Extract
We reviewed the literature to determine the important advances related to primary bone tumors during the past few years. In the present update, we will discuss malignant tumors (including Ewing sarcoma, osteosarcoma, chondrosarcoma, and chordoma) and benign tumors (including benign cartilaginous tumors, giant cell tumor of bone, and aneurysmal bone cysts).
We reviewed the literature to determine the important advances related to primary bone tumors during the past few years. In the present update, we will discuss malignant tumors (including Ewing sarcoma, osteosarcoma, chondrosarcoma, and chordoma) and benign tumors (including benign cartilaginous tumors, giant cell tumor of bone, and aneurysmal bone cysts).
With regard to malignant tumors, much effort has been focused on finding new potential targets for systemic therapy. Additional efforts have been made in an attempt to identify disease markers that will correlate with outcome. For benign tumors, the focus has been on less aggressive treatment over time. For example, twenty-five years ago, giant cell tumor of bone was often treated with en bloc excision, whereas now, local curettage with or without an adjuvant is more routine. Presently, drugs that act on osteoclasts, such as denosumab (an antibody to RANK ligand), may result in management of giant cell tumors without surgery particularly with very large or recurrent tumors. We will review some of the newer aspects of detection and treatment of some of the more common primary malignant and benign bone tumors.
Ewing Sarcoma
Ewing sarcoma is a member of the Ewing family of tumors (EFT) and, unlike most other primary tumors of bone, has a characteristic translocation most commonly involving the eleventh and twenty-second chromosomes. The protein product of that translocation is EWS-FLI1 and has been postulated to act as an aberrant transcription factor driving the pathogenesis of Ewing sarcoma1. EWS-FLI1 forms a transcriptional complex with RNA helicase A (RHA), and this complex has been implicated in the pathogenesis of Ewing sarcoma. A recent study in Nature Medicine blocked the binding of EWS-FLI1 to RHA and subsequently induced apoptosis and inhibited growth in a xenograft model, providing proof of the concept that this interaction may be important in the pathogenesis of Ewing sarcoma2. Other investigators have corroborated the concept that the EWS-FLI1 transcription complexes can modulate transcription synthesis and degradation, indicating that these fusion proteins are an important part of the pathogenesis of Ewing sarcoma3. Contrary to previous reports, a prospective study did not demonstrate that the different EWS-FLI1 fusion protein subgroups impacted survival4.
Ewing sarcoma can occur primarily in soft tissues as well. Applebaum et al. compared the presentation and outcomes of the bone variant and the less common soft-tissue variant5. Skeletally based Ewing sarcoma was more likely to occur in younger patients, was more common in males, and occurred in the extremity more commonly than did extra-skeletal Ewing sarcoma. The five-year survival was lower for skeletal Ewing sarcoma as compared with extra-skeletal Ewing sarcoma. Contrary to the findings of Applebaum et al., Pradhan et al. noted no difference in survival between skeletal and extra-skeletal Ewing sarcoma, although the study by Pradhan et al. included fewer patients (300 versus 2200)5,6.
In another recent clinical study, Gupta et al. evaluated the survival rates between adults and children with Ewing sarcoma7. The authors found that the three-year overall survival rate was 81% in children, compared with 59% in adults (p = 0.02). They postulated that the difference was in part due to the use of lower doses of chemotherapeutic agents in adults. Another recent study from Germany investigated the impact of treating the primary site of disease compared with systemic therapy only and found that local treatment was an important predictor of survival8.
Targeting the insulin-like growth factor (IGF) tyrosine kinase pathway has garnered considerable interest in recent years. However, many Ewing sarcoma tumors lack sensitivity to anti-IGF-1 therapy and others develop resistance to it over time. Garofalo et al. found that tumors that are resistant to anti-IGF-1 therapy seem to upregulate the IGF-2/insulin-receptor A pathway to stimulate downstream proteins common to the two parallel pathways9. Scotlandi et al. found that almost all Ewing sarcomas express components of the IGF pathway but also found that increased expression correlated with improved survival and that decreased IGF activity correlated with the aggressiveness of the tumor10.
