Sarcoma treatment in the era of molecular medicine
2020; Springer Nature; Volume: 12; Issue: 11 Linguagem: Inglês
10.15252/emmm.201911131
ISSN1757-4684
AutoresThomas G. P. Grünewald, Marta M. Alonso, Sofia Avnet, Ana Banito, Stefan Burdach, Florencia Cidre‐Aranaz, Gemma Di Pompo, Martin Distel, Heathcliff Dorado García, Javier García‐Castro, Laura González‐González, Agamemnon E. Grigoriadis, Merve Kasan, Christian Koelsche, Manuela Krumbholz, Fernando Lecanda, Silvia Lemma, Dario Livio Longo, Claudia Madrigal‐Esquivel, Álvaro Morales‐Molina, Julian Musa, Shunya Ohmura, Benjamin Ory, Miguel Pereira‐Silva, Francesca Perut, René Rodrı́guez, Carolin Seeling, Nada Al Shaaili, Shabnam Shaabani, Kristina Shiavone, Snehadri Sinha, Eleni M. Tomazou, Marcel Trautmann, María Vela, Yvonne M.H. Versleijen‐Jonkers, Julia D. Visgauss, Marta Zalacaín, Sebastian Johannes Schober, Andrej Lissat, William English, Nicola Baldini, Dominique Heymann,
Tópico(s)Cancer Research and Treatments
ResumoReview13 October 2020Open Access Sarcoma treatment in the era of molecular medicine Thomas GP Grünewald Corresponding Author Thomas GP Grünewald [email protected] orcid.org/0000-0003-0920-7377 Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Hopp Children's Cancer Center (KiTZ), German Cancer Consortium (DKTK), Heidelberg, Germany Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany Search for more papers by this author Marta Alonso Marta Alonso orcid.org/0000-0002-7520-7351 Program in Solid Tumors and Biomarkers, Foundation for the Applied Medical Research, University of Navarra Pamplona, Pamplona, Spain Search for more papers by this author Sofia Avnet Sofia Avnet Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Ana Banito Ana Banito Pediatric Soft Tissue Sarcoma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany Search for more papers by this author Stefan Burdach Stefan Burdach Department of Pediatrics and Children's Cancer Research Center (CCRC), Technische Universität München, Munich, Germany Search for more papers by this author Florencia Cidre-Aranaz Florencia Cidre-Aranaz orcid.org/0000-0002-0246-7179 Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Search for more papers by this author Gemma Di Pompo Gemma Di Pompo Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Martin Distel Martin Distel Children's Cancer Research Institute, Vienna, Austria Search for more papers by this author Heathcliff Dorado-Garcia Heathcliff Dorado-Garcia Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany Search for more papers by this author Javier Garcia-Castro Javier Garcia-Castro Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain Search for more papers by this author Laura González-González Laura González-González Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain Search for more papers by this author Agamemnon E Grigoriadis Agamemnon E Grigoriadis Centre for Craniofacial and Regenerative Biology, King's College London, London, UK Search for more papers by this author Merve Kasan Merve Kasan Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Search for more papers by this author Christian Koelsche Christian Koelsche Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany Search for more papers by this author Manuela Krumbholz Manuela Krumbholz Department of Pediatrics, University Hospital, Erlangen, Germany Search for more papers by this author Fernando Lecanda Fernando Lecanda Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain Search for more papers by this author Silvia Lemma Silvia Lemma Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Dario L Longo Dario L Longo Institute of Biostructures and Bioimaging (IBB), Italian National Research Council (CNR), Turin, Italy Search for more papers by this author Claudia Madrigal-Esquivel Claudia Madrigal-Esquivel Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Álvaro Morales-Molina Álvaro Morales-Molina Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain Search for more papers by this author Julian Musa Julian Musa Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany Search for more papers by this author Shunya Ohmura Shunya Ohmura Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Search for more papers by this author Benjamin Ory Benjamin Ory Université de Nantes, Inserm, U1238, Nantes, France Search for more papers by this author Miguel Pereira-Silva Miguel Pereira-Silva Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal Search for more papers by this author Francesca Perut Francesca Perut Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Rene Rodriguez Rene Rodriguez orcid.org/0000-0002-0768-7306 Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain CIBER en oncología (CIBERONC), Madrid, Spain Search for more papers by this author Carolin Seeling Carolin Seeling Institute of Pathology, Ulm University, Ulm, Germany Search for more papers by this author Nada Al Shaaili Nada Al Shaaili Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Shabnam Shaabani Shabnam Shaabani Department of Drug Design, University of