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Bone sarcomas: an update of the recent literature

Jones, Louis Baxter MD; Barr, Jennifer Sobeski MD

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doi: 10.1097/BCO.0000000000000443
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Osteosarcoma is the most common primary sarcoma of bone. The majority of diagnoses occur in patients in their second decade. Diagnosis is made with tissue biopsy and should be made by, or in conjunction with, the sarcoma surgeon responsible for definitive treatment. Treatment includes neoadjuvant chemotherapy, followed by wide resection, and adjuvant chemotherapy. The presence of metastases at diagnosis and a poor response to neoadjuvant chemotherapy (tumor necrosis on resection specimen) portend the worst prognosis.

Osteosarcoma is a rare, aggressive primary bone tumor that predominantly affects children. Its high heterogeneity has made clear delineation of its pathogenesis difficult. There are limited targeted therapies available for patients who do not respond to standard chemotherapeutic regimens. Identifying signal transduction pathways that are critical to osteosarcoma development and its metastatic potential is critical for developing novel, targeted therapy. In a recent review, Adamopoulos et al.1• discussed several of these potential pathways, including receptor activator for nuclear factor-kappaB (RANK), Wnt, Notch, phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, and mechanotransduction. In addition, they remarked on the importance of epigenetics in the regulation of osteosarcoma development as well as the interplay between bone cells and the immune system.

Advances in molecular genetics have allowed for a rapid improvement in identification of factors that will help identify targets for future therapy, response to therapy, and even prognostication. Alterations in the signaling axes of insulin like growth factor (IGF)-1 and transforming growth factor (TGF)-beta have been identified as important factors in the pathogenesis of osteosarcoma.2 In addition, several protein groups have been identified as being overexpressed in osteosarcoma, and their expression may indicate a worse prognosis. These include enhancer of zeste homologue2 (EZH2) and FK506-binding protein 14 (FKBP14). Studies have examined their respective roles as oncogenes and cell cycle regulators.3,4

Glucose transporter protein-1 (Glut-1), a factor in glucose metabolism, also has been studied as a prognostic factor in several tumors. Recent investigation has revealed that Glut-1 expression in biopsy specimens was negatively correlated with disease-free survival.5 This study also discussed the interplay between glucose metabolism and tumor vascularity, suggesting an inverse relationship between Glut-1 expression and tumor angiogenesis. The immunohistochemical staining performed in this study was on biopsy specimens. Increased microvascular density in biopsy specimens portends a favorable response to chemoptherapy.5 Benezech et al.6• investigated the significance of peritumoral vascular invasion on surgical specimens after neoadjuvant chemotherapy. They found significantly lower 2-year event free survival and overall survival in the group with vascular invasion when compared to a group without vascular invasion. The authors concluded that a pathological description of peritumoral vascular invasion can be considered a prognostic factor.6•

Laboratory markers of bone turnover, such as alkaline phosphatase (AP) and lactate dehydrogenase (LDH), have been used as a prognostic tool. Zumarraga et al.7 reported a retrospective study investigating the relationship between levels of alkaline phosphatase and lactate dehydrogenase and percentage of tumor necrosis. Levels were drawn before and after neoadjuvant chemotherapy. They found no statistically significant correlation between serum values and percentage of tumor necrosis. They concluded that AP and LDH are not good predictors of tumor necrosis.7

A new surgical staging system has been proposed that incorporates tumor response to chemotherapy as well as size of the surgical margin. Jeys et al.8•• reported a retrospective study utilizing a prospectively collected database to examine its validity in patients with localized high-grade osteosarcoma. Response to chemotherapy was good (>90% necrosis) or poor (<90%). Margins were good (≥2 mm) or poor (<2 mm). They found that this system was more predictive of local recurrence as well as overall survival than the Musculoskeletal Tumor Society (MSTS) classification. Furthermore, they proposed that the validity be tested with a prospective multi-institutional study supported by the International Society of Limb Salvage.8••

The importance of margin status in regards to patients with nonmetastatic extremity osteosarcoma has recently been investigated. Bertrand et al.9 retrospectively studied the impact of margin status on local recurrence, the development of metastases, and overall survival. They found that patients with positive margins had a greater chance of developing a local recurrence as well as lower overall survival when compared to patients with negative margins.