Recently, zoledronic acid, a bisphosphonate, has been used to help to prevent untoward skeletal events in patients with metastatic bone disease. Zoledronic acid appears to have intrinsic anti-tumor capacity. Odri et al. found that zoledronic acid combined with one dose of ifosfamide had the same effect on Ewing sarcoma cells as three doses of ifosfamide alone in a mouse model11. The authors suggested that zoledronic acid, to affect osteoclast turnover, combined with lower doses of conventional chemotherapy may provide effective oncologic treatment with fewer side effects.
Osteosarcoma
The grade of sarcomas is most important in the staging process. Patients with low-grade osteosarcoma do not require chemotherapy, and the survival of such patients is rarely affected by the disease. In contrast, high-grade tumors tend to metastasize and are routinely treated with chemotherapy in addition to surgical resection, with a survival rate of approximately 70%. The quest continues for surrogate markers to help to predict the outcomes for patients with high-grade osteosarcoma. The histological response to neoadjuvant chemotherapy remains the primary means of predicting survival. It would be useful to predict which patients are not responding well early in the course of treatment in order to channel them into an experimental arm or at least spare them some of the toxicity associated with chemotherapy. Multiple approaches have been taken to try to predict response, including using imaging modalities, circulating factors, and gene expression patterns from tumor cells, all with the goal of predicting survival. Li et al. evaluated the association between circulating chemokines and clinical outcomes in a study of patients with osteosarcoma12. They found that CXCL4 and CXCL6 were expressed in >90% of osteosarcoma cases and that higher levels of these chemokines were associated with a worse prognosis.
Recent studies have evaluated some of the subsets of higher-grade osteosarcomas that are less common. Cesari et al. reported the Rizzoli Institute’s experience with periosteal osteosarcoma, with a ten-year overall survival rate of 84% in a series in which all patients but one were managed with resection13. The overall survival rate for patients managed with chemotherapy and resection did not differ from that for patients managed with resection alone. Ruggieri et al. confirmed that Pagetic osteosarcoma carries a very poor prognosis, with twenty-two of twenty-six patients dying from the disease and four patients remaining alive with no evidence of disease14. All patients who were managed without surgery died of the disease. Probably the most aggressive of the osteosarcomas are those that are radiation-induced. Samartzis et al., in a prospective series that included 80,181 survivors of the atomic bombs dropped on Hiroshima and Nagasaki, identified nineteen cases of bone sarcoma, with osteosarcoma being the most common cell type15. The authors found a dose threshold of 0.85 Gy, which was much lower than previously had been thought to be associated with a risk of developing a secondary sarcoma. They concluded that health risks are incurred even with what might previously have been considered low levels of ionizing radiation.
For all high-grade osteosarcomas, surgery and chemotherapy remain the standards of care. However, current chemotherapy is not effective for some patients, and current treatment protocols are associated with known side effects. Choy et al. discovered multiple mutations in the phosphoinositide-3-kinase (PI3k) pathway in osteosarcoma cell lines in tissues, which may lead to further clinical trials using targeted therapies directed at the PI3k pathway in osteosarcoma16. Yang et al. discovered that the vascular endothelial growth factor (VEGF) pathway (including VEGF-A) is amplified in osteosarcoma, revealing yet another potential target in this heterogeneous cancer17. Steinmann et al. used extracts from the magnolia tree known as Honokiol as a means of preventing metastasis in a mouse osteosarcoma model. They found profound inhibition of metastasis in their model and determined that Honokiol worked through a mechanism independent from apoptosis, necrosis, or autophagy18. Hassan et al. demonstrated high expression of IGF-2R in fourteen osteosarcoma cell lines19. They found variable expression of other receptors known to be expressed in osteosarcoma, including IGF-1R, HER-2, c-Met, PDGFR (platelet-derived growth factor receptor)-β, and VEGF-3. Noh et al. reported positive results targeting ERK 1/2 in a mouse model of osteosarcoma20. ERK inhibition seemed to upregulate proapoptotic genes and to inhibit Bcl-2-mediated resistance to osteosarcoma.