Groningen, Groningen, The Netherlands Search for more papers by this author Kristina Shiavone Kristina Shiavone Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Snehadri Sinha Snehadri Sinha Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland Search for more papers by this author Eleni M Tomazou Eleni M Tomazou Children's Cancer Research Institute, Vienna, Austria Search for more papers by this author Marcel Trautmann Marcel Trautmann orcid.org/0000-0002-5842-1196 Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, Münster University Hospital, Münster, Germany Search for more papers by this author Maria Vela Maria Vela Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain Search for more papers by this author Yvonne MH Versleijen-Jonkers Yvonne MH Versleijen-Jonkers Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands Search for more papers by this author Julia Visgauss Julia Visgauss Medical Center, Duke University, Durham, NC, USA Search for more papers by this author Marta Zalacain Marta Zalacain Institute of Biostructures and Bioimaging (IBB), Italian National Research Council (CNR), Turin, Italy Search for more papers by this author Sebastian J Schober Sebastian J Schober Department of Pediatrics and Children's Cancer Research Center (CCRC), Technische Universität München, Munich, Germany Search for more papers by this author Andrej Lissat Andrej Lissat University Children′s Hospital Zurich – Eleonoren Foundation, Kanton Zürich, Zürich, Switzerland Search for more papers by this author William R English William R English Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Nicola Baldini Corresponding Author Nicola Baldini [email protected] orcid.org/0000-0003-2228-3833 Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy Search for more papers by this author Dominique Heymann Corresponding Author Dominique Heymann [email protected] orcid.org/0000-0001-7777-0669 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Université de Nantes, Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine, Saint-Herblain, France Search for more papers by this author Thomas GP Grünewald Corresponding Author Thomas GP Grünewald [email protected] orcid.org/0000-0003-0920-7377 Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Hopp Children's Cancer Center (KiTZ), German Cancer Consortium (DKTK), Heidelberg, Germany Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany Search for more papers by this author Marta Alonso Marta Alonso orcid.org/0000-0002-7520-7351 Program in Solid Tumors and Biomarkers, Foundation for the Applied Medical Research, University of Navarra Pamplona, Pamplona, Spain Search for more papers by this author Sofia Avnet Sofia Avnet Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Ana Banito Ana Banito Pediatric Soft Tissue Sarcoma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany Search for more papers by this author Stefan Burdach Stefan Burdach Department of Pediatrics and Children's Cancer Research Center (CCRC), Technische Universität München, Munich, Germany Search for more papers by this author Florencia Cidre-Aranaz Florencia Cidre-Aranaz orcid.org/0000-0002-0246-7179 Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Search for more papers by this author Gemma Di Pompo Gemma Di Pompo Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Martin Distel Martin Distel Children's Cancer Research Institute, Vienna, Austria Search for more papers by this author Heathcliff Dorado-Garcia Heathcliff Dorado-Garcia Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany Search for more papers by this author Javier Garcia-Castro Javier Garcia-Castro Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain Search for more papers by this author Laura González-González Laura González-González Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain Search for more papers by this author Agamemnon E Grigoriadis Agamemnon E Grigoriadis Centre for Craniofacial and Regenerative Biology, King's College London, London, UK Search for more papers by this author Merve Kasan Merve Kasan Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Search for more papers by this author Christian Koelsche Christian Koelsche Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany Search for more papers by this author Manuela Krumbholz Manuela Krumbholz Department of Pediatrics, University Hospital, Erlangen, Germany Search for more papers by this author Fernando Lecanda Fernando Lecanda Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain Search for more papers by this author Silvia Lemma Silvia Lemma Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Dario L Longo Dario L Longo Institute of Biostructures and Bioimaging (IBB), Italian National Research Council (CNR), Turin, Italy Search for more papers by this author Claudia Madrigal-Esquivel Claudia Madrigal-Esquivel Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Álvaro Morales-Molina Álvaro Morales-Molina Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain Search for more papers by this author Julian Musa Julian