Translational research in diagnosis and management of soft tissue tumours
© The Author(s). 2016
Received: 1 March 2016
Accepted: 21 May 2016
Published: 7 June 2016
Finding a soft tissue mass in the superficial regions is a common event in daily clinical practice. Correct management of the diagnostic process is crucial to avoid blunders. Diagnosis is posed by pathology, although both imaging and a better understanding of the cellular and molecular mechanisms play an important a role in the characterization, staging and follow-up of soft tissue masses. Cellular and molecular mechanisms can explain either the development of chemo-resistance and the underlying pre- and post-surgery metastasis formation. These are mandatory to improve prognosis and unveil novel parameters predicting therapeutic response. Imaging mainly involves ultrasound and MR and is fundamental not only in diagnosis but also in the first step of therapy: the biopsy. Novel imaging techniques like Ultrasound Elastosonography, Dynamic Contrast-Enhanced MR imaging (DCE), Diffusion Weighted MR imaging (DWI) and MR Spectroscopy (MRS) are discussed. This paper aims at reviewing and discussing pathological methods and imaging in the diagnosis of soft tissue masses underscoring that the most appropriate treatment depends on advanced molecular and radiological studies.
KeywordsSarcoma Biomarkers Signalling pathways Molecular imaging Magnetic resonance imaging Ultrasound elastosonography
Soft tissue sarcomas (STS) represent 1 % of all malignant tumours [1, 2] with more than 50 histological subtypes associated with distinctive clinical and/or molecular profiles, prognosis and response to tailored therapy. STS are mostly benign with an incidence of 100 to 1 and 75 % involve limbs. Malignancy increases with age, and is significantly higher in adult patients compared to children where 75 % of masses are benign .
Surgical removal of tumours in association with radiation and chemotherapy has brought an increase in the 5-year disease-free survival of localized STS, while clinical outcome of patients with advanced or metastatic disease remains strongly unfavorable. Metastasis are usually located in the lung. However, a significant amount of STS are associated with bone metastases and this along with adverse histological and radiological indicators are considered predictive factors for mortality [6, 7]. In order to improve the sarcoma grading and prognosis, Chibon et al.  established a “complexity index in sarcoma” (CINSARC) by relating gene expression to mitosis and chromosome management. Recently, multicentric studies confirmed the relationship between multidrug resistance factors and STS patient survival .
Soft tissue sarcoma molecular subtypes
STS with simple genomics
More frequent translocations
STS with complex genomics
Ewing sarcoma family (ES/PNET)
Malignant peripheral nerve-sheath tumor (MPNST)
Desmoplastic Small Round Cell Tumor (DSRCT)
Undifferentiated Pleomorphic Sarcoma (UPS)
Alveolar soft part sarcoma
Pleomorphic Liposarcoma (PLPS)
Myxoid Liposarcoma (LPS)
Malignant melanoma of soft parts
Embryonal/Pleomorphic RMS (ERMA/PRMS)
Synovial sarcoma (SS)
Angiosarcoma Myxofibrosarcoma (MFS)
Alveolar Rhabdomyosarcoma (ARMS)
DermatoFibroSarcoma Protuberance (DFSP)
Clear cell sarcoma (CCS)
Angiomatoid fibrous histiocytoma
Low grade fibromyxoid sarcoma
Endometrial stromal sarcoma
Inflammatory myofibroblastic tumor
Extraskeletal myxoid chondrosarcoma
To date, high histological grade, deeply seated and greater than 5 cm in size are universally established risk factors for STS metastatic progression. In these cases magnetic resonance (MR) imaging can help define lesions with an atypical appearance . Imaging is of outstanding importance particularly in STS where novel techniques like ultrasound elastosonography, dynamic contrast-enhanced MR imaging (DCE), diffusion weighted MR imaging (DWI) and MR spectroscopy (MRS) are essential for a better understanding of the lesion.
In contrast molecular biomarkers for STS patient stratification useful as targets for tailored molecular therapies are not yet well documented.
Given these evidences, a multidisciplinary approach combining molecular aspects with pathological, radiological and clinical features is required to understand specific defects leading to metastasis formation and development of chemo-resistance in distinct STS subsets.
Cell signalling pathways and molecular targets
Sarcomas are a heterogeneous group of mesenchymal tumours where molecular studies demonstrated biological differences even in tumours with the same diagnosis that share many histological and MR imaging features, but have a different prognosis and therapeutic strategies [11, 13].
This requires a new classification that relies on the definition of distinct biological entities followed by the need to stratify high-risk patients for whom more appropriate therapies should be planned. In the setting of malignant phenotype different cellular signalling pathways drive metastatic progression converging into common interconnection endpoints. Although consensus is emerging that treatment should be histology-driven, recent studies suggest tailored therapies against these common molecular targets [14–16] identifying the effects of genetic aberrations on downstream signalling pathways with activation of key intracellular mediators that may represent targets for biological therapies.
