Primary Bone Cancers: Latest Trends in Pathogenesis, Diagnosis and Management


  • Nursuffi Rathiyah binti Mohd Hizam International Medical School, Management and Science University (MSU), University Drive, Off Persiaran Olahraga, 40100 Shah Alam, Selangor, Malaysia
  • Kaswinna Malar A/P Ananthan International Medical School, Management and Science University (MSU), University Drive, Off Persiaran Olahraga, 40100 Shah Alam, Selangor, Malaysia
  • Nur Zahrin Syahirah binti Raman International Medical School, Management and Science University (MSU), University Drive, Off Persiaran Olahraga, 40100 Shah Alam, Selangor, Malaysia
  • Kishore Gopal Banerjee Corresponding author: Senior Lecturer, Department of Pathology, International Medical School, Management & Science University, 40100 Shah Alam, Selangor, Malaysia


Primary bone tumour, osteosarcoma, Ewing sarcoma, chondrosarcoma, pathogenesis, treatment, diagnosis


Primary bone tumours arising from the bony tissue are further classified into three groups; bone-producing, cartilage-producing, and tumours of unknown origin. In this review article, we have analyzed the latest trends in the pathogenesis, diagnosis, and management of the key primary malignant tumours (osteosarcoma, chondrosarcoma, and Ewing sarcoma) of bony origin. The Hippo-Yap signaling pathway is a newly discovered pathogenesis for osteosarcoma, and the inhibition contributes to the treatment of the malignancy. Moreover, carbon-ion particle therapy is proven to be a remedy for radioresistant tumours. The advancement of diagnosis methods for osteosarcoma is hastened with the identification of biomarker microRNA, liquid biopsy, and ‘Omic’ technology. Chondrosarcoma has a different and tailored approach to manage patients. Due to the unknown pathogenesis, treatments are being considered holistically depending on the patients’ age, overall health, medical history, type and stages of chondrosarcoma, the severity of the carcinoma, and patients' preference or opinion on the treatment plans. It has no specific treatment, and the ideal goal is to remove the mass and reduce the likelihood of relapse.  Lastly, for Ewing sarcoma, there is a variety of new targeted therapy such as Lysine-specific demethylase-1(LSD-1), PRKCB, Poly(ADP-Ribose)polymerase1 inhibitors(PARBP1)  have been developed to treat recurrent ES, and a large dose of chemotherapy with autologous hematopoietic stem cell has been identified to cause toxicity in Ewing sarcoma. The origin of Ewing sarcoma remained unknown, but the rearrangement of the gene is thought to be the cause of tumorigenesis of Ewing sarcoma.


. S. Xin and G. Wei, “Prognostic factors in osteosarcoma: A study level meta-analysis and systematic review of current practice,” J. Bone Oncol., vol. 21, Apr. 2020, doi: 10.1016/j.jbo.2020.100281.

. B. R. Eaton et al., “Osteosarcoma,” Pediatr. Blood Cancer, no. January, pp. 1–7, 2020, doi: 10.1002/pbc.28352.

. D. A. Müller and U. Silvan, “On the biomechanical properties of osteosarcoma cells and their environment,” Int. J. Dev. Biol., vol. 63, no. 1–2, pp. 1–8, 2019, doi: 10.1387/ijdb.190019us.

. M. Mustafa, H. M. Iftikhar, E. M. IIIzam, M. K. Nang, and A. M. Sharifa, “Osteosarcoma: Current treatment trends and outcome,” no. November, 2018, doi: 10.9790/0853-1711023238.

. M. S. Isakoff, S. S. Bielack, P. Meltzer, and R. Gorlick, “Osteosarcoma: Current treatment and a collaborative pathway to success,” J. Clin. Oncol., vol. 33, no. 27, pp. 3029–3035, 2015, doi: 10.1200/JCO.2014.59.4895.

. G. Calaminus et al., “Quality of life of patients with osteosarcoma in the european american osteosarcoma study-1 (EURAMOS-1): Development and implementation of a questionnaire substudy,” JMIR Res. Protoc., vol. 8, no. 9, pp. 1–16, 2019, doi: 10.2196/14406.

. C. C. Wu and J. A. Livingston, “Genomics and the immune landscape of osteosarcoma,” Adv. Exp. Med. Biol., vol. 1258, pp. 21–36, 2020, doi: 10.1007/978-3-030-43085-6_2.

. R. A. Durfee, M. Mohammed, and H. H. Luu, “Review of Osteosarcoma and Current Management,” Rheumatol. Ther., vol. 3, no. 2, pp. 221–243, 2016, doi: 10.1007/s40744-016-0046-y.

