Bone sarcomas: ESMO–EURACAN–GENTURIS–ERN PaedCan Clinical Practice Guideline for diagnosis, treatment and follow-up

•This Clinical Practice Guideline provides key recommendations on the management of bone sarcomas.•Recommendations have been agreed following a consensus meeting representatives from ESMO, EURACAN, GENTURIS and ERNPaedCan.•Authorship includes multidisciplinary group experts different institutions countries worldwide. Primary sarcomas (BSs) account for <0.2% malignant neoplasms across all ages.1Gatta G. Capocaccia R. Botta L. et al.Burden centralised treatment in Europe rare tumours: results RARECAREnet-a population-based study.Lancet Oncol. 2017; 18: 1022-1039Abstract Full Text PDF PubMed Scopus (160) Google Scholar The overall incidence rate ranges between 0.8 0.9 cases per 100 000/year, with single BS types having no more than 0.3 incident 000/year. Osteosarcoma Ewing sarcoma (ES) relatively high second decade life, whereas conventional chondrosarcomas are common older age.2de Pinieux Karanian M. Le Loarer F. al.Nationwide connective tissue tumors intermediate malignancy over four years using an expert pathology review network.PLoS One. 2021; 16 (e0246958)Crossref (42) is most (incidence: 0.3/100 000/year). higher adolescents (0.8-1.1/100 000/year at age 15-19 years) but there significant peak seventh eighth decades life.1Gatta Scholar,2de male to female ratio 1.4 : 1. In younger patients, osteosarcomas arise extremities, proportion axial tumour sites increases age. Risk factors occurrence osteosarcoma include previous radiotherapy (RT), Paget disease germline genetic abnormalities associated Li–Fraumeni syndrome, Werner Rothmund–Thomson Bloom syndrome hereditary retinoblastoma.3Fuchs B. Pritchard D.J. Etiology osteosarcoma.Clin Orthop Relat Res. 2002; 397: 40-52Crossref (185) ES round cell (RCS) marked by gene fusion involving member FET family ETS transcription factors. third ∼0.1/100 000/year) occurs frequently children also seen adults. Median diagnosis 15 predominance. primary extremity bones (50%), followed pelvis, ribs vertebrae. Any can potentially be affected, however, soft origin possible, especially adults (30% cases). currently regarded as distinct rarer recently identified entities such RCS EWSR1 non-ETS fusions, CIC-rearranged BCOR alteration.4WHO Classification Tumours Editorial BoardSoft Tissue Bone Tumours.5th ed. IARC Publications, Lyon2020Google Among RCSs EWSR1-NFATC2 commonest, has strong predominance, affects population mainly bone.5Diaz-Perez J.A. Nielsen G.P. Antonescu C. al.EWSR1/FUS-NFATc2 rearranged sarcoma: clinicopathological series 4 literature review.Hum Pathol. 2019; 90: 45-53Crossref (36) mostly tissues bone.6Antonescu C.R. Owosho A.A. Zhang al.Sarcomas CIC-rearrangements pathologic entity aggressive outcome: clinicopathologic molecular study 115 cases.Am J Surg 41: 941-949Crossref (189) alterations, BCOR-CCNB3 variant predominantly paediatric internal tandem duplication described tumours infancy.7Kao Y.C. Sung Y.S. al.BCOR-CCNB3 positive sarcomas: analysis 36 comparison morphologic spectrum clinical behavior other sarcomas.Am 2018; 42: 604-615Crossref (139) Scholar,8Kao al.Recurrent YWHAE-NUTM2B fusions undifferentiated infancy: overlapping features clear kidney.Am 2016; 40: 1009-1020Crossref (122) Conventional chondrosarcoma frequent adulthood ∼0.2/100 000/year), median 30 60 gender predominance.1Gatta Dedifferentiated (DCS), mesenchymal (MCS) clear-cell ultra-rare subtypes, <0.1/100 Extraskeletal myxoid chondrosarcoma, although originally thought cartilaginous neoplasm, does not show cartilage differentiation classified uncertain differentiation. This covered European Society Medical Oncology-European Reference Network Rare Adult Solid Cancers-European Genetic Tumour Syndromes (ESMO-EURACAN-GENTURIS) (CPG) (STSs).9Gronchi A. Miah A.B. Dei Tos A.P. al.Soft visceral ESMO-EURACAN-GENTURIS Guidelines diagnosis, follow-up.Ann 32: 1348-1365Abstract (73) chordomas even BS, approximately 0.08/100 years. There slight poorly differentiated subtypes.1Gatta Scholar,10Frezza A.M. Trama al.Chordoma: update disease, epidemiology, biology medical therapies.Curr Opin 31: 114-120Crossref Giant (GCTB) locally aggressive, rarely metastasising represents 5% tumours, ∼1/1 000 000/year.1Gatta High-grade spindle/pleomorphic heterogeneous that do fulfil histological criteria osteosarcoma, or ES.11Sbaraglia Righi Gambarotti presenting bone; diagnostic pitfalls.Surg Pathol Clin. 10: 705-730Abstract (16) A general strategy shown