Histological and morphological similarities in biologically heterogenic STS may become a challenge in posing a differential diagnosis. By using an array approach, Subramanian et al.  demonstrated that the expression profile of noncoding microRNA (miRNA) was unique for each type of tumour defining some biological differences useful in sarcoma classification. It is well known that mRNAs post-transcriptionally repress gene expression by recognizing complementary target sites and this makes them one of the largest families of genome regulators.
Recently, we identified differentially expressed miRNAs in a series of poorly differentiated sarcomas and recognized associated chromosome regions and gene targets that may improve differential diagnosis .
In STS with simple karyotype, genomic aberrations are rare and the presence of gene specific alterations as KIT mutation in GIST and translocations establish constant diagnostic criteria. Secondary mutations occur during metastatic progression.
The biological separation between well-differentiated LPS and myxoid LPS relies on mutually exclusive genetic alterations. Well-differentiated LPS present amplification of chromosome region 12q13-15 that address to a therapeutic strategy with anti- CDK4 and MDM2 inhibitors, while myxoid LPS is characterized by chromosomal translocation t(12;16)(q13;p11) resulting in the FUS-DDIT3 chimeric gene that plays a critical role in LPS pathogenesis.
During malignant progression from well-differentiated LPS and myxoid LPS to de-differentiated and round-cell histotypes respectively, the secondary genetic mutations lead to an increased genomic complexity, multiple numerical and structural chromosome aberrations and loss of specific targets . Immunohistochemical analyses carried out on myxoid/round cell LPS specimens showed higher expression of platelet-derived growth factor receptor (Fig. 1c) in metastatic compared to localized lesions .
The interaction between fusion genes and signalling pathways has been fully studied in synovial sarcoma (SS) providing indication for combined therapies. The majority of patients with SYT/SSX1 had overexpression of HER2/neu oncoprotein associated with poor outcome . In vitro studies showed high expression of insulin growth factor receptor IGF-1R and loss of function of PTEN in SS18-SSX -positive tumours [29, 30]. Since the central role of SS18-SSX fusion oncoprotein in tumorigenesis involves its interaction with the transcription factors ATF2 and TLE1 , a treatment with histone deacetylase (HDAC) inhibitors was suggested [30, 31].
After a retrospective analysis of a series SS patients , we correlated the expression of some potential biomarkers with clinical parameters and found that nuclear expression of IGF-1R (Fig. 1d) and chemokine receptor CXCR4 together with age, tumour size and use of radiotherapy resulted to be strongly independent adverse prognostic factors for overall survival . This agrees with the observation that CXCR4 is implicated in sarcoma development and is considered a prognostic marker for poor clinical outcome . Currently, immunotherapeutic strategies are promising anticancer effects in SS and in myxoid/round cell liposarcoma that present a high expression of immunogenic NY-ESO1, also useful for the differential diagnosis from other mesenchymal tumours .
Clinical trials using NY-ESO-1-targeted immunotherapy with genetically modified T-cells reported a clinical response in malignant melanoma and synovial sarcoma patients .
The link between genetic alterations and therapeutic strategies has been emphasized in other translocation-related sarcomas as Ewing’s sarcoma and alveolar RMS where the respective fusion products, EWS-FLI1 and PAX3-FOXO1, inducing activation of IGF-1R pathway stimulate proliferation in vitro and vivo . Although also fusion negative RMS may present a high IGF expression, the real effectiveness of small molecules or antibodies directed at IGF-1R receptor is still under investigation .
Role of the imaging
Magnetic resonance imaging: traditional MR
Magnetic resonance imaging: new MRI techniques
As for bone tumours, newer MRI techniques such as DCE, DWI, MR Spectroscopy MRS can be used not only to cope with the problem of differentiating between benign and malignant tumours but also to improve the possibility of a correct diagnosis [44, 45]. Quantitative DCE or DCE is a non invasive technique that estimates the percentage of necrosis in malignant tumours by comparing pre- and post- treatment examination. This new technique can identify not only post treatment necrosis but also early changes during treatment to modify ineffective therapies. In STS voxels of the necrotic area enhance slowly compared to those of the remaining viable area. In DCE, although the estimate of necrosis is obtained from the whole tumour volume, results are reliable and superimposable to histopathological evaluation obtained from micron thick sections of the resected specimen . DCE is also used to differentiate benign from malignant soft tissue lesions . Malignant lesions usually reveal an increased rate of enhancement of vascularity compared to the benign with a DCE ratio of 3:1 or 4:1 at the first passage [45, 48]. However, DCE poses a problem with highly cellular benign tumours that overlap with STS .