. I. Lilienthal and N. Herold, “Targeting molecular mechanisms underlying treatment efficacy and resistance in osteosarcoma: A review of current and future strategies,” Int. J. Mol. Sci., vol. 21, no. 18, pp. 1–56, 2020, doi: 10.3390/ijms21186885

. M. H. Osteosarcoma, “MicroRNA-Based Diagnosis and Treatment of,” pp. 1–14, 2019.

. S. Morice, G. Danieau, F. Rédini, B. Brounais-Le-royer, and F. Verrecchia, “Hippo/yap signaling pathway: A promising therapeutic target in bone paediatric cancers?,” Cancers (Basel)., vol. 12, no. 3, 2020, doi: 10.3390/cancers12030645.

. I. Corre, F. Verrecchia, V. Crenn, F. Redini, and V. Trichet, “The Osteosarcoma Microenvironment: A Complex But Targetable Ecosystem,” Cells, vol. 9, no. 4, pp. 1–25, 2020, doi: 10.3390/cells9040976.

. P. F. M. Choong, M. L. Broadhead, J. C. M. Clark, D. E. Myers, and C. R. Dass, “The molecular pathogenesis of osteosarcoma: A review,” Sarcoma, vol. 2011, 2011, doi: 10.1155/2011/959248.

. S. Gambera et al., “Role of Activator Protein-1 Complex on the Phenotype of Human Osteosarcomas Generated from Mesenchymal Stem Cells,” Stem Cells, vol. 36, no. 10, pp. 1487–1500, 2018, doi: 10.1002/stem.2869.

. Y. sheng Li, Q. Liu, J. Tian, H. bo He, and W. Luo, “Angiogenesis Process in Osteosarcoma: An Updated Perspective of Pathophysiology and Therapeutics,” Am. J. Med. Sci., vol. 357, no. 4, pp. 280–288, 2019, doi: 10.1016/j.amjms.2018.12.004.

. M. Cheng et al., “Growth hormone receptor promotes osteosarcoma cell growth and metastases,” FEBS Open Bio, vol. 10, no. 1, pp. 127–134, 2020, doi: 10.1002/2211-

. J. W. V. de Azevedo et al., “Biology and pathogenesis of human osteosarcoma (Review),” Oncol. Lett., vol. 19, no. 2, pp. 1099–1116, 2020, doi: 10.3892/ol.2019.11229.

. J. Zhang, X. H. Yu, Y. G. Yan, C. Wang, and W. J. Wang, “PI3K/Akt signaling in osteosarcoma,” Clin. Chim. Acta, vol. 444, pp. 182–192, 2015, doi: 10.1016/j.cca.2014.12.041.

. E. Tirtei, M. Cereda, E. De Luna, P. Quarello, S. D. Asaftei, and F. Fagioli, “Omic approaches to pediatric bone sarcomas,” Pediatr. Blood Cancer, vol. 67, no. 2, pp. 1–7, 2020, doi: 10.1002/pbc.28072.

. J. R. Barnett, P. Gikas, C. Gerrand, T. W. Briggs, and A. Saifuddin, “The sensitivity, specificity, and diagnostic accuracy of whole-bone MRI for identifying skip metastases in appendicular osteosarcoma and Ewing sarcoma,” Skeletal Radiol., vol. 49, no. 6, pp. 913–919, 2020, doi: 10.1007/s00256-019-03364-0.

. A. Kamal and R. Prasetyo, “Association between laboratory markers and oncological outcomes in patients with osteosarcoma-A review of osteosarcoma treatment in Indonesia,” Formos. J. Surg., vol. 51, no. 3, pp. 111–117, 2018, doi: 10.4103/fjs.fjs_140_17.

. S. Zhang et al., “miR-766-3p Targeting BCL9L Suppressed Tumorigenesis, Epithelial-Mesenchymal Transition, and Metastasis Through the β-Catenin Signaling Pathway in Osteosarcoma Cells,” Front. Cell Dev. Biol., vol. 8, no. October, pp. 1–15, 2020, doi: 10.3389/fcell.2020.594135.

. A. Misaghi, A. Goldin, M. Awad, and A. A. Kulidjian, “Osteosarcoma : a comprehensive review,” 2018.

. M. F. Wedekind, L. M. Wagner, and T. P. Cripe, “Immunotherapy for osteosarcoma: Where do we go from here?,” Pediatr. Blood Cancer, vol. 65, no. 9, pp. 1–9, 2018, doi: 10.1002/pbc.27227.