Daw et al. conducted a phase-2 clinical trial in which seventy-five patients from St. Jude’s research hospital were managed with neoadjuvant carboplatin, ifosfamide, and doxorubicin without cisplatin or methotrexate21. The authors compared their results with those of a previous trial in which high-dose methotrexate was used but cisplatin was not. The authors argued that cisplatin and high-dose methotrexate add morbidity and that administering methotrexate is technically difficult because of the need for complex pharmacokinetic monitoring. Patients were followed for a median of 5.1 years (range, 2.2 to 9.9 years). The authors found that 60% of their subjects had a good histological response (defined as >90% necrosis), and they estimated the five-year survival to be 79%. The authors concluded that carboplatin, ifosfamide, and doxorubicin-based chemotherapy can be used as an effective alternative to cisplatin or methotrexate-based chemotherapy. This was not a prospective randomized trial comparing the regimes, and firm conclusions can only be drawn from a head-to-head trial.
Ciernik et al. studied the impact of proton-based radiation therapy on local control and survival in fifty-five patients with unresectable or incompletely resected osteosarcoma22. Unresectable tumor is an arbitrary term because what is resectable to one surgeon may be unresectable to another and much is based on the morbidity that the patient is willing to accept. In this study, the average total radiation dose was 68.4 Gy, the overall five-year survival rate was 67%, and the five-year local control rate was 72%. Proton-based radiation offered promising local control and survival benefits for select patients with osteosarcoma.
Guo et al. studied sixty-nine patients with nonmetastatic osteosarcoma with use of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to assess the microvasculature characteristics of the tumors23. DCE-MRI was able to predict event-free survival and overall survival in pretreated patients, and the imaging findings correlated with the histologic response to neoadjuvant chemotherapy23.
Thallium uptake was reconsidered as a predictor of event-free survival in osteosarcoma. It had previously been reported to correlate with necrosis. This finding created interest as a means of assessing the efficacy of chemotherapy prior to definitive resection or completion of therapy. A follow-up study by Magnan et al., however, did not demonstrate a correlation with decreased thallium uptake and event-free survival24. The authors cautioned that thallium uptake should not be used as a predictor of necrosis.
Ichikawa et al. explored the nature of procoagulants in osteosarcoma by examining the presence of osteosarcoma cells in venous thrombi adjacent to tumors25. Osteosarcoma cells were present in these small clots and were associated with a poor prognosis. This is the reason why limb salvage may be considered inappropriate in certain situations involving vascular invasion by tumor cells. More aggressive osteosarcoma cell lines were particularly procoagulant, and cell growth was inhibited by low-molecular-weight heparin. The authors concluded that the coagulation cascade may play a role in the pathogenesis of osteosarcoma and may serve as a treatment target. Kubo et al. compared the protein expression of interferon-α/β in forty patients with high-grade osteosarcoma and evaluated whether expression patterns were associated with survival26. The authors found that high expression of interferon-α/β (based on immunohistochemistry findings) was an independent predictor of better survival and concluded that their results provided further support for an ongoing clinical trial using interferon-α therapy in patients with osteosarcoma.
The bisphosphonate pamidronate has an effect on tumor cells in vitro and is known to prevent bone turnover in vivo, as discussed in the section on Ewing sarcoma. Concerns had been raised about the impact of pamidronate on the efficacy of chemotherapy, given its effect on bone turnover. Meyers et al.27, in a study from Memorial Sloan-Kettering Cancer Center, reported that pamidronate did not hinder the efficacy of chemotherapy, with a five-year overall survival rate of 93%. The authors postulated that the addition of pamidronate may improve the durability of limb reconstruction.
Chondrosarcoma
Histological grade remains the best indicator of prognosis in cases of chondrosarcoma. Chen et al. evaluated the role of the von Hippel-Lindau (VHL) tumor-suppressor gene in chondrosarcoma and found that decreased expression of VHL correlated with lower rates of apoptosis and higher histological grade but did not correlate with survival28. Nakagawa et al. correlated the clinical outcomes in patients with chondrosarcoma with gene expression from the nitric oxide pathway (NOS1, NOS2, NOS3) and COX-2 as well as CD34 (a marker of neurovascularization)29. Higher expression of COX-2 and CD34 were found in higher-grade tumors, whereas NOS2 was associated with a lower rate of local disease-free survival. NOS1 and NOS2 were associated with a lower overall survival rate.