DWI is an MR technique that is sensitive to the random motion of water. Enhancement identifies areas of inflammatory post-surgical change as well as recurrence of disease. Unlike morphological MR imaging sequences and DCE, adds functional information about tissue composition without intravenous contrast . DWI techniques depict tissues with signal intensity that vary in proportion to the average distance by which water molecules are displaced per unit time through the processes of water self-diffusion. DWI is based on the principle that diffusion of the water molecules produces a net dephasing of the spinning protons within a voxel resulting in a reduced signal intensity and image brightness. When examining volume by DWI, signal intensity decreases as the average speed of water, which travels along a temporarily generated magnetic field gradient increases. The quantity of water molecules displaced is described by the diffusion constant which varies with the direction. When the distance of water displacement is the same in all directions diffusion is isotropic. DW images are direction independent, that is, they are independent from the direction along which the magnetic field is applied. In the human body this occurs in fluids where mobile water molecules are free to move in all directions like CSF, brain ventricules or fluids in cystic lesions. The diffusion constant and average water displacement in these fluids are high and equal in all directions. The result: strong signal attenuation (dark) on DWI. In structures where the movement of water molecules is restricted by body structures diffusion is not the same in all directions, but is direction dependent or anisotropic. For example, brain water molecules diffuse faster along the axon with intact myelin sheaths than perpendicular to them. In other words diffusion signal loss is higher when the gradient is applied along the axons axis and lower when applied perpendicular. This technique was first used to detect acute brain ischemia, but during the last decade it has become an imaging biomarker for oncology applied to the entire body. Today DWI is used to identify and detect tissues where pathologic processes have altered the motion of fluids outside vessels and capillaries. However, unfortunately, there is no evidence relating imaging to genetic mutations, VEGF expression, KI 67 expression, and to several other relevant markers.
Features of a cystic lesion on conventional no contrast MRI.
Features of a solid lesion on DCE.
High PIDC values with easy diffusion ADC maps on DWI.
These three features are very important because myxoid liposarcomas (about 50 % of all liposarcomas) have less than 10 % mature fat, that is a low/intermediate signal intensity on T1-weighted images on conventional MR.
Small round blue cell tumours (SRBC) are a group of less differentiated and aggressive embryonal tumours with similar histologic features and immunochemistry. They include neuroblastoma, rhabdomyosarcoma, non-Hodgkin lymphoma, Ewing sarcoma. These tumours show more restricted diffusion than other STS. For this reason the differential diagnosis of a tumour with restricted diffusion on ADC maps and very low PIDC values, small round cell tumours should be the main diagnostic hypothesis, when conventional MRI and CT both with and without contrast give clues to this hypothesis.
Fibroblastic, myofibroblastic and fibrohistiocytic tumours, the most common in all age groups, usually present low signal intensity in all sequences and a flimsy to moderate signal intensity increase after contrast on conventional MRI. These signs together with increased PIDC values and a restricted diffusion on ADC maps can help in the differential diagnosis between benign and malignant masses with morphological features of fibrous tumours on conventional MRI. It must be underlined that that there are not differences in PIDC values between benign and intermediate fibrous tumours.
It is also possible to differentiate necrotic masses such as hematomas and abscesses from necrotic hemorrhagic in malignant soft tumours by ADC map values both in the central component and on the peripheral rim. Malignant tumours for their high cellularity have a more restricted diffusion on ADC maps in the peripheral rim than in the central necrotic area. This measure associated to the typical morphological features of hematomas on conventional time based T1- and T2- MR images allow to differentiate benign from malignant necrosis.
Giant Cell Tumour is a bone and soft tissue tumour presenting low PIDC values and restricted diffusion on ADC maps. These parameters can be useful in the diagnosis and management of local recurrences by revealing differentiation of post-surgical fibrosis from recurrences .
As in bone sarcomas the knowledge of tumour biology has been reinforced by advances in the field of molecular imaging that allow visualization of cell metabolic functions with the use of targets that include cell membrane receptors and enzymes of intracellular transport. The signal for imaging origins from the target molecules and their derivates . A former precursor of functional metabolic imaging was bone scan with 99 metastable TC-MDP, a nuclear isomer complex introduced in the early seventies and still in use, nevertheless others are available today. However, this radiopharmaceutical agent is more sensitive for primary or secondary lesions of the bone. Procedures that follow this scheme are positron emission tomography (PET), MR with molecular MDC, optical imaging and single photon emission tomography (SPECT). Some are used only in research like optical imaging while others are used pre-clinically and clinically .
