Michiel A. J. van de Sande

The Clinical Approach Toward Giant Cell Tumor of Bone

We provide an overview of imaging, histopathology, genetics, and multidisciplinary treatment of giant cell tumor of bone (GCTB), an intermediate, locally aggressive but rarely metastasizing tumor. Overexpression of receptor activator of nuclear factor κB ligand (RANKL) by mononuclear neoplastic stromal cells promotes recruitment of numerous reactive multinucleated giant cells. Conventional radiographs show a typical eccentric lytic lesion, mostly located in the meta-epiphyseal area of long bones. GCTB may also arise in the axial skeleton and very occasionally in the small bones of hands and feet. Magnetic resonance imaging is necessary to evaluate the extent of GCTB within bone and surrounding soft tissues to plan a surgical approach. Curettage with local adjuvants is the preferred treatment. Recurrence rates after curettage with phenol and polymethylmethacrylate (PMMA; 8%-27%) or cryosurgery and PMMA (0%-20%) are comparable. Resection is indicated when joint salvage is not feasible (e.g., intra-articular fracture with soft tissue component). Denosumab (RANKL inhibitor) blocks and bisphosphonates inhibit GCTB-derived osteoclast resorption. With bisphosphonates, stabilization of local and metastatic disease has been reported, although level of evidence was low. Denosumab has been studied to a larger extent and seems to be effective in facilitating intralesional surgery after therapy. Denosumab was recently registered for unresectable disease. Moderate-dose radiotherapy (40-55 Gy) is restricted to rare cases in which surgery would lead to unacceptable morbidity and RANKL inhibitors are contraindicated or unavailable.

Quantitative Assessment of Fatty Degeneration in Rotator Cuff Muscles Determined With Computed Tomography

Objectives:Reliable assessment of fatty degeneration of rotator cuff muscles is desirable to predict the outcome of shoulder surgery. Currently used qualitative assessments are limited by relatively high inter- and intraobserver variability. It was hypothesized that a quantitative measurement of muscle density using computed tomography (CT) was more reliable and reproducible. Materials and Methods:Thirty shoulders from patients with rheumatoid arthritis were analyzed using parasagittal multiplanar reconstructions acquired from a 16-slice CT scanner. Three observers visually rated the severity of fatty degeneration and independently outlined the rotator cuff muscles, after which the mean density was calculated. Inter- and intraobserver agreement on both measurements was expressed by the interclass correlation coefficient (ICC) and the standard deviation of the differences (SDD) between the measurements. Results:A strong correlation was found between the quantitative measure and the visual rating (R2 = 0.94; P < 0.0001). The SDD in muscle density did not exceed 2.3 Hounsfield units, and the mean rotator cuff ICC (0.98) was substantially greater than that of the visual rating (0.63). Conclusions:This study describes a reproducible method to quantify fatty degeneration of the rotator cuff muscles in CT images, with a higher interobserver agreement than the visual score, and may prove a reliable tool to evaluate the quality of the rotator cuff muscles.

Outcome of advanced, unresectable conventional central chondrosarcoma

For patients who have chondrosarcoma with unresectable disease, because of tumor location, tumor size, or extensive metastatic disease, treatment options are very limited because of their relative resistance to radiotherapy and chemotherapy. The overall survival of this patient population is poor; however, specific studies are lacking, and large series have not been published. Therefore, the authors conducted this retrospective, 2‐center study to gain insight into the outcome of patients with advanced, unresectable, conventional central chondrosarcoma.

Clinical implications of rotator cuff degeneration in the rheumatic shoulder.

OBJECTIVE In rheumatoid arthritis (RA) of the shoulder, loss of cartilage and soft tissue degeneration coexists with pain and reduced range of motion. We evaluated the presence of bony and rotator cuff degeneration in RA of the shoulder joint and assessed their relationship with pain and loss of functioning. We hypothesized that rotator cuff degeneration plays an important role in the presence of pain and loss of functioning of the rheumatic shoulder. METHODS We used a cross-sectional study to assess both bony and rotator cuff involvement using plain anteroposterior radiographs, ultrasound, and computed tomography images. Additionally, we used an electromagnetic tracking device and a force transducer to evaluate range of motion and maximum force of the shoulder muscles. Between January 2003 and July 2004 we included 26 consecutive patients (51 shoulders). Twenty-one shoulders showed no or slight joint destruction, 15 showed intermediate destruction, and 15 showed severe destruction. RESULTS Only 19 shoulders showed an intact rotator cuff. Proximal migration of the humeral head and fatty degeneration of the infraspinatus muscle especially showed a significantly strong correlation with increased pain and function loss (R2 = 0.36, P < 0.001). In a multivariate regression analysis, proximal migration and fatty degeneration of the infraspinatus muscle were related most significantly with pain and reduced functioning in the shoulder joint. CONCLUSION Rotator cuff degeneration plays an important role in the daily functioning of the rheumatic shoulder. Prevention of rotator cuff degeneration may therefore play an important part in the treatment of the rheumatic shoulder.

