Abstract

Primary bone tumours are rare, accounting for 25 years old, ES has an incidence of 0.3 per 100 000 per year [1.Stiller C.A. Trama A. Serraino D. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.Eur J Cancer. 2013; 49: 684-695Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 2.Whelan J. McTiernan A. Cooper N. et al.Incidence and survival of malignant bone sarcomas in England 1979-2007.Int J Cancer. 2012; 131: E508-E517Crossref PubMed Scopus (0) Google Scholar, 3.Valery P.C. Laversanne M. Bray F. Bone cancer incidence by morphological subtype: a global assessment.Cancer Causes Control. 2015; 26: 1127-1139Crossref PubMed Scopus (32) Google Scholar, 4.Van den Berg H. Kroon H.M. Slaar A. Hogendoorn P. Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration “PALGA”.J Pediatr Orthop. 2008; 28: 29-35Crossref PubMed Scopus (0) Google Scholar], and it is even rarer in the African and Asian population. The genetic basis for the difference between ethnical groups has been recently linked to a common genomic germline variant, which extends a microsatellite, thereby facilitating the binding of the EWSR1–FLI1 chimeric protein to the EGR2 gene locus, leading to higher expression of the transcription factor early growth response 2 (EGR2) and increased susceptibility to ES [7.Grünewald T.G. Bernard V. Gilardi-Hebenstreit P. et al.Chimeric EWSR1–FLI1 regulates the Ewing sarcoma susceptibility gene EGR2 via a GGAA microsatellite.Nat Genet. 2015; 47: 1073-1078Crossref PubMed Scopus (0) Google Scholar]. The most common ES primary sites are the extremity bones (50% of all cases), followed by pelvis, ribs and vertebra. However, any bone can potentially be affected and a soft tissue origin is also possible, especially in adults (30% of cases). Chordomas are even rarer compared with other subtypes, with an incidence of ∼ 0.5 per million per year [1.Stiller C.A. Trama A. Serraino D. Descriptive epidemiology of sarcomas in Europe: report from the RARECARE project.Eur J Cancer. 2013; 49: 684-695Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar, 2.Whelan J. McTiernan A. Cooper N. et al.Incidence and survival of malignant bone sarcomas in England 1979-2007.Int J Cancer. 2012; 131: E508-E517Crossref PubMed Scopus (0) Google Scholar, 3.Valery P.C. Laversanne M. Bray F. Bone cancer incidence by morphological subtype: a global assessment.Cancer Causes Control. 2015; 26: 1127-1139Crossref PubMed Scopus (32) Google Scholar, 4.Van den Berg H. Kroon H.M. Slaar A. Hogendoorn P. Incidence of biopsy-proven bone tumors in children: a report based on the Dutch pathology registration “PALGA”.J Pediatr Orthop. 2008; 28: 29-35Crossref PubMed Scopus (0) Google Scholar]. High-grade spindle/pleomorphic sarcomas of bone are a heterogeneous group of primary malignant bone tumours that do not fulfil the histological criteria for a diagnosis of OS, CS or ES [8.Pakos E.E. Grimer R.J. Peake D. et al.The ‘other’ bone sarcomas: prognostic factors and outcomes of spindle cell sarcomas of bone.J Bone Joint Surg Br. 2011; 93: 1271-1278Crossref PubMed Scopus (9) Google Scholar]. Giant cell tumour (GCT) of bone is a benign, locally aggressive and rarely metastatic intramedullary bone tumour composed of mononuclear cells and osteoclast-like multinucleated giant cells, with a variable and unpredictable potential for aggressive growth. It represents ∼ 5% of primary bone tumours, with an incidence of approximately 1 per million per year [9.Liede A. Bach B.A. Stryker S. et al.Regional variation and challenges in estimating the incidence of giant cell tumor of bone.J Bone Joint Surg Am. 2014; 96: 1999-2007Crossref PubMed Scopus (0) Google Scholar]. A general diagnostic strategy for bone sarcomas is shown in Figure 1. The medical history should focus on characteristic symptoms such as duration, intensity and timing of pain. The presence of persistent non-mechanical bone pain, predominantly at night, should prompt a radiological assessment. Swelling and functional impairment can be present if the tumour has progressed through the cortex and distended the periosteum, but they are often later signs. The differential diagnosis of a bone sarcoma includes osteomyelitis, benign tumours and bone metastases, all of which outnumber primary bone sarcomas [10.Hauben E.I. Hogendoorn PCW. Epidemiology of primary bone tumors and economical aspects of bone metastases.in: Heymann D. Bone Cancer. Progression and Therapeutic Approaches. 1. Academic Press, London2009: 3-8Google Scholar, 11.Malhas A.M. Grimer R.J. Abudu A. et al.The final diagnosis in patients with a suspected primary malignancy of bone.J Bone Joint Surg Br. 2011; 93: 980-983Crossref PubMed Scopus (6) Google Scholar, 12.Grimer R.J. Briggs T.W. Earlier diagnosis of bone and soft-tissue tumours.J Bone Joint Surg Br. 2010; 92: 1489-1492Crossref PubMed Scopus (46) Google Scholar]. The diagnosis can be strongly oriented by patient age. For patients 60%. In general, ChT is administered before and after surgery, although a formal proof that giving ChT preoperatively improves survival is lacking. The extent of histological response to preoperative ChT predicts survival [25.Bramer J.A. van Linge J.H. Grimer R.J. Scholten R.J. Prognostic factors in localized extremity osteosarcoma: a systematic review.Eur J Surg Oncol. 