Limb-sparing surgery is the treatment of choice for nonmetastatic osteosarcoma of the extremity thanks to advances in technique, implant design, and availability of allograft. The procedures are wrought with complications, due in large part to the growth potential remaining in patients affected by osteosarcoma. Epiphyseal sparing resections can be performed when margins allow. Aponte-Tinao et al.10 retrospectively analyzed their experience using an epiphyseal sparing approach with allograft reconstruction for patients with osteosarcomas in the distal femur and proximal tibia. They found no recurrences in the epiphysis. However, 9% did develop local recurrence in the soft tissue. Other orthopaedic complications included infection, fracture, and nonunion. They advocated for larger studies to be performed looking at this procedure compared to alternatives, specifically endoprosthetic reconstruction and osteoarticular allograft reconstruction.10

Microwave ablation has been used intraoperatively as an adjunct to performing epiphyseal sparing resections and maintaining a negative margin. A recent study found no local recurrences with twelve patients using this technique. Two of the patients did experience osteonecrosis of the epiphysis, likely resulting from thermal necrosis.11

Endoprosthetic reconstruction around the knee has benefited from advances in implant design. It allows for wide resection and immediate stability, allowing for weight bearing mobilization. Patients with nonmetastatic disease who display a good response to chemotherapy can expect a 5-year survival rate around 80% with negative margins at the time of resection. Therefore, functional outcomes are important in this active, young patient population. Lang et al.12 found that activity level preoperatively was predictive of long-term postoperative function. Activity levels increased from the 1-year follow-up to 5-year follow-up.12 This study can aid in setting expectations for patients and families prior to resection and reconstruction.

Complications are high in endoprosthetic reconstruction for primary bone sarcomas. Studies reporting these complications are often limited to small cohorts due to the rarity of primary bone sarcomas. Statistical methods utilized often are Kaplan-Meier estimations and Cox regression models. A recent study compared the use of a Kaplan-Meier analysis to a competing risk model. They found that by using competing risk analysis, the estimates of complications and failures were significantly reduced. This has important implications for future studies, as death as a competing event is a realistic outcome.13


Ewing sarcoma represents the second most common bone sarcoma in children. It is characterized by a t(11:22) reciprocal translocation, its histology characterized by monotonous small round blue cells. Patients often present with complaints of pain and fever. About half of the tumors are found in the diaphysis of long bones. The primary location of the tumor has prognostic importance, with tumors found in the pelvis having worse overall survival than tumors found in the extremity. A bone marrow biopsy is part of the workup to evaluate for marrow metastases. Treatment includes chemotherapy and limb salvage resection when possible. Controversies in treatment are focused on the efficacy of radiation therapy compared with surgical resection.

Ewing sarcoma is characterized by the reciprocal translocation t(11;22)(q24;q12) giving rise to the chimeric protein EWS-Fli1. This fusion protein acts as a transcription factor with diverging actions. It has both activating and repressing functions within the epigenetic environment. The bromodomain and extraterminal domain (BET) proteins are a class of epigenetic readers that are associated with cancer progression, specifically in osteosarcoma, lung cancer, and prostate cancer models. Jacques et al.14 recently showed that inhibition of BET bromodomains repressed EWS-Fli1 transcription in vitro and increased mice survival in vivo.14 A significant number of patients with Ewing sarcoma are resistant to current chemotherapy regimens, which has focused research efforts on understanding the mechanisms of resistance, as well as downstream targets for novel therapy. PRAS40, Trk, lysine-specific demethylase 1 (LSD1), and IGF-1 all may play a role in progression of Ewing sarcoma and have shown promise as potential targets.15–17

New techniques in genetic sequencing allow for rapid analysis of entire cellular transcriptomes to search for target discovery. Next-generation deep RNA sequencing is one such technique and has been used coupled with a database of cell surface protein genes to discover proteins that may be used as targets for future antibody mediated drugs. Leucine-rich repeat and Ig domain protein 1 (LINGO1) was found to be expressed in over 90% of Ewing sarcoma tumors using these methods. LINGO1 is a surface protein that is internalized when bound by antibody, making it a biomarker that could be targeted by an antibody-drug conjugate (ADC). An anti-LINGO1 antibody has been derived and is in clinical trials.18