The treatment of low-grade cartilage lesions continues to generate interest and some conflict in management. One recent retrospective study with a minimum duration of follow-up of five years demonstrated no recurrences in sixteen patients who had been managed with wide resection and two recurrences in fifteen patients who had been managed with intralesional resection30. Both recurrences were successfully treated with resection. Another long-term follow-up study examined fifteen patients with Grade-1 chondrosarcomas in the proximal part of the humerus and distal part of the femur who were managed with curettage and cryosurgery, with no local recurrences and no complications31. Mohler et al. reported a 4.3% rate of local recurrence after curettage and cryosurgery for the treatment of low-grade extremity cartilage tumors and concluded that curettage and cryosurgery is a reasonable alternative to wide resection for the treatment of low-grade cartilage lesions32. de Camargo et al. reported a local recurrence rate of 26% for Grade-1 chondrosarcoma33. Notably, five of the six local recurrences had progressed to Grade 2. These recurrences were treated with wide resection, and none of the patients who initially had Grade-1 chondrosarcoma had died from the disease.
Imatinib mesylate has not been found to be efficacious for the treatment of disseminated or unresectable chondrosarcoma. Grignani et al., in a Phase-2 trial of imatinib that involved twenty-six patients with chondrosarcomas that expressed activated PDGF-B, did not observe an objective response to treatment or freedom from disease progression in any patient34. Goda et al. advocated using radiation as an adjuvant to surgery for the treatment of high-risk chondrosarcoma35. In that study, sixty patients were managed with radiation (delivered at doses between 50 and 60 Gy) as neoadjuvant or adjuvant therapy. After a mean of seventy-five months, the authors reported local control rates of 100% for R0 resections, 94% for R1 resections, and 42% for R2 resections. Particularly notable was the fact that five of the eight patients with R2 resections had stable disease without progression. The authors concluded that resection with negative margins remains the standard of care but that radiation is a useful adjuvant.
Chordoma
Chordoma, a rare disease, occurs in about 300 individuals per year in the United States and affects the axial skeleton in regions of regressed notochord cells. Most cases occur in the sacrum, followed by the skull base. The disease historically has been difficult to treat, with high rates of local recurrence. Surgery alone has been the mainstay of treatment for tumors in these difficult anatomic locations. Staged sacral resections have become more common, and data from the Mayo Clinic demonstrated improved outcomes, better resource management, and decreased hospital costs in association with staged approaches36. However, surgeons at some centers have reported renewed enthusiasm for posterior-only approaches to these tumors37. The use of radiation therapy for the treatment of chordoma continues to spark debate. Recent studies have lent further support to the previously reported efficacy of high-dose radiation therapy for the treatment of chordoma38. Systemic therapy for this tumor remains experimental at this time. A recent Phase-2 clinical trial in which imatinib was used for the treatment of advanced chordoma demonstrated stable disease after six months in thirty-five of fifty patients, with one patient experiencing a partial response39.
Researchers continue to explore potential mechanisms behind the etiology of chordoma. The transcription factor T-brachyury is expressed in most chordomas and also notochord remnants, from which chordomas are thought to arise. Yang et al. used high-resolution array-based comparative genomic hybridization (CGH) to identify unique duplications of a region on chromosome 6q27 in four multiplex families with at least three cases of chordoma40. The duplicated region contained the T-brachyury gene, lending credence to the notion that T-brachyury may play a role in the pathogenesis of familial chordoma. This same duplication has not been found in sporadic cases of chordoma.
The primary goal of treating malignant bone sarcomas, at least those of higher grade, is a negative surgical margin without entry into the tumor or its surrounding reactive zone. Low-grade malignant bone tumors may be less aggressively treated, and the resulting bone defect requires less aggressive treatment.
High-grade tumors usually require aggressive surgical resection, which results in a large osseous defect. The reconstruction of resulting defects has been approached with a variety of methods. Unlike routine joint reconstruction, the osseous defects are quite large and the amount of bone loss quite substantial. What may be even more important is the resulting soft-tissue defect being a major challenge that may even affect the ability to perform limb-salvage surgery.