. Y. Yang et al., “Advances in limb salvage treatment of osteosarcoma,” J. Bone Oncol., vol. 10, no. November 2017, pp. 36–40, 2018, doi: 10.1016/j.jbo.2017.11.005.

. V. Subbiah et al., “Alpha particle radium 223 dichloride in high-risk osteosarcoma: A phase i dose escalation trial,” Clin. Cancer Res., vol. 25, no. 13, pp. 3802–3810, 2019, doi: 10.1158/1078-0432.CCR-18-3964.

. P. M. Anderson et al., “223-Radium for metastatic osteosarcoma: Combination therapy with other agents and external beam radiotherapy,” ESMO Open, vol. 5, no. 2, pp. 1–10, 2020, doi: 10.1136/esmoopen-2019-000635.

. P. M. Anderson, V. Subbiah, and E. Rohren, “Bone-seeking radiopharmaceuticals as targeted agents of osteosarcoma: Samarium-153- EDTMP and Radium-223,” Adv. Exp. Med. Biol., vol. 804, pp. 291–304, 2014, doi: 10.1007/978-3-319-04843-7_16.

. Warren A ChowDepartment of Medical Oncology & Therapeutics Research, City of Hope, 1500 E. Duarte Rd, Duarte, CA, 91010, USA,Version Chondrosarcoma: biology, genetics, and epigenetics, 2018; 1826.

. Faten Limalem, Donald Davis, Kristin Sticco, Chondrosarcoma CME, PubMed- chondrosarcoma,2020,19483.

. Zhan Wang, Genlian Chen, Xiaowei Chen, Xin Huang, Meng Liu, Weibo Pan, Xiaobo Yan, Nong Lin, and Zhaoming Ye, Predictors of the survival of patients with chondrosarcoma of bone and metastatic disease at diagnosis J Cancer. 2019; 10(11): 2457–2463.

. Julian Fromm, Alexander Klein, Andrea Baur-Melnyk, Thomas Knösel, Lars Lindner, Christof Birkenmaier, Falk Roeder, Volkmar Jansson & Hans Roland Dürr, Survival and prognostic factors in conventional central chondrosarcoma, 2018, 849

. JASON L. FERGUSON,SEAN P. TURNER, Bone Cancer: Diagnosis and Treatment Principles,2018 Aug 15;98(4):205-213.

. Jie Xu, Dasen Li, Lu Xie, Shun Tang, Wei Guo, Mesenchymal Chondrosarcoma of Bone and Soft Tissue: A Systematic Review of 107 Patients in the Past 20 Years, 2015 April 7, 10(4).

. Jack E. Pullan; Deepa P. Budh, Primary Bone Cancer, July 2020, SatPear 202.

. Meera Hameed MD, Howard Dorfman MD, Recent Development on Primary Malignant Bone Tumours, Volume 28, Issue 1, February 2011, Pages 86-101

. Annemiek M van Maldegem, Judith VMG Bovée, Hans Gelderblom, Comprehensive analysis of published studies involving systemic treatment for chondrosarcoma of bone between 2000 and 2013, 2014, 4-11.

. Aggerholm-Pedersen N, Maretty-Nielsen K, Baerentzen S, Jørgensen PH, Hansen BH, Baad-Hansen T, Keller J, Safwat A, Chondrosarcoma: the impact of comorbidity – 30 years of experience from a population-based database including 199 consecutive chondrosarcoma patients, 3 September 2019 ,Volume 2019:11 Pages 109—116.

. Anthony A. Catanzano,David L. Kerr, Alexander L. Lazarides, Brian L. Dial, Whitney O. Lane, Dan G. Blazer, Nicole A. Larrier, David G. Kirsch, Brian E, Brigman, William C. Eward, Revisiting the Role of Radiation Therapy in Chondrosarcoma: A National Cancer Database Study, 2019, Open Access-Volume 2019-Article ID 4878512

. Iona J MacDonald, Chih-Yang Lin, Shu-Jui Kuo,Chen-Ming Su ,Chih-Hsin Tang, An update on current and future treatment options for chondrosarcoma, 2019,773-786.

. Abbas, Kiran, Siddiqui, Amber T, Evaluation of different treatment and management options for chondrosarcoma; the prognostic factors determining the outcome of the disease, 2018, 3- 58.