Liquid nitrogen or phenolization for giant cell tumor of bone?: a comparative cohort study of various standard treatments at two tertiary referral centers

BACKGROUND The rate of recurrence of giant cell tumor of bone is decreased by use of adjuvant treatments such as phenol, liquid nitrogen, or polymethylmethacrylate (PMMA) during curettage. We assessed recurrence and complication rates and functional outcome after curettage with use of phenol and PMMA, liquid nitrogen and PMMA, and liquid nitrogen and bone grafts. METHODS We retrospectively compared the relative effectiveness of treatment of giant cell tumors of bone at two tertiary centers with a regional function from 1990 to 2010. The 132 (of 201) patients who met the inclusion criteria had a mean age of thirty-three years (range, eleven to sixty-nine years). Treatment assignment depended purely on the center, with primary treatment consisting of curettage with use of phenol and PMMA (n = 82) at one center and with use of either liquid nitrogen and PMMA (n = 26) or liquid nitrogen and bone grafts (n = 24) at the other center. Recurrence and complication rates were determined, and functional outcome was assessed on the basis of the Musculoskeletal Tumor Society (MSTS) score. RESULTS The mean duration of follow-up was eight years (range, two to twenty-two years). Recurrence rates were comparable among the groups (28% for phenol and PMMA, 31% for liquid nitrogen and PMMA, and 38% for liquid nitrogen and bone grafts; p = 0.52). Soft-tissue extension increased the recurrence risk (hazard ratio [HR] = 2.1, 95% confidence interval [CI] = 1.1 to 4.0, p = 0.024). The complication rate was 33% after use of liquid nitrogen and bone grafts, 27% after liquid nitrogen and PMMA, and 11% after phenol and PMMA (p = 0.019); complications included osteoarthritis, infection, postoperative fracture, nonunion, transient nerve palsy, and PMMA leakage. The complication risk was increased by the presence of a pathologic fracture (HR = 4.1, 95% CI = 1.7 to 9.5, p = 0.001) and use of liquid nitrogen (HR = 3.9, 95% CI = 1.5 to 10, p = 0.006 for liquid nitrogen and bone grafts; HR = 3.1, 95% CI = 1.1 to 8.6, p = 0.028 for liquid nitrogen and PMMA). The mean MSTS score was 26 (range, 8 to 30) and was comparable among all three groups (p = 0.52). CONCLUSIONS Recurrence rates were comparable for treatment with phenol and PMMA, liquid nitrogen and PMMA, and liquid nitrogen and bone grafts. Complication rates were higher after use of liquid nitrogen. The functional outcome was excellent in all three cohorts.

What Are the Long-term Results of MUTARS® Modular Endoprostheses for Reconstruction of Tumor Resection of the Distal Femur and Proximal Tibia?