The reconstructive procedures for large osseous defects vary according to the preference of the surgeon, the surgical site, the disease process, and sometimes the availability of the materials for the reconstructive procedure. Reconstructive options include structural allograft transplantation, endoprosthetic replacement, and composite reconstruction with use of allografts and metal prostheses. As sarcomas are rare, it has been difficult to assemble a large number of cases. In 2011, Henderson et al. assembled a large series of endoprostheses and defined a classification scheme for failure41. This classification scheme described both mechanical and nonmechanical failures. Mechanical failures included soft-tissue failure (Type 1), aseptic loosening (Type 2), and structural failure (Type 3). Descriptions of each type of mechanical and nonmechanical failure were provided. Infection (Type-4 failure) is devastating and often results in removal of the implant. During reconstruction, leaving more bone and soft tissues around the resection can aid in the functional status postoperatively but unfortunately results in higher rates of local recurrence. The classification scheme described in this large multi-institutional series will also serve as a model for further collaborative efforts.
Giant Cell Tumor
Giant cell tumor of the spine and sacrum as well as recurrent giant cell tumors can pose a difficult surgical problem. Ruggieri et al., in a large series of patients with sacral giant cell tumors, highlighted the complications associated with the surgical treatment of these tumors42. In that series, adjuvants were not helpful with local control. While excellent local control was obtained, two deaths were associated with treatment. This series, like previous series, highlighted the need for better systemic therapy for the treatment of giant cell tumors. Thomas et al. reported promising results in a prospective trial targeting giant cells using a monoclonal antibody against RANKL43. The premise behind targeting RANKL is that receptors for RANKL exist on giant cells and activation of giant cells may rely in part on RANKL. It was hypothesized that if one were to block giant cell activation by binding RANKL, one could inhibit growth of giant cell tumors. This trial included thirty-seven patients with recurrent or unresectable giant cell tumors who underwent monthly subcutaneous injections of denosumab (Amgen, Thousand Oaks, California). The primary end point was tumor response, defined as elimination of at least 90% of giant cells or no radiographic progression of the target lesion up to Week 25. Thirty-five patients were included in the analysis, and thirty (86%) met the tumor-response criteria. Notably, the post-treatment histological findings demonstrated regions of new bone formation in places where histologically proven giant cell tumor had existed before treatment. It is unclear what risks are associated with long-term treatment with a RANKL inhibitor. At least one case of osteonecrosis of the jaw has been reported44.
Enthusiasm for targeting the RANK/RANKL pathway is leading others to consider its merits in the treatment of chondroblastoma and aneurysmal bone cysts, both of which possess giant cells. A Korean study evaluated the relative expression of RANK on giant cells from these tumors and compared it with RANK expression in giant cell tumors45. Chondroblastomas expressed higher levels of RANK than did giant cells from giant cell tumors, whereas aneurysmal bone cysts expressed lower levels of RANK than did giant cell tumors. Interestingly, the expression of osteoprotegerin was also much higher in chondroblastomas.
Bisphosphonates have also been used as an adjuvant for local control of giant cell tumors. A recent study evaluated the elution characteristics of zoledronic acid from acrylic bone cement and correlated them with their cytotoxic effects on stromal cells from a giant cell tumor in vitro46. The study demonstrated a dose-dependent effect on cellular cytotoxicity with incremental increases in zoledronic acid concentrations. Most of the zoledronic acid was released in the first twenty-four hours, and a plateau was reached by four days. The authors concluded that the cytotoxic effects of zoledronic acid were not mitigated by cement polymerization.
Klenke et al., in a large clinical series from the Mayo Clinic, evaluated the outcomes for 118 patients who underwent treatment of giant cell tumor of bone47. Although wide resection was associated with better local control, the authors were able to manage local recurrence well with additional surgery. Furthermore, they found a 4% risk of pulmonary metastasis, which was treated effectively with multimodal therapy. The authors found a lower risk of local recurrence in association with polymethylmethacrylate (PMMA) filling of bone defects than with allograft chips. They concluded that the vast majority of giant cell tumors of bone can be treated with curettage and PMMA packing, with a local recurrence rate of about 20%. A parallel study from the same center evaluated recurrent giant cell tumors and concluded that intralesional curettage and PMMA packing allowed for good local control even in the recurrent setting48. Furthermore, local failures were usually amenable to additional surgery.