The introduction of powerful high field MR scanners, 3 Tesla in clinical practice, up to 7–9 Tesla in clinical research, has led to two main advantages. The first is a better spatial resolution that detects smaller lesions before undetectable. The second is a stronger chemical shift disparity that makes MRS an even more unique window to cellular metabolism by non-invasively detecting the concentration of small mobile biological components. In vivo MRS allows, either with a single voxel or multi-voxels study, to identify and quantify the metabolites present within the body volume studied revealing simultaneously anatomic and physiologic information. MRS can isolate and examine the body volume without interference from the nearby structures. It can be used to measure the level of different metabolites giving quantitative chemical information reflecting the molecular composition of a tumour. Changes in metabolite level may be useful indicators of therapeutic response or of recurrence. Moreover, in molecular imaging the intrinsic contrast can be improved by the use of targeted contrast agents in both experimental and clinical settings. The evolving field of molecular imaging requires development of a novel class of MR-detectable agents that can provide image contrast to target specific disease processes . However, conventional DCE and DWI are still of topical interest, and they provide the most relevant and available MR biomarkers in today clinical practice and research [56–63].
The impact of genetic changes on signalling pathway deregulation may be recognized by molecular imaging based on mass spectrometry. Mass spectrometry imaging (MALDI) technique uses matrix assisted laser desorption ionization where the sample, often a thin tissue section or a cell lysate, is moved in two dimensions while the mass spectrum is recorded. MALDI may identify regions of the proteome, as well as unmodified or post-translationally modified proteins or peptides, that today are a new area of interest for new biomarkers [16, 67, 68]. As complement of in vitro and ex vivo molecular biology assays, molecular imaging is also currently used in research animals for development of future clinical strategies providing a in vivo quantitative representation of the biological processes. By using intravital microscope we demonstrated that the capacity of fluorescently labelled LMS cells to invade lymphatic vessels in living mice  is increased by ectopic expression of proteoglycan NG2 involved in tumour cell-environment interaction, found also overexpressed in advanced/metastatic STS patients . Deregulation of adhesion and invasion processes (Fig. 8b), degradation of extracellular matrix and the capability of tumour cells of migrating across endothelium is an essential pre-requisite for metastatic spread of tumour cells and represent one of the multiple hallmarks in tumour progression . In high-grade STS characterized by tissue heterogeneity, cellular and molecular imaging may contribute to improve patient survival through in vivo detection of prognostic metabolic indicators and efficacy of treatment.
Translation from laboratory characterization to clinical application passes through molecular imaging in patients. Measurement of biological endpoints and visualization of functional and metabolic changes to malignant transformation and progression provide early detection of disease and monitoring of therapy efficacy. Thus, the integration of cell and molecular biology, pathology, bioinformatics, molecular imaging, new radiological imaging techniques and clinical features may identify new indicators of disease or therapeutic effects through the quantitative representation of biological processes. In particular, this system-biology analysis may categorize subgroups of distinct endpoints involved in metastatic progression and drug-resistance. Up to now despite the advances in identifying gene abnormalities and deregulated pathways few specific endpoints represent direct targets in sarcoma treatment and chemotherapy remains the first choice treatment of advanced/metastatic sarcoma.