Background Modular endoprostheses are commonly used to reconstruct defects of the distal femur and proximal tibia after bone tumor resection. Because limb salvage surgery for bone sarcomas is relatively new, becoming more frequently used since the 1980s, studies focusing on the longterm results of such prostheses in treatment of primary tumors are scarce. Questions/purposes (1) What proportion of patients experience a mechanical complication with the MUTARS 1 modular endoprosthesis when used for tumor reconstruction around the knee, and what factors may be associated with mechanical failure? (2) What are the nonmechanical complications? (3) What are the implant failure rates at 5, 10, and 15 years? (4) How often is limb salvage achieved using this prosthesis? Methods Between 1995 and 2010, endoprostheses were the preferred method of reconstruction after resection of the knee in adolescents and adults in our centers. During that period, we performed 114 MUTARS 1 knee replacements in 105 patients; no other endoprosthetic systems were used. Four patients (four of 105 [4%]) were lost to followup, leaving 110 reconstructions in 101 patients for review. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 8.9 years (95% confidence interval [CI], 8.0‐9.7). Mean age at surgery was 36 years (range, 13‐82 years). Predominant diagnoses were osteosarcoma (n = 56 [55%]), leiomyosarcoma of bone (n = 10 [10%]), and chondrosarcoma (n = 9 [9%]). In the early period of our study, we routinely used uncemented uncoated implants for primary reconstructions. Later, hydroxyapatite (HA)-coated implants were the standard. Eighty-nine reconstructions (89 of 110 [81%]) were distal femoral replacements (78 uncemented [78 of 89 {88%}, 42 of which were HA-coated [42 of 78 {54%}]) and 21 (21 of 110 [19%]) were proximal tibial replacements. In 26 reconstructions (26 of 110 [24%]), the reconstruction was performed for a failed previous reconstruction. We used a competing risk model to estimate the cumulative incidence of implant failure. The institution of one or more of the authors (MPAB, MAJvdS, PDSD) has received, during the study period, funding from implantcast GmbH, Buxtehude, Germany. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research 1 editors and board members are on file with the publication and can be viewed on request. Clinical Orthopaedics and Related Research 1 neither advocates nor endorses the use of any treatment, drug, or device. Readers are encouraged to always seek additional information, including FDAapproval status, of any drug or device prior to clinical use. Each author certifies that his or her institution approved the human protocol for this investigation, that all investigations were conducted in conformity with ethical principles of research, and that informed consent for participation in the study was obtained. This work was performed at Leiden University Medical Center, Leiden, The Netherlands.

Fusion events lead to truncation of FOS in epithelioid hemangioma of bone

Epithelioid hemangioma of bone is a locally aggressive vascular neoplasm. It can be challenging to diagnose because of the wide histological spectrum, which can make it difficult to differentiate from other vascular neoplasms such as epithelioid hemangioendothelioma or epithelioid angiosarcoma. COBRA‐FISH karyotyping identified a balanced t(3;14) translocation. Transcriptome sequencing of the index case and two other epithelioid hemangiomas revealed a recurrent translocation breakpoint involving the FOS gene, which was fused to different partners in all three cases. The break was observed in exon 4 of the FOS gene and the fusion event led to the introduction of a stop codon. In all instances, the truncation of the FOS gene would result in the loss of the transactivation domain (TAD). Using FISH probes we found a break in the FOS gene in two additional cases, in none of these cases a recurrent fusion partner could be identified. In total, FOS was split in 5/7 evaluable samples. We did not observe point mutations leading to early stop codons in any of the 10 cases where RNA was available. Detection of FOS rearrangement may be a useful diagnostic tool to assist in the often difficult differential diagnosis of vascular tumors of bone. Our data suggest that the translocation causes truncation of the FOS protein, with loss of the TAD, which is thereby a novel mechanism involved in tumorigenesis.

Mid-Term Outcome After Curettage with Polymethylmethacrylate for Giant Cell Tumor Around the Knee: Higher Risk of Radiographic Osteoarthritis?