Aneurysmal Bone Cyst
Additional work has been done to elucidate the underlying mechanisms behind aneurysmal bone cysts, which are known to express a TRE17/USP6 translocation. This translocation causes TRE17 (a ubiquitin-specific protease) to be highly expressed, whereas it is typically expressed at very low levels in human tissues. A recent study demonstrated that TRE17 expression leads to increased matrix metalloproteinase (MMP)-9 and increased MMP-10 activity via the NFκB pathway49. Both MMP-9 and 10 have been associated with degradation and remodeling of bone matrix. Furthermore, MMP-9 activity has been associated with release of VEGF, leading to increased vascularity. This study sheds new light on the etiology of aneurysmal bone cysts and may lead to subsequent molecular targets.
While we await systemic therapies to assist in the treatment of aneurysmal bone cysts, investigators are reporting the results of repetitive sclerotherapy in lieu of surgery. In the study by Varshney et al., ninety-four patients were randomized into two groups, with one group being managed with curettage and high-speed burring and the other group being managed with repetitive intraosseous sclerotherapy with use of polidocanol50. The authors hypothesized that the bone healing rate would be similar between groups. They reported a healing rate of 93% in the sclerotherapy group, compared with 85% in the curettage group. Furthermore, 31% of the patients in the sclerotherapy group had healing after one injection. The sclerotherapy procedure is an outpatient procedure, and pain relief was achieved immediately following the injection. The authors concluded that sclerotherapy is a safe and effective means of treating aneurysmal bone cysts.
The results of sclerotherapy compared favorably with those in another large series of aneurysmal bone cysts that were treated with curettage, high-speed burring, and argon beam coagulation51. In that series, local control was achieved in 92% of patients; however, the use of argon beam was associated with an increased fracture risk.
Benign Cartilaginous Tumors
Pedrini et al. studied 529 patients with multiple hereditary exostoses in order to correlate disease severity with various risk factors such as the presence of EXT1 as compared with EXT2 mutations, sex, and number of exostoses52. The authors found that female sex, having fewer than five sites with exostoses, the presence of EXT2 mutations, and the absence of EXT1/2 mutations were most commonly associated with a mild form of disease, as defined by the absence of deformity and functional limitations. On the other hand, male sex, EXT1 mutations, and having more than twenty sites with exostoses were associated with the severe form of the disease, as defined by the presence of deformities and functional limitations. Malignant degeneration occurred in 5% of the cohort, and the development of malignancy was not linked to EXT mutations, sex, the severity of the disease, or the number of sites with exostoses. Malignancy was more likely to occur in exostoses from the pelvis, scapula, and proximal part of the femur, and malignant degeneration occurred in patients with a family history of multiple hereditary exostoses (n = 20) rather than sporadic forms of the disease (n = 2).
EXT has been implicated in the pathogenesis of osteochondromas; however, its exact role has not been elucidated. One theory is that the development of an osteochondroma requires biallelic mutations in EXT genes. A recent study evaluated the presence of biallelic mutations in multiple hereditary osteochondromas, solitary osteochondromas, and chondrosarcomas53. There was no correlation between the presence of biallelic mutations in EXT and the pathogenesis of osteochondromas.
Additional work on multiple hereditary exostoses implicated microRNAs as a potential impediment to cartilage maturation and/or differentiation, potentially contributing to the pathogenesis and phenotypic variability in multiple hereditary exostoses54.
One study identified loss-of-function mutations in PTPN11 in individuals with metachondromatosis55. Metachondromatosis is a rare autosomal dominant condition in which patients manifest multiple enchondromas and multiple exostoses. Mutations were noted in eleven of seventeen families with known metachondromatosis, but there were no mutations in individuals with multiple enchondromatosis disorders, such as Ollier disease or Maffucci syndrome.
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Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support of any aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. No author has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.