We thank Ms. Cristina Ghinelli for the graphics.
ER performed radiological analysis, conceived the study and participated in its design and coordination and drafted the manuscript. MSB contributed to molecular analysis, conceived the study design and coordination and drafted the manuscript. Alberto Bazzocchi contributed to radiological analysis, conceived the study and helped to draft the manuscript. Alba Balladelli participated in the sequence alignment and drafted the manuscript. GF participated in the sequence alignment and helped to draft the manuscript. GR contributed to the radiological analysis. ST contributed in image analysis. DV controlled and checked the manuscript. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
- Hajdu SI. Soft tissue sarcoma classification and natural history. CA Cancer J Clin. 1981;31(5):271–80.View ArticlePubMedGoogle Scholar
- Walker EA, Song AJ, Murphey MD. Magnetic resonance imaging of soft tissue masses. Semin Roentgenol. 2010;45(4):277–97.View ArticlePubMedGoogle Scholar
- Brisse H, Orbach D, Klijanienko J, Frèneaux P, Neuenschwander S. Imaging and diagnostic strategy of soft tumours in children. Eur Radiol. 2006;16:1147–64.View ArticlePubMedGoogle Scholar
- SEER Cancer Stat Fact Sheets (Sheer Web Site). Available at: http://www.seer.cancer.gov/statfacts/index.html. Accessed April 4, 2011
- Cormier JN, Pollock RE. Soft tissue sarcomas. CA Cancer J Clin. 2004;54(2):94–109.View ArticlePubMedGoogle Scholar
- Campanacci M. Introduction. In: Bone and soft tissue tumours: clinical features, imaging, pathology and treatment. 2nd ed. Padova: Piccin nuova libraria; 1999. p. 18–29.View ArticleGoogle Scholar
- Pike J, Clarkson PW, Masri BA. Soft tissue sarcomas of the extremities: How to stay out of trouble. BC Med J. 2008;50(6):310–8.Google Scholar
- Chibon F, Lagarde P, Salas S, Pérot G, Brouste V, Tirode F, et al. Validated prediction of clinical outcome in sarcomas and multiple types of cancer on the basis of a gene expression signature related to genome complexity. Nat Med. 2010;16(7):781–7.View ArticlePubMedGoogle Scholar
- Martin-Broto J, Gutierrez AM, Ramos RF, Lopez-Guerrero JA, Ferrari S, Stacchiotti S, et al. MRP1 overexpression determines poor prognosis in prospectively treated patients with localized high-risk soft tissue sarcoma of limbs and trunk wall: an ISG/GEIS study. Mol Cancer Ther. 2014;13(1):249–59.View ArticlePubMedGoogle Scholar
- Gibault L, Pérot G, Chibon F, Bonnin S, Lagarde P, Terrier P, et al. New insights in sarcoma oncogenesis: a comprehensive analysis of a large series of 160 soft tissue sarcomas with complex genomics. J Pathol. 2011;223(1):64–71.View ArticlePubMedGoogle Scholar
- Toguchida J, Nakayama T. Molecular genetics of sarcomas: Applications to diagnoses and therapy. Cancer Sci. 2009;100:1573–80.View ArticlePubMedGoogle Scholar
- Mertens F, Antonescu CR, Hohenberger P, Ladanyi M, Modena P, D’Incalci M, et al. Translocation-related sarcomas. Semin Oncol. 2009;36(4):312–23.View ArticlePubMedGoogle Scholar
- Van Vliet M, Kliffen M, Krestin GP, van Dijke CF. Soft tissue sarcomas at a glance: clinical, histological, and MR imaging features of malignant extremity soft tissue tumors. Eur Radiol. 2009;19(6):1499–511.View ArticlePubMedGoogle Scholar
- Flores RJ, Li Y, Yu A, Shen J, Rao PH, Lau SS, et al. A system biology approach reveals common metastatic pathway in osteosarcoma. BMC Sys Biol. 2012;6:50.View ArticleGoogle Scholar
- Janeway KA, Makin RG. New strategies in sarcoma therapy: linking biology and novel agents. Clin Cancer Res. 2012;18:5837–44.View ArticlePubMedGoogle Scholar
- Conti A, Espina V, Chiechi A, Magagnoli G, Novello C, Pazzaglia L, et al. Mapping protein signal pathway interaction in sarcoma bone metastasis: linkage between rank, metalloproteinases turnover and growth factor signaling pathways. Clin Exp Metastasis. 2014;31(1):15–24.View ArticlePubMedGoogle Scholar