Transgenic mouse models of malignancy have been developed for alveolar rhabdomyosarcoma, synovial sarcoma, myxoid liposarcomas, and clear cell sarcoma. These models are important for further understanding disease pathogenesis as well as for developing new, targeted therapies. A transgenic mouse model has not been developed for Ewing sarcoma. Minas et al.19 published the combined results of six different laboratories’ failed attempts at creating a transgenic model. They noted unique difficulties of this task. The expression of EWS-FLI1 induces growth arrest or apoptosis. The deletion of additional tumor suppressor genes did not help with the formation of Ewing sarcoma. The cell of origin remains controversial, which further impedes attempts at a model by making it impossible to target the correct oncologic cell at the correct stage. The study provides valuable information for researchers that should allow research to progress without repeating documented failures.19••

Survival in patients with Ewing sarcoma is influenced by a variety of factors, including tumor size, tumor location, presence or absence of metastatic disease, and response to neoadjuvant chemotherapy. A primary pelvic site has a worse prognosis than extremity tumors. Ng et al.20 sought to better understand the survival characteristics for a series of patients treated by a single surgeon with an approach involving neoadjuvant chemotherapy, perioperative radiation therapy, and surgical resection. Survival characteristics were compared to patients receiving surgery alone or radiation therapy alone. The use of surgery with radiation therapy was not associated with improved survival when compared to either modality alone. The absence of metastases was the strongest predictor of survival. The results of this study are difficult to interpret, but the discussion illustrates an important concept of Ewing sarcoma care. While histologic response to chemotherapy has prognostic importance, a significant number of patients who have an excellent response to chemotherapy die and a significant number of those with lung metastases survive. They discuss the importance of local control of disease and the contribution of refractory or residual disease to relapse.20 A recent study from Taiwan reported outcomes of 50 patients with Ewing sarcoma tumors that were treated at a single institution. They found that 42% of patients were metastatic at diagnosis. The key negative prognostic factor was metastasis at diagnosis, with 5-year overall survival and progression free survival a mere 18.8% an 15.4%, respectively.21

A retrospective study from the Children’s Oncology Group investigated local control modality and local recurrence for patients with localized Ewing sarcoma of the femur treated with a standardized chemotherapy regimen. Interestingly, they did not find a significant correlation between local control modality and disease outcome. The modalities were surgery alone, surgery plus radiation therapy, or radiation alone. Surgical resection is generally favored for Ewing sarcoma of the femur, but when resection is not feasible or is associated with significant morbidity, radiation therapy is an alternative that should be discussed with the patient and family.22 Patients with local relapse of Ewing sarcoma have less than 25% of 5-year overall survival. Given that, modalities to improve local control are critical to improve outcomes. Foulon et al.23 investigated the role of postoperative radiotherapy in local control in a group of patients with nonmetastatic Ewing sarcoma and a good histological response to chemotherapy (>90% tumor necrosis). They found a statistically significant reduction in local relapse in the patients treated with surgery and radiation when compared to surgery alone.23


Chondrosarcomas can either be primary tumors or secondary, arising from benign cartilage lesions. Accurate diagnosis can be difficult, and tumor location is important when interpreting histologic samples, as axial tumors have a more aggressive course. Chondrosarcomas are generally resistant to chemotherapy and radiation therapy, so treatment involves extended intralesional curettage or wide resection depending on tumor grade. Chondrosarcomas show significant heterogeneity, and making an accurate diagnosis of cartilaginous lesions is challenging. Distinguishing between an atypical cartilaginous tumor (low-grade) and a grade 2 or 3 (high-grade) lesion has important clinical implications because low-grade tumors of long bones can be treated with curettage, whereas intermediate or high-grade tumors are treated with en bloc resection. Roitman et al.24 sought to determine the concordance of preoperative core needle biopsies and postoperative grading in tumors of the extremity and compare that to the concordance of preoperative and postoperative grading in the pelvis. They found a much higher concordance in long bones than in the pelvis (83% vs. 36%), which is consistent with findings previously published. They concluded that clinicians should consider all available diagnostic information, including clinical, radiographic, and histologic characteristics before making a final diagnosis.24

