This Update provides a review of work published in the area of primary musculoskeletal tumors between May 2015 and June 2016. The studies are largely Level III and IV, in part due to the rarity and varied nature of such tumors. The articles were identified by searching PubMed and reviewing prominent journals.
Margins and local recurrence were the focus of several osteosarcoma studies. Bertrand et al. reviewed 51 high-grade extremity sarcomas with localized disease at presentation and found that a positive margin compared with a negative margin of >1 mm was the only factor that independently predicted local recurrence1. They confirmed that patients with a positive surgical margin had an increased risk of death from disease compared with those with negative margins. In another study, no local recurrences were noted among 11 patients followed for a minimum of 37 months who had undergone joint-sparing surgery for proximal tibial osteosarcoma that invaded the physis2. The proximal edge of the tumors was treated with intraoperative microwave ablation prior to tumor resection. The proximal osteotomies were planned at the edge of the tumor, but there were no positive margins.
As Ewing sarcoma survival has improved, the factors influencing long-term outcomes have become more important. Stish et al. analyzed scores of the Toronto Extremity Salvage Score (TESS) and Pediatric Quality of Life Inventory (PedsQL) for 74 patients at an average duration of follow-up of 17.8 years3. They found that TESS results were better for those diagnosed at <18 years of age and that PedsQL scores were better for male patients than for female patients. Pelvic tumors were associated with decreased functional outcomes but not lower quality-of-life scores compared with tumors from other sites. The authors were not able to measure an effect of local therapy modality.
Survival among those with pelvic Ewing sarcoma is related to the size and extent of pelvic involvement. Of 40 pelvic Ewing sarcomas treated at a single institution, there was no statistical difference in survival for those treated with surgery and radiation or with radiation alone4. The size and extent of tumors in these groups were similar, but the radiation-alone group had a 29% higher rate of metastases at presentation. It was encouraging that 100% patient survival with no evidence of disease was noted at a mean of 85.6 months of follow-up for the 11 single-location tumors that were treated with surgery and radiation.
Relapse in Ewing sarcoma is common. Ferrari et al. reviewed the experience of several centers treating 97 relapsed cases5. They noted that high-dose consolidation chemotherapy including busulfan and melfalan was not statistically found to be helpful in the treatment of recurrent disease. Survival after recurrence was 19% at 5 years and averaged 12 months. Survival was related to the pattern of disease and the recurrence-free interval and was generally worse for older patients, with a spike of worse outcomes among those aged 15 to 17 years. Those who responded to secondary treatment and achieved a second remission had a 48% five-year survival rate.
Roitman et al. found that the pathologic grade reported from preoperative needle biopsies of chondrosarcomas of the extremities and pelvis was at times different from the grade of the resected specimens6. Concordance between the preoperative biopsy and the final grade in terms of whether the tumor grade was high or low was 90% for the long bones, while for the pelvis, it was only 67%. The authors used these data to caution that biopsies of pelvic chondrosarcomas may be misleading, and thus a treatment plan must include imaging and clinical information as well.
In another study, patients who had surgery for local recurrence after resection of grade-2 or higher chondrosarcomas had a better 5-year disease-specific survival if they were <50 years old and experienced recurrence ≥1 year after the initial resection7. Patients with inadequate surgical margins had 5 times the risk of recurrence as patients with wide margins.
The rate of sacral insufficiency fractures observed in patients treated for chordoma with high-dose radiation therapy of >50 Gy was higher among patients who also had surgery8. Patients treated with surgery underwent radiation preoperatively and postoperatively with a median dose of 70.2 Gy. All fractures in the surgery group were in the patients who underwent high sacrectomy (resection level at S3 and above) (25 of 33 patients, 76%). Only 4 (22%) of the 18 patients treated with radiation alone at a median of 77.4 Gy experienced fractures. The 1, 2, and 5-year fracture-free survival probabilities for radiation plus high sacrectomy compared with radiation alone were 0.53, 0.36, and 0.14 compared with 0.83, 0.77, and 0.77, respectively.
Several articles described large groups of patients with chordoma and detailed characteristics of survival and recurrence. Varga et al. reviewed 167 patients with sacral chordoma treated surgically at 13 centers and found significant associations between local recurrence and both previous surgery and intralesional treatment in their multivariate analysis9. Older patients (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00 to 1.04) and those with preoperative motor deficits of C or D according to the Frankel and American Spinal Injury Association (ASIA) scores (HR, 2.83; 95% CI, 1.46 to 5.48) had significantly worse overall survival. En bloc resection was not shown to influence survival, but the average duration of follow-up was only 3.2 years.