- Taylor BS, Barretina J, Maki RG, Antonescu CR, Singer S, Ladanyi M. Advances in sarcoma genomics and new therapeutic targets. Nat Rev Cancer. 2011;11(9):68.View ArticleGoogle Scholar
- Serrano C, George S. Leiomyosarcoma. Hematol Oncol Clin N Am. 2013;27(5):957–74.View ArticleGoogle Scholar
- Huang HY, Illei PB, Zhao Z, Mazumdar M, Huvos AG, Healey JH, et al. Ewing sarcomas with p53 mutation or p16/p14ARF homozygous deletion: a highly lethal subset associated with poor chemoresponse. J Clin Oncol. 2005;23(3):548–58.View ArticlePubMedGoogle Scholar
- Kresse SH, Ohnstad HO, Bjerkehagen B, Myklebost O, Meza-Zepeda LA. DNA copy number changes in human malignant fibrous histiocytomas by array comparative genomic hybridisation. PLoS One. 2010;5:e15378.View ArticlePubMedPubMed CentralGoogle Scholar
- Levard A, Tassy L, Cassier PA. Emerging therapies for soft-tissue sarcomas. Hematol Oncol Clin N Am. 2013;27(5):1063–78. doi:10.1016/j.hoc.2013.07.011.View ArticleGoogle Scholar
- Skubitz KM, Skubitz APN, Xu WW, Luo X, Lagarde P, Coindre J, Chibon F. Gene expression identifies heterogeneity of metastatic behavior among high-grade non-translocation associated soft tissue sarcomas. J Transl Med. 2014;12:176.View ArticlePubMedPubMed CentralGoogle Scholar
- Italiano A, Lagarde P, Brulard C, Terrier P, Laë M, Marques B, et al. Genetic profiling identifies two classes of soft-tissue leiomyosarcomas with distinct clinical characteristics. Clin Cancer Res. 2013;19(5):1190–6.View ArticlePubMedGoogle Scholar
- Bertucci F, Finetti P, Sabatier R, Birnbaum D. The CINSARC signature. Prognostic and predictive of response to chemotherapy? Cell Cycle. 2010;19:4025–7.View ArticleGoogle Scholar
- Subramanian S, Lui WO, Lee CH, Espinosa I, Nielsen TO, Heinrich MC, et al. MicroRNA expression signature of human sarcomas. Oncogene. 2008;27(14):2015–26.View ArticlePubMedGoogle Scholar
- Guled M, Pazzaglia L, Borze I, Mosakhani N, Novello C, Benassi MS, et al. Differentiating LMS and UPS soft tissue sarcomas: a miRNA analysis. Genes Chromosomes Cancer. 2014;53(8):693–702.View ArticlePubMedGoogle Scholar
- Hoffman A, Ghadimi MP, Demicco EG, Creighton CJ, Torres K, Colombo C, et al. Localized and metastatic myxoid/round cell liposarcoma: clinical and molecular observations. Cancer. 2013;119(10):1868–77.View ArticlePubMedGoogle Scholar
- Thomas DG, Giordano TJ, Sanders D, Biermann S, Sondak VK, Trent JC, et al. Expression of receptor tyrosine kinases epidermal growth factor receptor and HER-2/neu in synovial sarcoma. Cancer. 2005;103(4):830–8.View ArticlePubMedGoogle Scholar
- Tornkvist M, Natalishvili N, Xie Y, Girnita A, D’Arcy P, Brodin B, et al. Differential roles of SS18–SSX fusion gene and insulin-like growth factor-1 receptor in synovial sarcoma cell growth. Biochem Biophys Res Commun. 2008;368(3):793–800.View ArticlePubMedGoogle Scholar
- Su L, Cheng H, Sampaio AV, Nielsen TO, Underhill TM. EGR1 reactivation by histone deacetylase inhibitors promotes synovial sarcoma cell death through the PTEN tumor suppressor. Oncogene. 2010;29:4352–61.View ArticlePubMedGoogle Scholar
- Su L, Sampaio AV, Jones KB, Pacheco M, Goytain A, Lin S, et al. Deconstruction of the SS18-SSX fusion oncoprotein complex: insights into disease etiology and therapeutics. Cancer Cell. 2012;21(3):333–47.View ArticlePubMedPubMed CentralGoogle Scholar
- Palmerini E, Staals EL, Alberghini M, Zanella L, Ferrari C, Benassi MS, et al. Retrospective analysis of 250 patients treated at a single institution. Cancer. 2009;115(13):2988–98.View ArticlePubMedGoogle Scholar
- Palmerini E, Benassi MS, Quattrini I, Pazzaglia L, Donati D, Benini S, Gambri G gambarotti M, Picci P, Ferrari S. Prognostic and predictive role of CXCR4, IGF-1R and Ezrin expression in localized synovial sarcoma: is chemotaxis important to tumor? Orph J Rare Disease. 2014 doi:10.1186/s13023-014-0222-5
- Kim RH, Li BD, Chu QD. The role of chemokine receptor CXCR4 in the biologic behavior of human soft tissue sarcoma. Sarcoma. 2011;2011:593708. doi:10.1155/2011/593708.PubMedGoogle Scholar