2009; 35: 1030-1036Abstract Full Text Full Text PDF PubMed Scopus (123) Google Scholar, 26.Bielack S.S. Kempf-Bielack B. Delling G. et al.Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols.J Clin Oncol. 2002; 20: 776-790Crossref PubMed Scopus (1491) Google Scholar, 27.Picci P. Sangiorgi L. Rougraff B.T. et al.Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma.J Clin Oncol. 1994; 12: 2699-2705Crossref PubMed Google Scholar]. Low-grade parosteal OSs are malignancies with a lower metastatic potential and should be treated by surgery alone [IV, B]. Although ChT has been used for periosteal OSs, no benefit for ChT was shown in retrospective analyses [28.Grimer R.J. Bielack S. Flege S. et al.Periosteal osteosarcoma—a European review of outcome.Eur J Cancer. 2005; 41: 2806-2811Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 29.Cesari M. Alberghini M. Vanel D. et al.Periosteal osteosarcoma: a single-institution experience.Cancer. 2011; 117: 1731-1735Crossref PubMed Scopus (0) Google Scholar, 30.Laitinen M. Parry M. Albergo J.I. et al.The prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma.Bone Joint J. 2015; 97-B: 1698-1703Crossref PubMed Scopus (10) Google Scholar], and its use is not routinely recommended in this setting [IV, D]. Surgery should be carried out by a surgical team familiar with the wide range of surgical reconstructive options. Paediatric and adolescent patients need to be treated by surgeons with great experience in the field of paediatric bone tumours, including age-specific reconstruction challenges, such as the reconstruction of growing bones. The goal of surgery is to safely remove the tumour and yet preserve as much function as possible, striving to obtain microscopically clear surgical margins [27.Picci P. Sangiorgi L. Rougraff B.T. et al.Relationship of chemotherapy-induced necrosis and surgical margins to local recurrence in osteosarcoma.J Clin Oncol. 1994; 12: 2699-2705Crossref PubMed Google Scholar]. Most patients should be considered candidates for limb salvage. Either intralesional or marginal margins increase the local relapse rate, which is associated with reduced overall survival. Thus, clear margins are the first goal of surgery [III, B]. Areas where there is suspicion of close margins should be marked on the surgical specimen sent to pathology. Pathological fracture does not necessarily necessitate an amputation. In chemosensitive tumours, primary neoadjuvant ChT can be used with the expectation that it will allow the fracture haematoma to contract and allow subsequent resection of the tumour and the involved soft tissues [31.Bramer J.A. Abudu A.A. Grimer R.J. et al.Do pathological fractures influence survival and local recurrence rate in bony sarcomas?.Eur J Cancer. 2007; 43: 1944-1951Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar]. Doxorubicin, cisplatin, high-dose methotrexate (HD-MTX) and ifosfamide have antitumour activity in OS [I, A] [32.Ferrari S. Smeland S. Mercuri M. et al.Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups.J Clin Oncol. 2005; 23: 8845-8852Crossref PubMed Scopus (336) Google Scholar, 33.Whelan J.S. Davis L.E. Osteosarcoma, chondrosarcoma, and chordoma.J Clin Oncol. 2018; 36: 188-193Crossref PubMed Scopus (106) Google Scholar, 34.Bielack S.S. Smeland S. Whelan J.S. et al.Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative map: first results of the EURAMOS-1 good response randomized controlled trial..J Clin Oncol. 2015; 33: 2279-2287Crossref PubMed Scopus (0) Google Scholar, 35.Whelan J.S. Bielack S.S. Marina N. et al.EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.Ann Oncol. 2015; 26: 407-414Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar]. The MAP (doxorubicin/cisplatin/HD-MTX) regimen is most frequently used as the basis of treatment in children and young adult patients [30.Laitinen M. Parry M. Albergo J.I. et al.The prognostic and therapeutic factors which influence the oncological outcome of parosteal osteosarcoma.Bone Joint J. 2015; 97-B: 1698-1703Crossref PubMed Scopus (10) Google Scholar]; however, HD-MTX can be difficult to manage in adults. In patients aged > 40, regimens combining doxorubicin, cisplatin and ifosfamide without HD-MTX can also be used in these patients [III, B] [33.Whelan J.S. Davis L.E. Osteosarcoma, chondrosarcoma, and chordoma.J Clin Oncol. 2018; 36: 188-193Crossref PubMed Scopus (106) Google Scholar, 34.Bielack S.S. Smeland S. Whelan J.S. et al.Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative map: first results of the EURAMOS-1 good response randomized controlled trial..J Clin Oncol. 2015; 33: 2279-2287Crossref PubMed Scopus (0) Google Scholar, 35.Whelan J.S. Bielack S.S. Marina N. et al.EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.Ann Oncol. 2015; 26: 407-414Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar, 36.Marina N.M. Smeland S. Bi