One center devised a new 100-point scale and found a trend of improved function in 122 patients with sacral chordoma treated surgically with every nerve level spared, and even better function at S3 with both roots spared compared with just one10. Local recurrence was most influenced by previous surgery and adequate margins and was noted at a mean of 42 months. The rates of local recurrence and metastasis-free survival at 5 years were 48% and 89%, respectively. This study had an average follow-up duration of 4.9 years.
The cohort study with the longest duration of follow-up was that by Radaelli et al., who followed 99 patients with chordoma for an average of 8.7 years and noted deterioration in the survival data over the entire length of follow-up11. At 5, 10, and 15 years, the overall survival rate was 92%, 63%, and 45%, respectively, while the disease-free survival rate was 62%, 36%, and 21%, respectively. The disease-free survival rate at 15 years for patients with a wide (R0) resection was 49%, but only 7% for those with a marginal (R1) resection. The crude cumulative incidence at 5, 10, and 15 years for local recurrence was 30%, 46%, and 56%, respectively, while for distant metastasis, it was 9%, 18%, and 23%, respectively. Margins impacted the disease-free survival rate, and tumor size had a significant effect on the overall survival and disease-free survival rates.
Giant Cell Tumor
A study of patients with giant cell tumors compared treatment by 1 surgeon who used subchondral bone graft plus polymethylmethacrylate (PMMA) with that of 2 others who used PMMA only12. Fewer nononcologic complications, such as fracture and arthritis, were noted among the patients treated with grafting. While the patients were not randomized, tumor size, recurrence rates, and functional scores of the 22 patients in the PMMA-only group were similar to those of the 21 patients treated with grafting. In the graft group, there was 1 fracture and 1 patient who progressed to arthritis. The PMMA-only group had 5 fractures and 7 patients who developed arthritis.
The authors of another study evaluated the challenge of periarticular location of giant cell tumors by using denosumab for 6 to 11 months before surgery in 20 patients deemed challenging to treat with joint preservation13. There were 7 Campanacci grade-II and 13 grade-III tumors. Joint preservation was possible in 90%, and the same percentage showed increased cortical and subchondral bone thickness. Denosumab did not decrease the overall size of the tumors, nor did it impact the recurrence rate.
Aneurysmal Bone Cyst (ABC)
Therapeutic strategies involving either percutaneous sclerotherapy injection or osteoclast-mediated bone resorption blockade via receptor activator of nuclear factor kappa-B ligand (RANKL) targeting are showing promise and may mitigate the morbidity of traditional surgical curettage and bone-grafting. Shiels et al. reported the outcomes of 16 patients with juxtaphyseal ABCs treated by injecting doxycycline in a protein foam into the tumor (off-label use)14. Patients received 2 to 14 treatments and were followed for 24 to 67 months. Osseous bars that developed correlated with areas of pretreatment ABC. No diffuse growth-plate arrest was observed. All patients demonstrated metaphyseal remodeling, and the recurrence rate was 6%.
Sclerotherapy using alcohol-based gel substances has also been described15. Alternatively, another nonsurgical targeted therapy exploits recent research confirming RANKL as a therapeutic target in the treatment of ABCs by using denosumab, a human monoclonal antibody against RANKL16. Clinical reports are verifying this strategy, although results remain anecdotal17. While a response to denosumab is promising, the durability of response remains to be elucidated.
There were no recurrences in a study of 108 patients treated surgically for atypical cartilaginous tumors, the new World Health Organization name for chondrosarcoma grade-1 tumors18. The authors of the study suspected residual tumor in 4.6%. The tumors were diagnosed with use of imaging, including magnetic resonance imaging (MRI), and with consensus achieved at a weekly multidisciplinary tumor meeting. All patients were treated with curettage, phenolization, filling of the defect, and internal fixation as needed. Preoperative radiofrequency ablation of tumors was also performed for some patients. Postoperatively, there were no pathologic upgrades or downgrades. Fractures occurred postoperatively in 10.2% of the patients. Given these results, the authors speculated that a less invasive approach may be a next step for evaluation.
Leet et al. confirmed fibrous dysplasia’s reputation for returning after curettage and bone-grafting, especially in children19. Bone grafts were reviewed at an average follow-up of 19.6 years in 23 patients with polyostotic fibrous dysplasia. In only 1 of the 12 patients who were <12 years old at the time of grafting was the graft maintained. There was no difference between structural or nonstructural graft maintenance among either the patients who were ≥18 years of age or those <18 years of age. The authors concluded that grafting is of limited value in younger children and alternative means of supporting the bone, such as internal fixation, should be considered.