- Lai J-P, Rosenberg AZ, Miettinen MM, Lee CC. NY-ESO-1 expression in sarcoma: diagnostic marker and immunotherapy target. Oncoimmunology. 2012;8:1409–10.View ArticleGoogle Scholar
- Robbins PF, Morgan RA, Feldman SA, Yang JC, Sherry RM, Dudley ME, et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J Clin Oncol. 2011;29:917–24.View ArticlePubMedPubMed CentralGoogle Scholar
- Janeway KA, Maki RG. New strategies in sarcoma therapy: linking biology and novel agents. Clin Cancer Res. 2012;18:5837–44.View ArticlePubMedGoogle Scholar
- Kolb EA, Gorlick R. Development of IGF-IR inhibitors in pediatric sarcomas. Curr Oncol Rep. 2009;11(4):307–13.View ArticlePubMedGoogle Scholar
- Chiou HJ, Chou YH, Chiu SY, Wang HK, Wm C, Chen TH, et al. Differentiation of benign and malignant superficial soft-tissue masses using grayscale and color Doppler ultrasonography. J Chin Med Assoc. 2009;72(6):307–15. doi:10.1016/S1726-4901(09)70377-6.View ArticlePubMedGoogle Scholar
- Pedersen M, Fredberg U, Langberg H. Sonoelastography as a diagnostic tool in the assessment of musculoskeletal alterations: a systematic review. Ultraschall Med. 2012;33(5):441–6. doi:10.1055/s-0032-1312923.View ArticlePubMedGoogle Scholar
- Loizidez A, Widmann G, Freuis T, Peer S, Gruber H. Optimizing ultrasound-guided biopsy of musculoskeletal masses by application of an ultrasound contrast agent. Ultraschall Med. 2011;32(3):307–10. doi:10.1055/s-0029-1245713.View ArticleGoogle Scholar
- Myhre-Jensen O. A consecutive 7-year series of 1331 soft tissue tumours. Clinicopathogic data. Comparison with sarcomas. Acta Orthop Scand. 1981;52(3):19–31.View ArticleGoogle Scholar
- Sundaram M, Mc Guire M, Herbold DR. Magnetic resonance imaging of soft tissue masses: an evaluation of fifty-three histologically proven tumors. Magn Reson Imaging. 1988;6(3):237–48.View ArticlePubMedGoogle Scholar
- Mirowitz SA, Totty WG, Lee JK. Characterization of musculoskeletal masses using dynamic Gd-DPTA enhanced spin-echo MRI. J Comput Assist Tomogr. 1992;16(1):120–5.PubMedGoogle Scholar
- van Rijswijk CS, Kunz P, Hogendoorn PC, Taminiau AH, Doornbos J, Bloem JL. Diffusion-Weigthe MRI in the characterization of soft tissue tumors. J Magn Reson Imaging. 2002;15(3):302–7.View ArticlePubMedGoogle Scholar
- Benassi MS, Rimondi E, Balladelli A, Ghinelli C, Magagnoli G, Vanel D. The role of imaging for translational research in bone tumors. Eur J Radiol. 2011;82(12):2115–23. doi:10.1016/j.ejrad.2011.11.031.View ArticlePubMedGoogle Scholar
- Benedikt RA, Jelinek JS, Kransdorf MJ, Moser RP, Berrey BH. MR imaging of soft tissue masses: role of gadopentetate dimeglumine. J Magn Reson Imaging. 1994;4(3):485–90.View ArticlePubMedGoogle Scholar
- van Rijswijk CS, Geirnaerdt MJ, Hogendoorn PC, Taminiau AH, van Coevorden F, Zwinderman AH, et al. Soft tissue tumors: value of static and dynamic gadopentetate dimeglumine-enhanced MR imaging in prediction of malignancy. Radiology. 2004;233(2):493–502.View ArticlePubMedGoogle Scholar
- Vilanova JC, Baleato A, Balliu E. Muscoloskeletal Application of DWI. In: Luna A, Ribes R, Soto JA, editors. In diffusion MRI outside the brain. Heidelberg: Springer; 2012. p. 339–64. 15.View ArticleGoogle Scholar
- Maeda M, Matsumine A, Kato H, Kusuzaki K, Maier SE, Uchida A, et al. Soft-tissue tumors evaluated by line-scan diffusion-weighted imaging: influence of myxoid matrix on the apparent diffusion coefficient. J Magn Reson Imaging. 2007;25(6):1199–204.View ArticlePubMedGoogle Scholar
- Costa FM, Ferreira EC, Vianna EM. Diffusion-weighted magnetic resonance imaging for the evaluation of musculoskeletal tumors. Magn Reson Imaging Clin N Am. 2011;19(1):159–80. doi:10.1016/j.mric.2010.10.007.View ArticlePubMedGoogle Scholar
- Hicks RJ. Functional imaging techniques for evaluation of sarcomas. Cancer Imaging. 2005;5(1):58–65.View ArticlePubMedPubMed CentralGoogle Scholar
- Morrison WB, Zoga AC, Daffner RH et al. Soft Tissue Masses. American College of Radiology. ACR Appropriatenes Criteria 2009. Available at http://www.acr.org pag Rad Clin of North Am 1195.