Musa Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany Search for more papers by this author Shunya Ohmura Shunya Ohmura Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany Search for more papers by this author Benjamin Ory Benjamin Ory Université de Nantes, Inserm, U1238, Nantes, France Search for more papers by this author Miguel Pereira-Silva Miguel Pereira-Silva Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal Search for more papers by this author Francesca Perut Francesca Perut Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Search for more papers by this author Rene Rodriguez Rene Rodriguez orcid.org/0000-0002-0768-7306 Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain CIBER en oncología (CIBERONC), Madrid, Spain Search for more papers by this author Carolin Seeling Carolin Seeling Institute of Pathology, Ulm University, Ulm, Germany Search for more papers by this author Nada Al Shaaili Nada Al Shaaili Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Shabnam Shaabani Shabnam Shaabani Department of Drug Design, University of Groningen, Groningen, The Netherlands Search for more papers by this author Kristina Shiavone Kristina Shiavone Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Snehadri Sinha Snehadri Sinha Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland Search for more papers by this author Eleni M Tomazou Eleni M Tomazou Children's Cancer Research Institute, Vienna, Austria Search for more papers by this author Marcel Trautmann Marcel Trautmann orcid.org/0000-0002-5842-1196 Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, Münster University Hospital, Münster, Germany Search for more papers by this author Maria Vela Maria Vela Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain Search for more papers by this author Yvonne MH Versleijen-Jonkers Yvonne MH Versleijen-Jonkers Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands Search for more papers by this author Julia Visgauss Julia Visgauss Medical Center, Duke University, Durham, NC, USA Search for more papers by this author Marta Zalacain Marta Zalacain Institute of Biostructures and Bioimaging (IBB), Italian National Research Council (CNR), Turin, Italy Search for more papers by this author Sebastian J Schober Sebastian J Schober Department of Pediatrics and Children's Cancer Research Center (CCRC), Technische Universität München, Munich, Germany Search for more papers by this author Andrej Lissat Andrej Lissat University Children′s Hospital Zurich – Eleonoren Foundation, Kanton Zürich, Zürich, Switzerland Search for more papers by this author William R English William R English Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Search for more papers by this author Nicola Baldini Corresponding Author Nicola Baldini [email protected] orcid.org/0000-0003-2228-3833 Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy Search for more papers by this author Dominique Heymann Corresponding Author Dominique Heymann [email protected] orcid.org/0000-0001-7777-0669 Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK Université de Nantes, Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine, Saint-Herblain, France Search for more papers by this author Author Information Thomas GP Grünewald *,1,2,3, Marta Alonso4, Sofia Avnet5, Ana Banito6, Stefan Burdach7, Florencia Cidre-Aranaz1, Gemma Di Pompo5, Martin Distel8, Heathcliff Dorado-Garcia9, Javier Garcia-Castro10, Laura González-González10, Agamemnon E Grigoriadis11, Merve Kasan1, Christian Koelsche3, Manuela Krumbholz12, Fernando Lecanda13, Silvia Lemma5, Dario L Longo14, Claudia Madrigal-Esquivel15, Álvaro Morales-Molina10, Julian Musa1,16, Shunya Ohmura1, Benjamin Ory17, Miguel Pereira-Silva18, Francesca Perut5, Rene Rodriguez19,20, Carolin Seeling21, Nada Al Shaaili15, Shabnam Shaabani22, Kristina Shiavone15, Snehadri Sinha23, Eleni M Tomazou8, Marcel Trautmann24, Maria Vela25, Yvonne MH Versleijen-Jonkers26, Julia Visgauss27, Marta Zalacain14, Sebastian J Schober7, Andrej Lissat28, William R English15, Nicola Baldini *,5,29 and Dominique Heymann *,15,30 1Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany 2Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), Hopp Children's Cancer Center (KiTZ), German Cancer Consortium (DKTK), Heidelberg, Germany 3Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany 4Program in Solid Tumors and Biomarkers, Foundation for the Applied Medical Research, University of Navarra Pamplona, Pamplona, Spain 5Orthopedic Pathophysiology and Regenerative Medicine Unit, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy 6Pediatric Soft Tissue Sarcoma Research Group, German Cancer Research Center (DKFZ), Heidelberg, Germany 7Department of Pediatrics and Children's Cancer Research Center (CCRC), Technische Universität München, Munich, Germany 8Children's Cancer Research Institute, Vienna, Austria 9Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany 10Cellular Biotechnology Unit, Instituto de Salud Carlos III, Madrid, Spain 11Centre for Craniofacial and Regenerative Biology, King's College