BACKGROUND It has been suggested that, when a patient has a giant cell tumor, subchondral bone involvement close to articular cartilage and a hyperthermic reaction from polymethylmethacrylate (PMMA) are risk factors for the development of osteoarthritis. We determined the prevalence, risk factors, and clinical relevance of osteoarthritis on radiographs after curettage and application of PMMA for the treatment of giant cell tumors around the knee. METHODS This retrospective single-center study included fifty-three patients with giant cell tumor around the knee treated with curettage and PMMA between 1987 and 2007. The median age at the time of follow-up was forty-two years (range, twenty-three to seventy years). There were twenty-nine women. Radiographic evidence of osteoarthritis was defined, preoperatively and postoperatively, as Kellgren and Lawrence grade 3 or 4 (KL3-4). We studied the influence of age, sex, tumor-cartilage distance, subchondral bone involvement (≤3 mm of residual subchondral bone), subchondral bone-grafting, intra-articular fracture, multiple curettage procedures, and complications on progression to KL3-4. Functional outcomes and quality of life were assessed with the Short Form-36 (SF-36), Musculoskeletal Tumor Society (MSTS) score, and Knee injury and Osteoarthritis Outcome Score (KOOS). RESULTS After a median duration of follow-up of eighty-six months (range, sixty to 285 months), six patients (11%) had progression to KL3, two (4%) had progression to KL4, and one had preexistent KL4. No patient underwent total knee replacement. The hazard ratio for KL3-4 was 9.0 (95% confidence interval [CI] = 2.0 to 41; p = 0.004) when >70% of the subchondral bone was affected and 4.2 (95% CI = 0.84 to 21; p = 0.081) when the tumor-cartilage distance was ≤3 mm. Age, sex, subchondral bone-grafting, intra-articular fracture, multiple curettage procedures, and complications did not affect progression to KL3-4. Patients with KL3-4 reported lower scores on the KOOS symptom subscale (58 versus 82; p = 0.01), but their scores on the other KOOS subscales, the MSTS score (21 versus 24), and the SF-36 (76 versus 81) were similar to those for the patients with KL0, 1, or 2 (KL0-2). CONCLUSIONS Seventeen percent of patients with giant cell tumor around the knee had radiographic findings of osteoarthritis after treatment with curettage and PMMA. A large amount of subchondral bone involvement close to articular cartilage increased the risk for osteoarthritis. The function and quality of life of the patients with KL3-4 were comparable with those for the patients with KL0-2, suggesting that radiographic findings of osteoarthritis at the time of intermediate follow-up had a modest clinical impact. Treatment with curettage and PMMA is safe for primary and recurrent giant cell tumors, even large tumors close to the joint. LEVEL OF EVIDENCE Therapeutic level IV. See Instructions for Authors for a complete description of levels of evidence.

LUMiC(®) Endoprosthetic Reconstruction After Periacetabular Tumor Resection: Short-term Results.

BackgroundReconstruction of periacetabular defects after pelvic tumor resection ranks among the most challenging procedures in orthopaedic oncology, and reconstructive techniques are generally associated with dissatisfying mechanical and nonmechanical complication rates. In an attempt to reduce the risk of dislocation, aseptic loosening, and infection, we introduced the LUMiC® prosthesis (implantcast, Buxtehude, Germany) in 2008. The LUMiC® prosthesis is a modular device, built of a separate stem (hydroxyapatite-coated uncemented or cemented) and acetabular cup. The stem and cup are available in different sizes (the latter of which is also available with silver coating for infection prevention) and are equipped with sawteeth at the junction to allow for rotational adjustment of cup position after implantation of the stem. Whether this implant indeed is durable at short-term followup has not been evaluated.Questions/purposes(1) What proportion of patients experience mechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (2) What proportion of patients experience nonmechanical complications and what are the associated risk factors of periacetabular reconstruction with the LUMiC® after pelvic tumor resection? (3) What is the cumulative incidence of implant failure at 2 and 5 years and what are the mechanisms of reconstruction failure? (4) What is the functional outcome as assessed by Musculoskeletal Tumor Society (MSTS) score at final followup?MethodsWe performed a retrospective chart review of every patient in whom a LUMiC® prosthesis was used to reconstruct a periacetabular defect after internal hemipelvectomy for a pelvic tumor from July 2008 to June 2014 in eight centers of orthopaedic oncology with a minimum followup of 24 months. Forty-seven patients (26 men [55%]) with a mean age of 50 years (range, 12–78 years) were included. At review, 32 patients (68%) were alive. The reverse Kaplan-Meier method was used to calculate median followup, which was equal to 3.9 years (95% confidence interval [CI], 3.4–4.3). During the period under study, our general indications for using this implant were reconstruction of periacetabular defects after pelvic tumor resections in which the medial ilium adjacent to the sacroiliac joint was preserved; alternative treatments included hip transposition and saddle or custom-made prostheses in some of the contributing centers; these were generally used when the medial ilium was involved in the tumorous process or if the LUMiC® was not yet available in the specific country at that time. Conventional chondrosarcoma was the predominant diagnosis (n = 22 [47%]); five patients (11%) had osseous metastases of a distant carcinoma and three (6%) had multiple myeloma. Uncemented fixation (n = 43 [91%]) was preferred. Dual-mobility cups (n = 24 [51%]) were mainly used in case of a higher presumed risk of dislocation in the early period of our study; later, dual-mobility cups became the standard for the majority of the reconstructions. Silver-coated acetabular cups were used in 29 reconstructions (62%); because only the largest cup size was available with silver coating, its use depended on the cup size that was chosen. We used a competing risk model to estimate the cumulative incidence of implant failure.ResultsSix patients (13%) had a single dislocation; four (9%) had recurrent dislocations. The risk of dislocation was lower in reconstructions with a dual-mobility cup (one of 24 [4%]) than in those without (nine of 23 [39%]) (hazard ratio, 0.11; 95% CI, 0.01–0.89; p = 0.038). Three patients (6%; one with a preceding structural allograft reconstruction, one with poor initial fixation as a result of an intraoperative fracture, and one with a cemented stem) had loosening and underwent revision. Infections occurred in 13 reconstructions (28%). Median duration of surgery was 6.5 hours (range, 4.0–13.6 hours) for patients with an infection and 5.3 hours (range, 2.8–9.9 hours) for those without (p = 0.060); blood loss was 2.3 L (range, 0.8–8.2 L) for patients with an infection and 1.5 L (range, 0.4–3.8 L) for those without (p = 0.039). The cumulative incidences of implant failure at 2 and 5 years were 2.1% (95% CI, 0–6.3) and 17.3% (95% CI, 0.7–33.9) for mechanical reasons and 6.4% (95% CI, 0–13.4) and 9.2% (95% CI, 0.5–17.9) for infection, respectively. Reasons for reconstruction failure were instability (n = 1 [2%]), loosening (n = 3 [6%]), and infection (n = 4 [9%]). Mean MSTS functional outcome score at followup was 70% (range, 33%–93%).ConclusionsAt short-term followup, the LUMiC® prosthesis demonstrated a low frequency of mechanical complications and failure when used to reconstruct the acetabulum in patients who underwent major pelvic tumor resections, and we believe this is a useful reconstruction for periacetabular resections for tumor or failed prior reconstructions. Still, infection and dislocation are relatively common after these complex reconstructions. Dual-mobility articulation in our experience is associated with a lower risk of dislocation. Future, larger studies will need to further control for factors such as dual-mobility articulation and silver coating. We will continue to follow our patients over the longer term to ascertain the role of this implant in this setting.Level of EvidenceLevel IV, therapeutic study.