Figure presence persistent often progressive non-mechanical pain, night, should prompt radiological assessment. Swelling functional impairment present if progressed through cortex distended periosteum, these later signs. differential diagnoses osteomyelitis, benign metastases, which outnumber BS. strongly oriented patient For patients <5 old, destructive lesion could interpreted either metastatic neuroblastoma Langerhans histiocytosis. aged ≥5 years, likelihood higher. After 40 age, metastases myeloma will diagnoses. radiography two planes first investigation. When cannot definitely excluded radiographs, magnetic resonance imaging (MRI) whole compartment adjacent joints carried out. MRI best modality local staging spine pelvis. Computed tomography (CT) may provide additional information involvement (presence calcification, periosteal formation cortical destruction) chosen preferred sites. All suspected basis referred reference centre institution belonging network.12Blay J.Y. Soibinet P. Penel N. al.Improved survival specialized board patients.Ann 28: 2852-2859Abstract (146) Children centres that, addition, age-specific expertise. biopsy out surgical team who carry definitive resection dedicated interventional radiologist after discussing surgeon.12Blay those whose pathological was obtained outside network, mandatory. core-needle biopsy, taken under guidance, appropriate alternative open biopsy. Contamination surrounding minimised, adequate multiple sampling representative areas must always provided. If required, longitudinal incision. tract channels drains placed considered contaminated removed, together specimen, effort minimise risk recurrence (LR). Therefore, tracts clearly ensure location recognised time procedure. case spinal column involvement, laminectomy decompression avoided unless necessary relieve cord compression, whenever suspected. Histology specimens experienced pathologist, collaboration radiologist, discussed (MDT). With increasing capability accurate samples quickly submitted assessment.13Bovee J.A.F. Baumhoer D. Bloem J.L. al.Primary histopathology reporting guide specimens. International Collaboration Cancer Reporting; Sydney, Australia.http://www.iccr-cancer.org/datasets/published-datasets/soft-tissue-boneDate: 2021Google collection fresh snap-frozen encouraged overcome damage nucleic acids resulting decalcification, allow subsequent nature specimen received recorded (i.e. needle curettage excision). It usually decalcify EDTA acid-based methods; latter, frozen essential diagnostics. type diagnosed according recent version World Health Organization (WHO) classification (2020).4WHO important note histotype determines grade, few exceptions.4WHO ancillary investigations (e.g. immunohistochemistry assessments) accurately relevant. Examples translocation detection MCS, isocitrate dehydrogenase (IDH1 IDH2) mutations MDM2 amplification parosteal intramedullary low-grade osteosarcoma. At tumour, specimens, size resected (at least maximal diameter, preferably three-dimensional measurement, mm). report describe extent spread, including specific anatomical compartments. whether margins (R0) microscopically (R1) macroscopically (R2) involved. negative margins, distance (in mm) nearest margin well closest osteotomy measured. complete, slab its largest dimension axis guided images, embedded microscopy grid manner. relevant neoadjuvant chemotherapy (ChT) assess response. percentage viable tumour/percentage response (including necrosis, fibrosis calcification) documented, this prognostic value, cut-off value 10% cells ≥90% used indicate good response.14Picci Bacci Campanacci al.Histologic evaluation necrosis induced chemotherapy. Regional mapping nonviable tumor.Cancer. 1985; 56: 1515-1521Crossref (205) ES, less defined. Recent studies suggest 100% optimal define ES.15Albergo J.I. Gaston C.L. Laitinen al.Ewing's only response.Bone Joint J. 98-B: 1138-1144Crossref Earlier reports, 90% calcification.16Akerman prognosis Ewing's sarcoma.Acta Scand Suppl. 1997; 273: 130-132Crossref Scholar,17Righi Pacheco Palmerini E. al.Histological localized bone: retrospective available scoring tools.Eur 47: 1778-1783Abstract (2) •The initial work-up centre, history, physical examination, assessment [IV, B].•Pathological made pathologist 2020 WHO supported A].•For site, status preoperative ChT [V, B]. Several systems use, unifying system accepted standard.18Enneking W.F. Spanier S.S. Goodman M.A. musculoskeletal sarcoma.Clin 1980; 153: 106-120Crossref (1780) Scholar, 19American Committee CancerAJCC Staging Manual.8th American Cancer, New York2017Google 20Brierley J.D. Gospodarowicz M.K. Wittekind TNM Malignant Tumours. 