gene amplification (MFS, p = .0001; DSS, p = .0083) were both univariately associated with worse outcomes. Together with nonextremity location and AJCC stage III disease, CDK6 overexpression independently portended inferior MFS (p = .0015, risk ratio [RR] = 7.411). This aberration, along with nonextremity location, was also an independent adverse prognosticator of DSS (p = .0069, RR = 6.006). In approximately a quarter of primary myxofibrosarcomas, CDK6 overexpression is mostly driven by gene amplification on 7q, associated with adverse prognosticators, and independently predictive of worse outcomes, highlighting its possible causative role in tumor aggressiveness.

Primary Cerebral Myxofibrosarcoma

Herein, we describe an intracerebral primary low-grade myxofibrosarcoma occurring in a 9-year-old boy. The lesion measured 7 cm and occupied the left parieto-occipital region. A gross-total removal of the tumor was performed. Nine months later, radiologic follow-up revealed a local recurrence which was again surgically removed. The patient then underwent radiotherapy and chemotherapy. He was well and disease-free at 6 months follow-up. The tumor was composed of spindle, stellated, and multinucleated cells embedded in a myxoid background. Foci of increased cellularity, pleomorphism, and high mitotic rate were present. The tumor borders were sharply demarcated from the non-neoplastic nervous parenchyma. Immunohistochemical staining showed that the neoplastic cells were vimentine and CD34 positive. Fluorescence in-situ hybridization analyses did not show FUS and EWSR1 gene rearrangements. Primary intracranial myxofibrosarcomas are very rare (to the best of our knowledge, less than 10 published cases in the international literature). We believe each new case should be recorded to produce a better clinical, pathologic, molecular, prognostic, and therapeutic characterization of this lesion.

Bone and/or joint attachment is a risk factor for local recurrence of myxofibrosarcoma

BackgroundMyxofibrosarcoma is characterized by a high local recurrence rate despite optimal surgical treatment. The definition of prognostic factors for recurrence offers high-risk patients a closer follow-up and a multi-disciplinary therapeutic approach. MethodsA cohort of 23 patients treated for primary myxofibrosarcoma was retrospectively analyzed. The patients (sex and age), tumors (size, stage, tumor location, bone and/or joint attachment), radiological findings (abnormal signal extension in MRI), histological findings (FNCLCC grade and microscopic extension along the muscle fascia), and treatment (surgical margin) characteristics were included in univariate prognostic factor analysis. ResultsAfter a median follow-up of 63.3 months (range 15–191), the overall recurrence rate was 34.7%. Median time between initial surgery and recurrence was 24.8 months (range 8–52). Inadequate surgical margins (p = 0.026) and bone and/or joint attachment (p = 0.001) were associated with an increased recurrence rate. ConclusionFor the further improvement of local recurrence-free survival of patients with myxofibrosarcoma, accurate diagnosis of the tumor extension and adequate planning for the surgical margin should be focused on in cases with bone and/or joint attachment.

Prognostic implication of MET overexpression in myxofibrosarcomas: an integrative array comparative genomic hybridization, real-time quantitative PCR, immunoblotting, and immunohistochemical analysis

It remains obscure in myxofibrosarcoma about the basis of tumorigenesis, progression, and metastasis. Chromosome 7 gains are common in some sarcomas, including myxofibrosarcoma, whereas the specific oncogenes are yet to be characterized. We performed an integrative study of MET gene at 7q31.2 to elucidate its implication in myxofibrosarcoma. Focused on candidate oncogenes on chromosome 7, 385K array comparative genomic hybridization was used to profile DNA copy number alterations of 12 samples. MET transcript was successfully quantified by real-time RT–PCR for 16 laser-microdissected tumors and two myxofibrosarcoma cell lines (NMFH-1, OH931). MET immunoexpression was assessable in 86 primary localized tumors with follow-up. To analyze endogenous MET expression and activation, NMFH-1 and OH931 cells, both with wild-type MET gene, were subjected to Western blotting and hepatocyte growth factor-treated NMFH-1 cells were evaluated for the kinetics of MET tyrosine phosphorylation. Non-random large-scale gains on 7q were detected in five cases, delineating three recurrent amplicons, 7q21.11–7q21.3, 7q22.1–22.3, and 7q31.1–7q32.3, in which the locus of MET displayed increased copy number, among others. MET mRNA was upregulated in OH931, NMFH-1, and nine tumors (56%), whereas neither gene dosage nor mRNA expression of MET was associated with clinicopathological factors. In contrast, MET protein overexpression, present in 67% of cases, was highly related to deep location (P=0.004), higher grades (P=0.001), and more advanced stages (P<0.001). Importantly, MET overexpression independently portended inferior metastasis-free survival (P=0.004) and overall survival (P=0.0221). Expressing activating phospho-MET at Tyr1234/Tyr1235, OH931 cells had more abundant total MET than NMFH-1 cells, whereas the latter became promptly phosphorylated on stimulation of hepatocyte growth factor. In primary myxofibrosarcomas, MET overexpression, as a frequent event, is likely driven by 7q gains with mRNA upregulation, associated with important prognosticators, and independently predictive of worse outcomes, highlighting its possible causative function in tumor aggressiveness and potentiality as a therapeutic target.