London, London, UK 12Department of Pediatrics, University Hospital, Erlangen, Germany 13Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain 14Institute of Biostructures and Bioimaging (IBB), Italian National Research Council (CNR), Turin, Italy 15Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK 16Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany 17Université de Nantes, Inserm, U1238, Nantes, France 18Department of Pharmaceutical Technology, Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal 19Instituto de Investigación Sanitaria del Principado de Asturias, Oviedo, Spain 20CIBER en oncología (CIBERONC), Madrid, Spain 21Institute of Pathology, Ulm University, Ulm, Germany 22Department of Drug Design, University of Groningen, Groningen, The Netherlands 23Department of Oral and Maxillofacial Diseases, University of Helsinki, Helsinki, Finland 24Division of Translational Pathology, Gerhard-Domagk-Institute of Pathology, Münster University Hospital, Münster, Germany 25Hospital La Paz Institute for Health Research (IdiPAZ), Madrid, Spain 26Department of Medical Oncology, Radboud University Medical Center, Nijmegen, The Netherlands 27Medical Center, Duke University, Durham, NC, USA 28University Children′s Hospital Zurich – Eleonoren Foundation, Kanton Zürich, Zürich, Switzerland 29Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy 30Université de Nantes, Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine, Saint-Herblain, France *Corresponding author. Tel: +49 6221 42 3718; E-mail: [email protected] *Corresponding author. Tel: +39 (0) 516 366 549; E-mail: [email protected] *Corresponding author. Tel: +33 (0) 240 679 841; E-mail: [email protected] EMBO Mol Med (2020)12:e11131https://doi.org/10.15252/emmm.201911131 See the Glossary for abbreviations used in this article. PDFDownload PDF of article text and main figures. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma. Glossary Cancer stem cells (CSCs) Cells within the tumor found in very small fractions that are thought to be responsible for resistance to cancer treatments and thus relapse. Cell dormancy Stage in cancer progression during which tumor cells cease dividing but survive in a quiescent state while waiting for appropriate environmental conditions. Chorioallantoic Membrane (CAM) models Chick embryo CAM models used to study tumor formation, angiogenesis, and metastasis. Circulating tumor cells (CTCs) Cells that leak into the vasculature or lymphatics from a primary tumor and are carried around the body in the blood circulation. Epigenomic alterations Heritable change that does not affect the DNA sequence but results in a change in gene expression. Extracellular vesicles (EVs) Heterogeneous family of vesicles generated from different subcellular compartments and released into the extracellular space or the blood circulation. Genomic alterations Permanent modifications in the DNA sequence including somatic mutations, copy-number variations (CNVs), and gene fusions. Immunotherapy Type of cancer treatment that aids the immune system to fight tumors. Oncolytic viruses Viruses that, by their intrinsic properties or through genetic engineering, specifically replicate in and kill cancer cells. Orthotopic xenografts Animal models based on the injection of tumor cell lines in the location where the tumors typically appear in humans. Patient-derived xenografts (PDXs) Animal model based on transplantation of human tumor biopsies that encompass tumor cells and the TME in immunodeficient animals. Pediatric tumors Tumors that typically arise between 0–14 years of age. Precision medicine Approach to patient care that allows physicians to select the treatments that are most likely to help patients based on a molecular understanding of their disease. Sarcomas Malignant neoplasms that originate from the skeleton or soft tissues. Tumor microenvironment (TME) Cellular environment in which cancer cells reside encompassing the extracellular matrix and stromal cells (endothelial cells, fibroblasts, and immune cells) Epidemiology of sarcoma Although sarcomas are rare among adult malignancies, they represent 12–15% of all pediatric tumors (Stiller et al, 2013). Despite the implementation and continuous optimization of multimodal therapies, around one-third of sarcoma patients still succumb to the disease. Historically, sarcomas have been clustered in two large subgroups, according to the anatomical site of occurrence—sarcomas of the skeleton and sarcomas of the soft tissues (hereafter referred to as "bone sarcomas" or "soft tissue sarcomas" [STSs], respectively). Both subgroups comprise a variety of histological subtypes, and recent technological advances have enabled to decipher a constantly increasing number of subtypes at the molecular level (Fig 1; Baldauf et al, 2018a; Koelsche et al, 2018a; Watson et al, 2018; Weidema et al, 2020). Table 1 summarizes the major sarcoma subtypes discussed in this review and their main features. Figure 1. Diversity of sarcomas as highlighted by DNA methylation profilingt-distributed stochastic neighbor