Chondrosarcoma is poorly responsive to traditional systemic therapies. Hypoxia and hypoxia-induced genetic alterations are hallmarks of some tumors, enacting angiogenic properties through expression of vascular endothelial growth factor (VEGF). Sun et al.25 compared human chondrosarcoma cell lines with normal articular cartilage and found overexpression of hypoxia-regulated microRNA in the chondrosarcoma line, which enhanced VEGF expression. Furthermore, they found that this overexpression could be inhibited. They concluded that antiangiogenic therapies could be a potential systemic treatment and that further study regarding delivery methods was warranted.25••

A recent study sought to investigate the relationship between multiple osteochondromas and the development of central chondrosarcomas. A prospectively collected database on patients with multiple osteochondromas was searched for those also diagnosed with central, intraosseous chondrosarcomas. The purpose was to establish any correlation between the two. Interestingly, they found a 3.65% prevalence of histologically confirmed low-grade central chondrosarcoma in this patient subset. This prevalence is comparable to the incidence of peripheral chondrosarcomas found in prior osteochondromas. This is the first reported finding of this correlation. The overall incidence of enchondromas found in this population was not investigated, which may warrant further study. Based on their findings, they advocate for careful evaluation and regular follow-up for patients with multiple osteochondromas also found to have enchondromas.26

Many of the study limitations related to skeletal tumors and disorders are due to the rarity of the conditions. To overcome this, Czajka et al.27 created a web-based survey that was distributed globally through online support groups to better characterize the burden of disease in patients with multiple hereditary exostoses, as well as the proportion who underwent malignant degeneration. They found a 2.7% proportion of patients with malignant degeneration. Almost 97% of responders either had not required surgery or had five or fewer procedures related to their multiple hereditary exostoses. Patients who reported malignant degeneration had a mean of 8.8 procedures.27

Schneiderman et al.28 sought to better understand the characteristics of mesenchymal chondrosarcoma. They used the Surveillance, Epidemiology, and End Results (SEER) database and identified 104 patients who were appropriate for analysis. They found overall survival at 5 and 10 yr to be 51% and 43%, respectively. They found a higher percentage of extraskeletal tumors than previously reported. They confirmed previous reports that increased tumor size and the presence of metastases were predictors of a worse prognosis. Interestingly, they found that cranial tumors displayed age-dependent behavior, with young patients having a good prognosis and increased mortality in old patients.28

Surgery remains the primary treatment for local control of chondrosarcoma. As such, management of local recurrence is challenging and thought to be associated with increased rates of metastases and decreased survival. Kim et al.29 examined a series of patients with local recurrence to evaluate oncologic outcomes after local recurrence, subsequent local recurrence, and to identify prognostic factors. They found a 58.6% 5-year survival for patients with local recurrence. Age older than 50 yr and a local recurrence within 1 yr of primary surgery were independently predictive of poor survival.29

A recent retrospective study found that a group of long-term chondrosarcoma survivors displayed a higher percentage of pathologic bone mineral density than the healthy population. Patients undergoing chemotherapy were excluded. As such, the authors suggested that further study into the reasons for low bone mineral density needed to be performed. The study was limited by a small sample size, which made it impossible to stratify by tumor grade, location, or surgical treatment.30


Chordoma is a malignant tumor of primitive notochordal origin. It is located most commonly in the sacrum and coccyx. Long-term survival is poor. Treatment is dependent on location and extent of disease. For inoperable tumors or for patients unwilling to accept the morbidity of a wide resection, radiation therapy is an option. For patients with operable tumors, wide resection with radiation reserved for positive margins is the standard of care.