- Shin DS, Shon OJ, Han DS, Choi JH, Chun KA, Cho IH. The clinical efficacy of (18)F-FDG-PET/CT in benign and malignant musculoskeletal tumors. Ann Nucl Med. 2008;22(7):603–9.View ArticlePubMedGoogle Scholar
- Shah C, Miller TW, Wyatt SK, McKinley ET, Olivares MG, Sanchez V, et al. Imaging biomarkers predict response to anti-HER2 (ErbB2) therapy in preclinical models of breast cancer. Clin Cancer Res. 2009;15(14):4712–21. doi:10.1158/1078-0432.CCR-08-2635.View ArticlePubMedPubMed CentralGoogle Scholar
- Subhawong TK, Durand DJ, Thawait GK, Jacobs MA, Fayad LM. Characterization of soft tissue masses: can quantitative diffusion weighted imaging reliably distinguish cysts from solid masses? Skeletal Radiol. 2013;42:1583–92.View ArticlePubMedGoogle Scholar
- Oka K, Yakushiji T, Sato H, Hirai T, Yamashita Y, Mizuta H. The value of diffusion-weighted imaging for monitoring the chemotherapeutic response of osteosarcoma: a comparison between average apparent diffusion coefficient and minimum apparent diffusion coefficient. Skeletal Radiol. 2010;39:141–6.View ArticlePubMedGoogle Scholar
- Schnapauff D, Zeile M, Niederhagen MB, Fleige B, Tunn PU, Hamm B, et al. Diffusion-weighted echo-planar magnetic resonance imaging for the assessment of tumor cellularity in patients with soft-tissue sarcomas. J Magn Reson Imaging. 2009;29:1355–9.View ArticlePubMedGoogle Scholar
- Surov A, Weber MA. Malignant and benign lesions of the skeletal musculature. Semin Ultrasound CT MR. 2014;35:290–307.View ArticlePubMedGoogle Scholar
- Surov A, Nagata S, Razek AA, Tirumani SH, Wienke A, Kahn T. Comparison of apparent diffusion coefficient values in different malignancies of the skeletal musculature. A multicentric analysis. Skeletal Radiol. 2015;44(7):995–1000.View ArticlePubMedGoogle Scholar
- Einarsdóttir H, Karlsson M, Wejde J, Bauer HC. Diffusion-weighted MRI of soft tissue tumours. Eur Radiol. 2004;14:959–63.View ArticlePubMedGoogle Scholar
- Razek A, Nada N, Ghaniem M, Elkhamary S. Assessment of soft tissue tumours of the extremities with diffusion echoplanar MR imaging. Radiol Med. 2012;117(1):96–101.View ArticlePubMedGoogle Scholar
- Nagata S, Nishimura H, Uchida M, Sakoda J, Tonan T, Hiraoka K, et al. Diffusion-weighted imaging of soft tissue tumors: usefulness of the apparent diffusion coefficient for differential diagnosis. Radiat Med. 2008;26(5):287–95.View ArticlePubMedGoogle Scholar
- Pazzaglia L, Chiechi A, Conti A, Gamberi G, Magagnoli G, Novello C, et al. Genetic and molecular alterations in rhabdomyosarcoma: mRNA overexpression of MCL1 and MAP2K4 genes. Histol Histopathol. 2009;24(1):61–7.PubMedGoogle Scholar
- Konstantinopoulos PA, Fountzilas E, Goldsmith JD, Bhasin M, Pillay K, Francoeur N, et al. Analysis of multiple sarcoma expression datasets: implications for classification, oncogenic pathway activation and chemotherapy resistance. PLoS One. 2010;5(4):e9747.View ArticlePubMedPubMed CentralGoogle Scholar
- Massoud TF, Gambhir SS. Molecular imaging in living subjects: seeing fundamental biological processes in a new light. Genes Dev. 2003;17:545–80.View ArticlePubMedGoogle Scholar
- Conti A, Rodriguez GC, Chiechi A, Blazquez RM, Barbado V, Krènacs T, et al. Identification of potential biomarkers for giant cell tumor of bone using comparative proteomics analysis. Am J Pathol. 2011;178(1):88–97.View ArticlePubMedPubMed CentralGoogle Scholar
- Chiechi A, Novello C, Magagnoli G, Petricoin 3rd EF, Deng J, Benassi MS, et al. Elevated TNFR1 and serotonin in bone metastasis are correlated with poor survival following bone metastasis diagnosis for both carcinoma and sarcoma primary tumors. Clin Cancer Res. 2013;19(9):2473–85.View ArticlePubMedPubMed CentralGoogle Scholar
- Cattaruzza S, Nicolosi PA, Braghetta P, Pazzaglia L, Benassi MS, Picci P, et al. NG2/CSPG4-collagen type VI interplays putatively involved in the microenvironmental control of tumour engraftment and local expansion. J Mol Cell Biol. 2013;5(3):176–93.View ArticlePubMedPubMed CentralGoogle Scholar
- Benassi MS, Pazzaglia L, Chiechi A, Alberghini M, Conti A, Cattaruzza S, et al. NG2 expression predicts the metastasis formation in soft-tissue sarcoma patients. J Orthop Res. 2009;27(1):135–40.View ArticlePubMedGoogle Scholar
- Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. doi:10.1016/j.cell.2011.02.013.View ArticlePubMedGoogle Scholar