. Johnathan R. Lex, Scott Evans, Jonathan D. Stevenson, Michael Parry, Lee M. Jeys & Robert J. Grimer , Dedifferentiated chondrosarcoma of the pelvis: clinical outcomes and current treatment, 2018, 23

. Dhinsa B.S., DeLisa M, Pollock R, Flanagan A.M, Whelan J.· Gregory J., Dedifferentiated Chondrosarcoma Demonstrating Osteosarcomatous Differentiation, 2018, 456-460.

. Rémy Nicolle, Mira Ayadi, Anne Gomez-Brouchet, Lucile Armenoult, Guillaume Banneau, Nabila Elarouci, Matthias Tallegas, Anne-Valérie Decouvelaere, Sébastien Aubert, Françoise Rédini, Béatrice Marie, Corinne Labit-Bouvier, Nicolas Reina, Marie Karanian, Louis-Romée le Nail, Philippe Anract, François Gouin, Frédérique Larousserie, Aurélien de Reyniès ,Gonzague de Pinieux, Integrated molecular characterization of chondrosarcoma reveals critical determinants of disease progression, 2019, 4622.

. Jeremy S. Whelan and Lara E. Davis, Osteosarcoma, Chondrosarcoma, and Chordoma, 2017, 36-2.

. AJ Gelderblom, MD, PhDJudith VMG Bovée, MD, PhD, Chondrosarcoma, 2020, UpToDate.

. Arthur G G C Kortena, Hans J W ter Berga, Geert H Spincemailleb, Ronald T van der Laana, Antoinet M Van de Welc, Intracranial chondrosarcoma: review of the literature and report of 15 cases, 2020, 163-175.

. Mi-Jung Kim, Kyung-Ja Cho, Alberto G. Ayala, and Jae Y. Ro, Chondrosarcoma: With Updates on Molecular Genetics, 2011, 18

. C. Michael Gibson, Rohan A. Bhimani,Chondrosarcoma pathophysiology, 2019, case study 1

. Aggerholm Pedersen N, Maretty-Nielsen K, Baerentzen S, Jorgensen PH, Hansen BH, Baad-Hansen T, Keller J, Safwat A,Chondrosarcoma: the impact of comorbidity-30 years of experience from a population-based database including 199 consecutive chondrosarcoma patents,2019,109-116.

. Rani P, Shyamala K, Girish H et al ‘Journal of Advanced Clinical & Research Insights (2015) 2 164-168 DOI: 10.15713/ins.jcri.70

. Gaspar, N., Hawkins, D. S., Dirksen, U., Lewis, I. J., Ferrari, S., Le Deley, M. C., Kovar, H., Grimer, R., Whelan, J., Claude, L., Delattre, O., Paulussen, M., Picci, P., Sundby Hall, K., van den Berg, H., Ladenstein, R., Michon, J., Hjorth, L., Judson, I., Luksch, R., … Oberlin, O. (2015). Ewing Sarcoma: Current Management and Future Approaches Through Collaboration. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 33(27), 3036–3046.

. . Brown, H. K., Schiavone, K., Gouin, F., Heymann, M. F., & Heymann, D. (2018). Biology of Bone Sarcomas and New Therapeutic Developments. Calcified tissue international, 102(2), 174–195.

. Bernstein, M., Kovar, H., Paulussen, M., Randall, R. L., Schuck, A., Teot, L. A., & Juergensg, H. (2006). Ewing’s Sarcoma Family of Tumors: Current Management. The Oncologist, 11(5), 503–519.

. Ozaki, T. (2015). Diagnosis and treatment of Ewing sarcoma of the bone: a review article. Journal of Orthopaedic Science, 20(2), 250–263.

. Burchill, S. A. (2003, February 1). Ewing’s sarcoma: Diagnostic, prognostic, and therapeutic implications of molecular abnormalities. Journal of Clinical Pathology.

. Vohar, V. (2008). Ewing’s tumour, a report on 27 cases. Indian Journal of Radiology and Imaging, 18(2), 106–112.

. Dubois, S. G. (2018). Ewing sarcoma. In The 5-Minute Pediatric Consult, 8th Edition (pp. 346–347). Wolters Kluwer Health.

. Lessnick, S. L., & Ladanyi, M. (2012). Molecular pathogenesis of Ewing sarcoma: New therapeutic and transcriptional targets. Annual Review of Pathology: Mechanisms of Disease.

. Juergens, C., Weston, C., Lewis, I., Whelan, J., Paulussen, M., Oberlin, O., … Craft, A. (2006). Safety assessment of intensive induction with vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) in the treatment of ewing tumors in the EURO-E.W.I.N.G. 99 Clinical Trial. Pediatric Blood and Cancer, 47(1), 22–29.