A recent retrospective study of 115 patients treated at a single institution showed a 5-year overall survival rate of 81%. The 5-year disease free survival rate was 52%. The 5-year conditional overall survival decreased with each year up until the fourth year, and then increased in the fifth year. Patients with negative margins had higher 5-year survival than those with positive margins. The study also reported the use of a new scoring system to assess sacral nerve function, which had good interobserver and intraobserver reliability in preliminary reports. The system had domains consisting of motor function, urination, uriesthesia, defecation, and rectal sensation. The authors recognized that the scoring system will need to be validated prior to wide acceptance.31


Papers of particular interest published within the annual period of review are highlighted as:

• of special interest

•• of outstanding interest

1. Adamopoulos C, Gargalionis AN, Basdra EK, et al. Deciphering signaling networks in osteosarcoma pathobiology. Exp Biol Med. 2016; 241:1296–13056. •Review article discussing different molecular mechanisms and the roles they may play in novel treatment options.
2. Yang R, Piperdi S, Zhang Y, et al. Transcriptional profiling identifies the signaling axes of IGF and transforming growth factor-β as involved in the pathogenesis of osteosarcoma. Clin Orthop Relat Res. 2015; 474:178–189.
3. Huang Z, Li J, Du S, et al. FKBP14 overexpression contributes to osteosarcoma carcinogenesis and indicates poor survival outcome. Oncotarget. 2016; 7:1–13.
4. Sun R, Shen J, Gao Y, et al. Overexpression of EZH2 is associated with the poor prognosis in osteosarcoma and function analysis indicates a therapeutic potential. Oncotarget. 2016; 7:1–14.
5. Kubo T, Shimose S, Fujimori J. Does expression of glucose transporter protein-1 relate to prognosis and angiogenesis in osteosarcoma? Clin Orthop Relat Res. 2014; 473:305–310.
6. Benezech S, Chabaud S, Chambon F, et al. Prognostic value of vascular invasion in pediatric osteosarcomas. Pathol Oncol Res. 2016; May 26:1–6. Epub ahead of print. •Traditional prognostic factors associated with survival in osteosarcoma included the presence or absence of metastatic disease at the time of diagnosis, the histological response to induction chemotherapy, and the adequacy of surgical margins. This study investigated the prognostic value of peritumoral vascular invasion as determined by surgical specimens after induction chemotherapy. The results suggest that this pathologic diagnosis may be used as an independent prognostic factor for 2-year event free survival and 2-year overall survival.
7. Zumárraga JP, Baptista AM, Rosa LDL, et al. Serum values of alkaline phosphatase and lactate dehydreogenase in osteosarcoma. Acta Ortop Bras. 2016; 24:142–146. d.
8. Jeys LM, Thorne CJ, Parry M, et al. A novel system for the surgical staging of primary high-grade osteosarcoma: the Birmingham classification. Clin Orthop Relat Res. 2016; May 2:1–9. Epub ahead of print. ••This retrospective study sought to establish a new classification system for osteosarcoma based on response to chemotherapy and surgical margins. The results are encouraging and the authors have recommended a larger scale collaborative study to confirm the findings.
9. Bertrand TE, Cruz A, Binitie O, et al. Do surgical margins affect local recurrence and survival in extremity, nonmetastatic, high-grade osteosarcoma? Clin Orthop Relat Res. 2015; 474:677–683.
10. Aponte-Tinao L, Ayerza MA, Muscolo DL, et al. Survival, recurrence, and function after epiphyseal preservation and allograft reconstruction in osteosarcoma of the knee. Clin Orthop Relat Res. 2014; 473:1789–1796.
11. Li J, Guo Z, Wang Z, et al. Does microwave ablation of the tumor edge allow for joint-sparing surgery in patients with osteosarcoma of the proximal tibia? Clin Orthop Relat Res. 2015; 473:3204–3211.
12. Lang NW, Hobusch GM, Funovics PT, et al. What sports activity levels are achieved in patients with modular tumor endoprostheses of osteosarcoma about the knee? Clin Orthop Relat Res. 2014; 473:847–854.