Outcome of Long-Term Bisphosphonate Therapy in McCune-Albright Syndrome and Polyostotic Fibrous Dysplasia.

McCune‐Albright syndrome (MAS) is a rare bone disorder characterized by fibrous dysplasia (FD), endocrinopathies, and café‐au‐lait patches. FD patients have been shown to respond favorably to treatment with bisphosphonates, but data are scarce in the more severe polyostotic form (PFD), including MAS, and factors determining treatment outcome are not known, particularly in the long‐term. We evaluated the biochemical (bone turnover markers [BTMs]) and clinical (pain reduction) outcome of bisphosphonate therapy in 11 patients with MAS and 30 patients with PFD: median duration of treatment 6 years (range, 2 to 25 years). Prognostic factors for treatment outcome were identified in both groups. Patients with MAS were younger at diagnosis (p = 0.001), all had precocious puberty, and four (36%) had additional growth hormone (GH) excess associated with severe craniofacial FD. Extent of skeletal disease was more severe in MAS compared to PFD. MAS patients had higher serum alkaline phosphatase (ALP) concentrations (p = 0.005), higher skeletal burden scores (p < 0.001), and more fractures (p = 0.021). MAS patients had also higher levels of FGF‐23 (p = 0.008) and higher prevalence of hypophosphatemia (p = 0.013). Twenty‐four of 30 PFD patients (80%) demonstrated a complete clinical and biochemical response within a year of starting treatment (p = 0.015), compared to only four of 11 MAS patients (36%). There were no nonresponders. In the whole group, FGF‐23, total ALP, P1NP, and CTX positively correlated with skeletal burden scores (all p ≤ 0.001), which was the only significant risk factor for an incomplete response to bisphosphonate therapy (p < 0.01). Our data suggest a beneficial and safe outcome of long‐term bisphosphonate therapy in the majority of patients with PFD, although response to therapy was limited by the higher skeletal disease burden in MAS patients. In the PFD/MAS population studied, the only identified prognostic factor that influenced the outcome of bisphosphonate therapy was a high skeletal burden score.