. Bilodeau, L., Prof, A., & Gaillard, F. (n.d.). Ewing sarcoma Radiographic features Related Radiopaedia articles Bone tumours Cases and figures, 22–23.

. Mackintosh, C., Madoz-Gúrpide, J., Ordóñez, J. L., Osuna, D., & Herrero-Martín, D. (2010, May 1). The molecular pathogenesis of Ewing’s sarcoma. Cancer Biology and Therapy.

. Thaler, M., & Khosravi, I. (2020, June 1). Therapy management in bone sarcoma. Memo - Magazine of European Medical Oncology. Springer Medizin.

. Hosseini, A., Mirzaei, A., Salimi, V., Jamshidi, K., Babaheidarian, P., Fallah, S., … Tavakoli-Yaraki, M. (2020). The local and circulating SOX9 as a potential biomarker for the diagnosis of primary bone cancer. Journal of Bone Oncology, 23.

. Khanna, N., Pandey, A., & Bajpai, J. (2017). Metastatic Ewing's Sarcoma: Revisiting the "Evidence on the Fence". Indian journal of medical and paediatric oncology : official journal of Indian Society of Medical & Paediatric Oncology, 38(2), 173–181.

. Toomey, E. C., Schiffman, J. D., & Lessnick, S. L. (2010). Recent advances in the molecular pathogenesis of Ewing’s sarcoma. Oncogene, 29(32), 4504–4516.

. Lessnick, S. L., Kowalewski, A. A., & Randall, R. L. (2011). Cell cycle deregulation in Ewing’s sarcoma pathogenesis. Sarcoma.

. Kelleher, F. C., & Thomas, D. M. (2012). Molecular pathogenesis and targeted therapeutics in Ewing sarcoma/primitive neuroectodermal tumours. Clinical Sarcoma Research, 2(1).

. Requilé, A., Clement, P. M., Bechter, O. E., Dumez, H., Verbiest, A., Sciot, R., … Schöffski, P. (2017). Single-Centre Experience of Systemic Treatment with Vincristine, Ifosfamide, and Doxorubicin Alternating with Etoposide, Ifosfamide, and Cisplatin in Adult Patients with Ewing Sarcoma. Sarcoma, 2017.

. Randall, L., Calvert, G., Spraker, H., & Teddy, T. N. (2010). Ewing ’ s Sarcoma Family of Tumors ( ESFT ) What is Ewing ’ s Sarcoma Family of Tumors ? What is a Translocation ? The EWS / FLI Fusion Protein Who Gets ESFT ? Differential Diagnosis in Young Children How Does Someone with ESFT Feel ? How is Ewing ’ s Sar, 1–3.

. (Al-Naggar et al., 2013) Al-Naggar, R. A., Bobryshev, Y. V., Abdulghani, M., Rammohan, S., Osman, M. T., & Abdul Kadir, S. Y. (2013). Complementary/alternative medicine use among cancer patients in Malaysia. World Journal of Medical Sciences, 8(2), 157–164.

. Ganasegeran, K., Rajendran, A. K., & Al-Dubai, S. A. R. (2014). Psycho-Socioeconomic Factors Affecting Complementary and Alternative Medicine Use among Selected Rural Communities in Malaysia: A Cross-Sectional Study. PLoS ONE, 9(11), e112124. doi:10.1371/journal.pone.0112124

. Al-Naggar, R. A., Bobryshev, Y. V., Abdulghani, M. A.-M. M., Rammohan, S., & Al-Jashamy, K. (2012). Knowledge and Perceptions of Cancer and Cancer Prevention among Malaysian Traditional Healers: a Qualitative Study. Asian Pacific Journal of Cancer Prevention, 13(8), 3841–3850.

. Rajendran, P., Alzahrani, A. M., Hanieh, H. N., Kumar, S. A., Ben Ammar, R., Rengarajan, T., & Alhoot, M. A. (2019). Autophagy and senescence: A new insight in selected human diseases. Journal of Cellular Physiology. doi:10.1002/jcp.28895




How to Cite

Hizam , N. R. binti M. ., Ananthan, K. M. A. ., Raman, N. Z. S. binti ., & Banerjee, K. G. . (2021). Primary Bone Cancers: Latest Trends in Pathogenesis, Diagnosis and Management. International Journal of Sciences: Basic and Applied Research (IJSBAR), 57(2), 39–56. Retrieved from