13. Schuh R, Kaider A, Windhager R, et al. Does competing risk analysis give useful information about endoprosthetic survival in extremity osteosarcoma? Clin Orthop Relat Res. 2014; 473:900–906.
14. Jacques C, Lamoureux F, Baud’huin M, et al. Targeting the epigenetic readers in Ewing Sarcoma inhibits the oncogenic transcription factor EWS/Fli1. Oncotarget. 2016; 7:1–16.
15. Kim S, Park Y. Ewing sarcoma: a chronicle of molecular pathogenesis. Human Pathology. 2016; 55:1–49.
16. Lv D, Liu J, Guo L, et al. PRAS40 deregulates apoptosis in Ewing sarcoma family tumors by enhancing the insulin receptor/Akt and mTOR signaling pathways. Am J Cancer Res. 2016; 6:486–497. March 2016:1-12.
17. Heinen T, Dos Santos R, Da Rocha A, et al. Trk inhibition reduces cell proliferation and potentiates the effects of chemotherapeutic agents in Ewing sarcoma. Oncotarget. 2016; 7:1–21.
18. Town J, Pais H, Harrison S, et al. Exploring the surfaceome of Ewing sarcoma identifies a new and unique therapeutic target. Proc Natl Acad Sci USA. 2016; 113:3603–3608.
19. Minas T, Surdez D, Javaheri T, et al. Combined experience of six independent laboratories attempting to create an Ewing sarcoma mouse model. Oncotarget. 2016; May 15:1–24. Epub ahead of print. ••This article reported sixteen methods of attempting to create a Ewing sarcoma mouse model able to undergo tumor initiation, and all of their failure mechanisms. It provides critical information to basic science researchers.
20. Ng VY, Jones R, Bompadre V, et al. The effect of surgery with radiation on pelvic Ewing sarcoma survival. J Surg Oncol. 2015; 112:861–865.
21. Lee C-Y, Yen C-C, Yen H-J, et al. Outcomes of 50 patients with Ewing sarcoma family of tumors treated at a single institution in Taiwan. Medicine. 2016; 95:e3830–e3837.
22. Daw NC, Laack NN, McIlvaine EJ, et al. Local control modality and outcome for Ewing sarcoma of the femur: a report from the Children’s Oncology Group. Ann Surg Oncol. 2016; 23:1–7.
23. Foulon S, Brennan B, Gaspar N, et al. Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E.W.I.N.G group. Europ J Cancer. 2016; 61(C):128–136.
24. Roitman PD, Farfalli GL, Ayerza MA, et al. Is needle biopsy clinically useful in preoperative grading of central chondrosarcoma of the pelvis and long bones? Clin Orthop Relat Res. 2016; Feb 16:1–7. Epub ahead of print.
25. Sun X, Wei L, Chen Q, et al. MicroRNA regulates vascular endothelial growth factor expression in chondrosarcoma cells. Clin Orthop Relat Res. 2014; 473:907–913. ••Cytotoxic chemotherapeutic agents have proven to be ineffective in the treatment of conventional chondrosarcoma. Targeted therapies are necessary to improve treatment options for patients. This study identified a specific micro-RNA that is overexpressed in chondrosarcoma that can be effectively targeted by a novel antagomir.
26. Goud AL, Wuyts W, Bessems J, et al. Intraosseous atypical chondroid tumor or chondrosarcoma grade 1 in patients with multiple osteochondromas. J Bone Joint Surg. 2015; 97:24–31.
27. Czajka CM, DiCaprio MR. What is the proportion of patients with multiple hereditary exostoses who undergo malignant degeneration? Clin Orthop Relat Res. 2015; 473:1–7.
28. Schneiderman BA, Kliethermes SA, Nystrom LM. Survival in mesenchymal chondrosarcoma varies based on age and tumor location: a survival analysis of the SEER database. Clin Orthop Relat Res. 2016; Mar 14:1–7. Epub ahead of print.
29. Kim H-S, Bindiganavile SS, Han I. Oncologic outcome after local recurrence of chondrosarcoma: Analysis of prognostic factors. J Surg Oncol. 2015; 111:957–961.
30. Hobusch GM, Tiefenboeck TM, Patsch J, et al. Do patients after chondrosarcoma treatment have age-appropriate bone mineral density in the long term? Clin Orthop Relat Res. 2016; 474:1508–1515.
31. Ji T, Guo W, Yang R, et al. What are the conditional survival and functional outcomes after surgical treatment of 115 patients with sacral chordoma? Clin Orthop Relat Res. 2016; Mar 14:1–11. Epub ahead of print.

osteosarcoma; Ewing’s sarcoma; chondrosarcoma; chordoma

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