The presence of RANKL-mediated osteolysis has been shown in fibrous dysplasia16. Whether or not this can be used as a targeted therapy for fibrous dysplasia remains to be seen.
In a study by van Wulfften Palthe et al., patients with more nerve roots spared tended to have better functional scores when surveyed at least 6 months after sacral resection20. Three institutions reviewed 74 patients, 58 of whom had chordoma. They determined patient-reported function using several Patient-Reported Outcome Measurement Information System (PROMIS) surveys (pain intensity, pain interference, sexual function, and global health) and the Modified Obstruction and Defecation Score survey. Notable differences between adjacent levels included better mental and physical health scores for patients in whom the nerve roots of S3 and above were spared compared with S2 and above. Patients in whom the nerve roots of S1 and above were spared had lower orgasm scores than those in whom the roots of S2 and above were spared. Colostomy did not impact mental health, physical health, or pain.
Research on compliant pre-stress osseointegration (CPS) (Compress; Biomet) that places static load on the bone-implant interface showed that most failures occurred in the first 2 years21. Spindle survival at 5 and 10 years was 91%, and survival from rotational failure at 5 and 10 years was 92%. Revising a conventional prosthesis with a CPS prosthesis showed similar good results. The 5 and 10-year mechanical failure rates were both 11%22.
Several studies highlighted the challenge of durability in expandable prostheses. One large series included patients who underwent lengthening with open surgery, with minimally invasive surgery, and without surgery23. Lengthening was possible, but 58 of the 71 patients had a total of 184 complications. An average of 4.4 lengthening procedures were performed, and complications required an average of 2.5 surgeries.
Complications of the noninvasively expandable Repiphysis prosthesis (MicroPort Orthopedics) were reported for a cohort of 15 patients24. Revision for mechanical failure was required in 9 of 10 survivors at an average of 62 months. Another study noted proximal tibial growth disturbance adjacent to the expandable prosthesis placed after distal femoral resection25. Typically, when treating a distal femoral tumor with an expandable prosthesis, the hinged total knee part of the prosthesis is attached to the tibia by first making a cut just deep enough to remove the articular cartilage and then drilling a hole in the proximal part of the tibia through the physis to accommodate a smooth uncemented stem. Arteau et al. noted that 65% of their patients had less proximal tibial growth in the operative compared with the contralateral limb25. Ten of these had progressive worsening of the difference over time, 5 had a ≥2.0-cm difference, 3 underwent epiphyseodesis on the contralateral side, and 1 of these needed an angular correction on the affected side.
Segmental Modular Universal Tumor and Revision System (MUTARS; Implantcast) endoprostheses implanted at various anatomic sites resulted in functional scores comparable with those of similar series26. However, cemented prostheses in this series had better average MSTS (Musculoskeletal Tumor Society) scores than cementless implants (84% compared with 66%). Nononcologic complications occurred in 12 (29%) of 41, including 5 uncemented stem failures and 6 cemented stem failures. MSTS scores were similar to those of other series, but femoral implants had the highest failure rates (57%), higher than in other series of segmental implants.
The durability of bipolar hemiarthroplasty has been questioned, but Drexler et al. studied radiographic wear and concluded that their results justified the continued use of bipolar hemiarthroplasty in patients with proximal femoral replacements27. They assessed 65 patients with an average age of 57.8 years; 18 had metastatic lesions or myeloma. At an average of 9.1 years of follow-up, only 3 had undergone revision to a total hip arthroplasty. Three (4.6%) had acetabular degenerative changes, and 9 (13.8%) had protrusion of the prosthetic head. The authors cautioned that patients with these findings have an association with the need for future total hip arthroplasty and should be monitored.
Patellar surgery and patellar complications were similar in resurfaced and nonresurfaced groups in the setting of a distal femoral replacement28. Radiographic parameters and physician-scored functional surveys were analyzed for 48 patients with patellar resurfacing and 60 without resurfacing. The age of patients with resurfacing was greater than that of those without (40.9 compared with 28.3 years). Degenerative disease was common in the nonresurfaced group (48%) but was not significantly associated with pain. Surgery for the patella (8% overall) and patellar complications were similar between the groups.
Longer term follow-up of early endoprostheses underscored the need for revision and the persistent risk of infection. Grimer et al. identified 230 patients with 25 to 43 years of follow-up after endoprosthetic replacement for primary bone tumors29. Those without infection had an average of 2.1 additional surgeries, while those with infection had an average of 4.6. It is important to note that the risk of infection after any subsequent surgery was found to be 2.7%. The risk of infection persisted at 1% per year over the lifetime of the prosthesis.