8th John Wiley & Sons, Oxford2016Google burden detectable main into consideration diseases. General distant scintigraphy chest CT. Whole-body (WB)-MRI [18F]2-fluoro-2-deoxy-d-glucose (FDG)–positron emission (PET)-CT PET-MRI increasingly utilised marrow skip lesions). Additional biopsies suspicious No laboratory tests routinely available. Baseline serum alkaline phosphatase (AP) lactate (LDH) given their proven use monitoring during treatment. Prognostic presentation; fracture lead dissemination increase recurrence, result renal, cardiac auditory dysfunction. Before starting therapy, baseline renal function testing, audiogram platinum derivatives) Sperm storage recommended reproductive consultation fertility physician about potential ovarian sampling, cryopreservation, gonadotrophin-releasing hormone agonists means suppression preservation considered, where still, limited scientific knowledge gonadotoxic effects variability health care policies nations. guidance TP53 testing provided Supplementary Material Table S1, https://doi.org/10.1016/j.annonc.2021.08.1995. •General CT, and/or WB-MRI FDG–PET-CT/MRI clinically indicated. AP LDH levels [III, Given rarity complexity management, standard within networks able access full expertise A]. centres/networks, therapy framework prospective, collaborative, established protocols. S2, https://doi.org/10.1016/j.annonc.2021.08.1995 lists systemic agents preliminary partial evidence activity BSs; they entered practice approved/reimbursed countries. Thus, available, depending context individualised patient–physician shared decisions. principles summarised 2. arises metaphysis long bone, commonly around knee, adolescents.2de Involvement skeleton craniofacial primarily observed adult patients. develop lung being site bones. based morphological findings, high-grade. Periosteal intermediate-grade chondroblastic. Low-grade central malignancies, arising surface, respectively. These malignancies sometimes high-grade components.21Ruengwanichayakun Frisoni T. al.Parosteal osteosarcoma: monocentric 195 patients.Hum 91: 11-18Crossref (13) component, helped amplification, >85% cases.22Duhamel L.A. Ye H. Halai al.Frequency Mouse Double Minute 2 (MDM2) (MDM4) subtypes.Histopathology. 2012; 60: 357-359Crossref (51) Adverse proximal large volume, elevated B].23Smeland S. Bielack Whelan al.Survival outcomes 2000 EURAMOS-1 (European Study) cohort.Eur Cancer. 109: 36-50Abstract (198) Curative consists surgery [II, Compared alone, multimodality high-grade, localised disease-free (DFS) probability <20% >60%. general, administered before surgery, giving improves survival, administered. allows ChT, predicts survival.23Smeland Surgery familiar wide range reconstructions. Paediatric adolescent need treated surgeons experience field reconstruction challenges, growing Most candidates limb salvage. R1 R2 both LR rate, reduced (OS). goal Areas suspicion close sent pathology. fracture, fixation contraindicated it disseminates further LR. External splintage recommended. Pathological necessarily require amputation. expectation haematoma contract involved tissues. Doxorubicin, cisplatin, high-dose methotrexate (HD-MTX) ifosfamide antitumour [I, A].24Marina N.M. Smeland al.Comparison MAPIE versus MAP poor newly (EURAMOS-1): open-label, international, randomised controlled trial.Lancet 17: 1396-1408Abstract (252) 25Whelan J.S. Marina al.EURAMOS-1, international pre-randomisation treatment.Ann 2015; 26: 407-414Abstract (176) 26Ferrari Mercuri al.Neoadjuvant Ifosfamide, methotrexate, doxorubicin extremity: joint Italian Scandinavian Sarcoma Groups.J Clin 2005; 23: 8845-8852Crossref (359) 27Bajpai Chandrasekharan Talreja V. al.Outcomes non-metastatic naive novel non-high dosemethotrexate-based, dose-dense combination regimen ‘OGS-12’.Eur 85: 49-58Abstract (26) doxorubicin/cisplatin/HD-MTX (MAP) front-line young patients;24Marina HD-MTX challenging administer adults.27Bajpai Scholar,28Piperno-Neumann Ray-Coquard I. Occean B.V. al.Results API-AI included French OS2006/Sarcome-09 study.Int 2020; 146: 413-423Crossref (10) >40 MTX (8 g/m2) non-MTX induction proved feasible, regimens combining doxorubicin, cisplatin alternative.24Marina Scholar,29Ferrari al.EURO-B.O.S.S.: bone-sarcoma outcome osteosarcoma.Tumori. 104: 30-36Crossref current protocols period facilitate response, support change alone.24Marina