embedding (t-SNE) plot of n = 18 major sarcoma and soft tissue tumor subtypes based on genome-wide DNA methylation profiling on Illumina EPIC arrays (Koelsche et al, 2018a,b). Web-link to classifier: www.molecularsarcomapathology.org. Download figure Download PowerPoint Table 1. Main sarcoma subtypes discussed in this review and their characteristics Sarcoma subtype Abbreviation Main features Bone sarcomas Chondrosarcomaa CHS Localization: Cartilage, bone surface, or centrally in bone Histopathology: Lobules composed of malignant chondrocytes entrapped in a chondroid matrix with calcified foci Identified mutations of IDH1/2, EXT1/2 Ewing sarcomaa EwS Localization: Long and flat bones (˜85%), extraskeletal sites (˜15%) Histopathology: Undifferentiated small round cells; mostly strong membranous CD99 immunoreactivity and PAS-positive cytoplasm Harbor somatic FET-ETS translocations (˜85% EWSR1-FLI1; ˜10% EWSR1-ERG; ˜5% rare subtypes) Osteosarcomaa OS Localization: Bone surface or centrally in bone Histopathology: Neoplastic cells with mesenchymal morphology and frequent polymorphism (epithelioid, fusiform, round, spindled, etc.) associated with an extracellular osteoid matrix Various subtypes including telangiectatic OS characterized by numerous hemorrhagic areas Complex highly aneuploidy karyotypes with multiple chromosomal aberrations (numerical and structural) Frequent TP53 and RB mutations and numerous other mutations defining a "BRCAness" signature Soft Tissue Sarcomas (STSs) Fibrosarcomaa Localization: Deep soft tissues of the extremities, trunk, and head & neck Histopathology: Composed of monomorphic fibroblastic cancer cells in collagenous matrix GastroIntestinal Stromal Tumors GIST Localization: Gastrointestinal track (main site: stomach and small intestine) Histopathology: broad morphological spectrum with mainly spindle cells and epithelioid cells (˜20% of cases) or mixed histology characterized by differentiation toward the interstitial cells of Cajal. Usually immunopositive for CD117 (KIT) and DOG1 Harbor frequent activating mutations in KIT and PDGFRA Leiomyosarcoma LMS Localization: Most commonly detected in the peritoneum and uterus (rarely in bone) Histopathology: Mesenchymal, spindle-shaped cells with smooth muscle differentiation (SMA, desmin and h-Caldesmon positivity) Highly complex karyotypes with genomic instability Liposarcomaa LPS Localization: Variable (most commonly in the retroperitoneal space) Histopathology: Cancer cells with variable adipocytic differentiation and heterogenous morphology embedded in a vascularized stroma (in case of myxoid LPS in myxoid stroma) Rhabdomyosarcoma RMS Localization: Variable Histopathology: Mesenchymal phenotype with variable myogenic differentiation (usually positive for myogenin and MYOD) Undifferentiated pleomorphic sarcomaa UPS Localization: Most frequently in extremities Histopathology: Undifferentiated cancer cells with a high degree of cellular atypia and pleomorphism Synovial sarcoma SS Localization: Mostly in deep soft tissues of the extremities Histopathology: Spindle cells with variable mesenchymal and/or epithelial differentiation (i.e., monophasic/biphasic SS) Harbor specific SS18-SSX1/2/4 fusion oncogenes a The most common bone sarcoma and STS subtypes (WHO Classification of Tumours: Soft Tissue and Bone Tumours, 2020). Among bone sarcomas, osteosarcoma (OS) is the most frequent subtype (Heymann, 2014). OS primarily affects adolescents and young adults, with the first and largest peak of incidence at age ~10–14 years. Coinciding with the pubertal growth spurt, the incidence rate of OS is 4 (3.5–4.6) for the range 0–14 years and 5 (4.6–5.6) for the range of 0–19 years per year per million persons (Ottaviani & Jaffe, 2009). The current standard of care was first introduced in the late 1970s and remains largely unaltered despite numerous efforts to improve outcomes (Rosen et al, 1976). Nowadays, patients with localized disease still face 5-year overall survival rates < 70%, and < 20% of patients who develop metastatic disease or relapse survive > 3 years (Roberts et al, 2019). Ewing sarcoma (EwS) is included in the group of bone sarcomas because it is an aggressive sarcoma of both bone (~85% of cases) and soft tissue (~15% of cases), and because it has an incidence and survival rate similar to OS. The STS subgroup comprises ~70–80% of all sarcomas with > 70 heterogenous histological subtypes (WHO Classification of Tumours: Soft Tissue and Bone Tumours, 2020). Although STSs represent < 1% of all cancers, they have the highest incidence among rare malignancies. Overall, the 5-year survival for STS is estimated at ~57–62% and can vary widely depending on the disease stage and the complex interplay between anatomical site and STS subtype (Lyu et al, 2019). Unfortunately, the epidemiological data on specific STS subtypes are limited and frequently incomplete. National initiatives are ongoing to improve the databases, and they likely will benefit from the use of "big data"
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