Segmental defects in children after tumor resection were reconstructed successfully with the induced membrane technique by Fitoussi and Ilharreborde30. They used a 2-stage technique that varied substantially from trauma use, given a much longer delay between stages. They waited an average of 8.4 months between stages from the completion of chemotherapy. The defects were filled with iliac crest autograft, a nonvascularized autologous fibular graft, and a bridging plate. The 8 patients all healed successfully at an average of 0.31 months per centimeter of defect. Healing took 4 to 8 months (average, 5.6 months). Three patients experienced fracture, all treated successfully.
Vascularized free fibular grafts are a powerful reconstruction tool after tumor resection, but complications are still common. Hilven et al. reported on a series of 74 of these grafts, 93% of which resulted in successful limb salvage and osseous union31. Complications arose in 47% of the patients, and 35% had complication-related revision surgery. They also noted that osseous union cannot be expected during chemotherapy, so weight-bearing must be protected during that time.
A particularly demanding pediatric intercalary resection and reconstruction is one that spares the epiphysis. Aponte-Tinao et al. reported on 35 patients with a minimum of 5 years of follow-up and in whom at least 1 cm of epiphysis was spared32. These patients had a planned margin of at least 10 mm. Fifty-four percent had complications, but the limb survival rate was 97% at both 5 and 10 years. Because of complications, 10 patients lost the allograft and 5 lost the original epiphysis. Three patients had local recurrence. All local recurrences were in the soft tissues and not the bone. The recurrence rate was a bit high but comparable with that of other series given the small numbers in this study.
Aponte-Tinao et al. also reviewed their experience treating infections of large allografts33. At 10 years, the infection rate was 9%. Debridement and antibiotics were successful in treating 18% of the infections. This failed in the remainder, resulting in graft removal and placement of a cement spacer, followed in most cases by a subsequent definitive surgery. Factors associated with infection included tibial allografts, male sex, procedures performed in a conventional operating room, and longer periods of postoperative antibiotics (3 months). Of the patients who underwent revision with a second allograft, 50% experienced new infection, while only 12% of the patients treated with endoprostheses during revision developed a second infection.
Among adults who underwent amputation for primary musculoskeletal tumors, the amputation level correlated with the TESS but was not obviously connected to quality of life34. Forty percent (100) of the surveyed patients completed function outcome questionnaires. At least some pain was noted by 91.6% of the patients, and pain negatively impacted their functional and quality-of-life survey responses.
To learn more about the latest advances in the treatment of bone tumors, the following meetings and events are scheduled for 2017.
* The Musculoskeletal Tumor Society will meet in Denver, Colorado, in October 2017, and sponsors a Specialty Day at the annual meeting of the American Academy of Orthopaedic Surgeons (AAOS), covering current topics in bone and soft-tissue tumors.
* The Connective Tissue Oncology Society will meet in Maui, Hawaii, from November 8-11, 2017. This multidisciplinary society showcases research from around the world in all specialty areas of diagnostic and therapeutic approaches to bone and soft-tissue tumors, particularly sarcomas.
* The International Society of Limb Salvage will meet in Kanazawa, Japan, from May 10-12, 2017, with a focus on research and education in limb preservation in the setting of musculoskeletal tumors.
Investigation performed at the University of Minnesota, Minneapolis, Minnesota
Specialty Update has been developed in collaboration with the Board of Specialty Societies (BOS) of the American Academy of Orthopaedic Surgeons.
Disclosure: One of the authors (C.M.O.) reports a stipend from JBJS for writing this work. On the Disclosure of Potential Conflicts of Interest forms, which are provided with the online version of the article, one or more of the authors checked “yes” to indicate that the author had a relevant financial relationship in the biomedical arena outside the submitted work.
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2. Li J, Guo Z, Wang Z, Fan H, Fu J. 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(10):3204–11. Epub 2015 Jul 8.
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14. Shiels WE 2nd, Beebe AC, Mayerson JL. Percutaneous doxycycline treatment of juxtaphyseal aneurysmal bone cysts. J Pediatr Orthop. 2016 ;36(2):205–12.
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16. Yamagishi T, Kawashima H, Ogose A, Ariizumi T, Sasaki T, Hatano H, Hotta T, Endo N. Receptor-activator of nuclear kappaB ligand expression as a new therapeutic target in primary bone tumors. PLoS One. 2016;11(5):e0154680. Epub 2016 May 10.
17. Skubitz KM, Peltola JC, Santos ER, Cheng EY. Response of aneurysmal bone cyst to denosumab. Spine (Phila Pa 1976). 2015 ;40(22):E1201–4.