Prognostic Implication of Ezrin Overexpression in Myxofibrosarcomas

The bases of tumorigenesis, progression, and metastasis remain obscure in myxofibrosarcoma. As a member of ezrin-radixin-moesin family, ezrin acts as a link between the cell membrane and actin cytoskeleton to integrate cell adhesion-mediated signaling. It is implicated in tumor progression and metastatic dissemination, and it is associated with adverse outcomes in several cancer types, including pediatric sarcomas. Ezrin immunostain could be assessed from tissue microarrays of 78 cases of primary localized myxofibrosarcomas and correlated with clinicopathological factors and patient survival. In two myxofibrosarcoma cell lines, ezrin mRNA expression was measured by real-time reverse transcriptase-polymerase chain reaction and the endogenous expression and activating phosphorylation of ezrin protein analyzed by Western blot test. Ezrin overexpression was significantly associated with remarkable tumor necrosis (P = 0.025), increased histological grades (P = 0.037), advanced American Joint Committee on Cancer stages (P = 0.034), and higher mitotic rate (P < 0.001). Importantly, ezrin overexpression independently predicted inferior metastasis-free survival (P = 0.012, risk ratio = 4.083) and disease-specific survival (P = 0.0337, risk ratio = 4.537). The mRNA and total protein of ezrin in various cells were comparable in the expression level. Despite variation in abundance, phosphorylated ezrin at threonine(567) was detectable in myxofibrosarcoma cell lines but not in fibroblasts. In primary myxofibrosarcomas, ezrin overexpression correlates with important prognostic elements and independently portends worse outcomes, highlighting the potential prognostic usefulness of ezrin in predicting tumor aggressiveness.

Primary Aortic Myxofibrosarcoma Mimicking Thrombus

Aortic sarcoma is a rare vascular malignancy. We report a case of primary aortic myxofibrosarcoma mimicking thrombus. This neoplasm demonstrated no contrast enhancement on computed tomography or magnetic resonance imaging and was clinically suspected to represent a large thrombus, although aortic primary neoplasm was considered in the differential diagnosis on the basis of imaging. Biopsies of the aortic lesion and a concurrent brain lesion were consistent with the diagnosis of aortic myxofibrosarcoma with brain metastasis. This report highlights overlapping imaging features between primary aortic sarcoma and vascular thrombus and the importance of considering neoplastic conditions in the differential diagnosis of large intravascular soft tissue lesions.

Primary Myxofibrosarcoma of the Left Atrium: Case Report and Review of the Literature

A 63-year-old woman with progressive dyspnea underwent transthoracic echocardiography and was found to have a large multilobed mass in the left atrium that was attached to lateral wall. On inspection during surgery, the tumor was found to infiltrate the posterior mitral annulus and leaflet. The patient underwent surgical resection of the tumor and mitral valve replacement. Histologic and cytochemical evaluation confirmed that the tumor was a myxofibrosarcoma. Despite chemotherapy, the tumor recurred and the patient died 3 months after surgery.

Skp2 Overexpression Is Highly Representative of Intrinsic Biological Aggressiveness and Independently Associated with Poor Prognosis in Primary Localized Myxofibrosarcomas

Two SCF(Skp2) ubiquitin ligase-related proteins, Skp2 and cyclin-dependent kinase subunit 1 (Cks1), are involved in posttranscriptional degradation of p27(Kip1) tumor suppressor. We analyzed the prognostic utility of p27(Kip1) and its interacting cell cycle regulators in myxofibrosarcomas. Clinicopathologic features and tissue microarray-based immunohistochemical expression of p27(Kip1), Skp2, Cks1, cyclin E, cyclin A, Ki-67, and minichromosome maintenance protein 2 (Mcm2) were assessed in 70 primary myxofibrosarcomas and correlated with clinical outcomes. Skp2 mRNA expression and the relationship between Skp2 and p27(Kip1) proteins were examined in six cases by semiquantitative reverse transcription-PCR and Western blotting, respectively. High indices of Skp2 (> or =10%), cyclin A (> or =10%), and Mcm2 (> or =50%) were adverse prognosticators at the univariate level. Furthermore, co-overexpression of Skp2 and cyclin A identified highly lethal cases in the entire cohort [P < 0.0001 for disease-specific survival (DSS), P = 0.0004 for overall survival (OS)] and the lower-grade subset (Fédération Nationale des Centres de Lutte Contre le Cancer grade 1 and 2; P = 0.0006 for DSS, P = 0.0093 for OS). In multivariate analyses, Skp2 overexpression overshadowed most intrinsic clinicopathologic factors and independently correlated with worse metastasis-free survival (P = 0.0012), DSS (P = 0.0234), and OS (P = 0.0056). Notably, positive margins independently predicted inferior local recurrence-free survival (P = 0.0012) and also negatively affected metastasis-free survival (P = 0.0471), DSS (P = 0.0152), and OS (P = 0.0173). Reverse transcription-PCR showed up-regulation of Skp2 mRNA in four cases and Western blotting displayed a matched expression pattern of Skp2. Margin status and intrinsic property of myxofibrosarcomas both affect patient survival. Skp2 overexpression is highly representative of the biological aggressiveness of myxofibrosarcomas and plays an important prognostic role.

Primary myxofibrosarcoma of the esophagus

J Thorac Cardiovasc Surg 2002;124:196-7

Primary Myxofibrosarcoma of the Heart With Occlusion of the Bifurcation of the Aorta

Primary Myxofibrosarcoma of the Heart With Occlusion of the Bifurcation of the Aorta