18. Dierselhuis EF, Gerbers JG, Ploegmakers JJ, Stevens M, Suurmeijer AJ, Jutte PC. Local treatment with adjuvant therapy for central atypical cartilaginous tumors in the long bones: analysis of outcome and complications in one hundred and eight patients with a minimum follow-up of two years. J Bone Joint Surg Am. 2016 ;98(4):303–13.
19. Leet AI, Boyce AM, Ibrahim KA, Wientroub S, Kushner H, Collins MT. Bone-grafting in polyostotic fibrous dysplasia. J Bone Joint Surg Am. 2016 ;98(3):211–9.
20. van Wulfften Palthe OD, Houdek MT, Rose PS, Yaszemski MJ, Sim FH, Boland PJ, Healey JH, Hornicek FJ, Schwab JH. How does the level of nerve root resection in en bloc sacrectomy influence patient-reported outcomes? Clin Orthop Relat Res. 2016 . [Epub ahead of print].
21. Goldman LH, Morse LJ, O’Donnell RJ, Wustrack RL. How often does spindle failure occur in compressive osseointegration endoprostheses for oncologic reconstruction? Clin Orthop Relat Res. 2016 ;474(7):1714–23. Epub 2016 Apr 22.
22. Zimel MN, Farfalli GL, Zindman AM, Riedel ER, Morris CD, Boland PJ, Healey JH. Revision distal femoral arthroplasty with the Compress(®) prosthesis has a low rate of mechanical failure at 10 years. Clin Orthop Relat Res. 2016 ;474(2):528–36. Epub 2015 Sep 22.
23. Schinhan M, Tiefenboeck T, Funovics P, Sevelda F, Kotz R, Windhager R. Extendible prostheses for children after resection of primary malignant bone tumor: twenty-seven years of experience. J Bone Joint Surg Am. 2015 ;97(19):1585–91.
24. Staals EL, Colangeli M, Ali N, Casanova JM, Donati DM, Manfrini M. Are complications associated with the Repiphysis(®) expandable distal femoral prosthesis acceptable for its continued use? Clin Orthop Relat Res. 2015 ;473(9):3003–13. Epub 2015 May 21.
25. Arteau A, Lewis VO, Moon BS, Satcher RL, Bird JE, Lin PP. Tibial growth disturbance following distal femoral resection and expandable endoprosthetic reconstruction. J Bone Joint Surg Am. 2015 ;97(22):e72.
26. Benevenia J, Kirchner R, Patterson F, Beebe K, Wirtz DC, Rivero S, Palma M, Friedrich MJ. Outcomes of a modular intercalary endoprosthesis as treatment for segmental defects of the femur, tibia, and humerus. Clin Orthop Relat Res. 2016 ;474(2):539–48.
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28. Etchebehere M, Lin PP, Bird JE, Satcher RL, Moon BS, Yu J, Li L, Lewis VO. Patellar resurfacing: does it affect outcomes of distal femoral replacement after distal femoral resection? J Bone Joint Surg Am. 2016 ;98(7):544–51.
29. Grimer RJ, Aydin BK, Wafa H, Carter SR, Jeys L, Abudu A, Parry M. Very long-term outcomes after endoprosthetic replacement for malignant tumours of bone. Bone Joint J. 2016 ;98-B(6):857–64.
30. Fitoussi F, Ilharreborde B. Is the Induced-membrane technique successful for limb reconstruction after resecting large bone tumors in children? Clin Orthop Relat Res. 2015 ;473(6):2067–75. Epub 2015 Jan 30.
31. Hilven PH, Bayliss L, Cosker T, Dijkstra PD, Jutte PC, Lahoda LU, Schaap GR, Bramer JA, van Drunen GK, Strackee SD, van Vooren J, Gibbons M, Giele H, van de Sande MA. The vascularised fibular graft for limb salvage after bone tumour surgery: a multicentre study. Bone Joint J. 2015 ;97-B(6):853–61.
32. Aponte-Tinao L, Ayerza MA, Muscolo DL, Farfalli GL. Survival, recurrence, and function after epiphyseal preservation and allograft reconstruction in osteosarcoma of the knee. Clin Orthop Relat Res. 2015 ;473(5):1789–96. Epub 2014 Oct 29.
33. Aponte-Tinao LA, Ayerza MA, Muscolo DL, Farfalli GL. What are the risk factors and management options for infection after reconstruction with massive bone allografts? Clin Orthop Relat Res. 2016 ;474(3):669–73.
34. Furtado S, Grimer RJ, Cool P, Murray SA, Briggs T, Fulton J, Grant K, Gerrand CH. Physical functioning, pain and quality of life after amputation for musculoskeletal tumours: a national survey. Bone Joint J. 2015 ;97-B(9):1284–90.