Sander Dijkstra

The Clinical Approach Towards Chondrosarcoma

This review provides an overview of the histopathology, classification, diagnostic procedures, and therapy of skeletal chondrosarcoma. Chondrosarcomas that arise de novo are primary chondrosarcomas, whereas chondrosarcomas developing superimposed on pre-existing benign cartilage neoplasms such as enchondromas or osteochondromas are referred to as secondary chondrosarcomas. Conventional chondrosarcomas can be categorized according to their location in bone into central, peripheral, and juxtacortical chondrosarcomas. Histological grading is related to prognosis; however, it is also subject to interobserver variability. Rare subtypes of chondrosarcoma, including dedifferentiated, mesenchymal, and clear cell chondrosarcoma, are discussed as well. Magnetic resonance imaging is necessary to delineate the extent of the intraosseous and soft tissue involvement preoperatively. Computed tomography is especially recommended in the pelvis and other flat bones where it may be difficult to discern the pattern of bone destruction and the presence of matrix mineralization. Wide, en-bloc excision is the preferred surgical treatment in intermediate- and high-grade chondrosarcoma. In low-grade chondrosarcoma confined to the bone, extensive intralesional curettage followed by local adjuvant treatment and filling the cavity with bone graft has promising long-term clinical results and satisfactory local control. Chondrosarcomas are relatively radiotherapy resistant; therefore, doses >60 Gy are needed in attempts to achieve local control after incomplete resection. Irradiation with protons or other charged particles seems beneficial in this curative situation. Chemotherapy is only possibly effective in mesenchymal chondrosarcoma, and is of uncertain value in dedifferentiated chondrosarcoma. Potential new systemic treatment targets are being discussed.

Prediction of survival in patients with metastases in the spinal column: results based on a randomized trial of radiotherapy.

Adequate prediction of survival is important in deciding on treatment for patients with symptomatic spinal metastases. The authors reviewed 342 patients with painful spinal metastases without neurologic impairment who were treated conservatively within a large, prospectively randomized radiotherapy trial. Response to radiotherapy and prognostic factors for survival were studied.

Atypical fractures and bisphosphonate therapy: A cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features

Atypical subtrochanteric/femoral shaft (ST/FS) fractures are increasingly reported in patients on long-term treatment with bisphosphonates (BPs). We estimated the frequency of atypical fractures and their association to BP use in patients aged ≥ 50 years consecutively admitted to a single center with a new femoral fracture. All individual radiographs were examined and fracture site confirmed. A case-control study of patients with low-energy ST/FS fractures, age- and sex-matched with patients with hip fractures (1:2 ratio), was performed. Patients with atypical ST/FS fractures were further compared with those with ordinary ST/FS fractures. Cortical thickness (CT) was measured in radiographs of cases and controls. Ninety-six of 906 patients (10.6%) had a ST/FS fracture. Of these, 63 with low-energy fractures were individually matched with 126 controls with hip fracture. BPs were used by 9.5% of cases and by 8.7% of controls (OR, 1.10; 95% CI, 0.39-3.06) with comparable duration of therapy between groups (54 ± 35 vs. 54 ± 52 months, P=0.53). CT was comparable between cases and controls, BP users and non-users, and was not related to treatment duration. Atypical fractures were observed in 10/63 ST/FS cases (15.9%). Compared to patients with ordinary ST/FS fractures, those with atypical fractures were using more frequently BPs (OR, 17.0; 95% CI, 2.6-113.3) and glucocorticoids (OR, 5.3; 95% CI, 0.9-28.6). Among patients with atypical fractures, CT was comparable between BP users and non-users. In conclusion, atypical femoral fractures have a low prevalence (1.1% of all femoral fractures), compared to ordinary ST/FS fractures are more frequent in bisphosphonate users, but equally occur in patients never treated with bisphosphonates.

Simple radiographic parameter predicts fracturing in metastatic femoral bone lesions: results from a randomised trial

BACKGROUND AND PURPOSE In the randomised Dutch Bone Metastasis Study on the palliative effect of a single fraction (SF) of 8 Gy versus six fractions of 4 Gy on painful bone metastases, 14 fractures occurred in 102 patients with femoral metastases. Purpose of the present study was to identify lesional risk factors for fracturing and to evaluate the influence of the treatment schedule. MATERIAL AND METHODS Pretreatment radiographs of femoral metastases were collected. Three observers separately measured the lesions and scored radiographic characteristics. RESULTS Ten fractures occurred after median 7 weeks in 44 SF patients (23%) and four after median 20 weeks in 58 multiple fraction patients (7%) (UV, P=0.02). In 110 femoral metastases, an axial cortical involvement >30 mm significantly predicted fracturing (MV, P=0.02). Twelve out of 14 fractured lesions and 40 out of 96 non-fractured metastases had an axial cortical involvement >30 mm (negative predictive value, 97%). When correcting for the axial cortical involvement, the treatment schedule was not predictive anymore (MV, P=0.07). CONCLUSIONS Fracturing of the femur mostly depended on the amount of axial cortical involvement of the metastasis. We recommend to treat femoral metastases with an axial cortical involvement < or =30 mm with an SF of 8 Gy for relief of pain. If the axial cortical involvement is >30 mm, prophylactic surgery should be performed to minimize the risk of pathological fracturing or, if the patients condition is limited, irradiation to a higher total dose.

No haploinsufficiency but loss of heterozygosity for EXT in multiple osteochondromas.

Multiple osteochondromas (MO) is an autosomal dominant disorder caused by germline mutations in EXT1 and/or EXT2. In contrast, solitary osteochondroma (SO) is nonhereditary. Products of the EXT gene are involved in heparan sulfate (HS) biosynthesis. In this study, we investigated whether osteochondromas arise via either loss of heterozygosity (2 hits) or haploinsufficiency. An in vitro three-dimensional chondrogenic pellet model was used to compare heterozygous bone marrow-derived mesenchymal stem cells (MSCs EXT(wt/-)) of MO patients with normal MSCs and the corresponding tumor specimens (presumed EXT(-/-)). We demonstrated a second hit in EXT in five of eight osteochondromas. HS chain length and structure, in vitro chondrogenesis, and EXT expression levels were identical in both EXT(wt/-) and normal MSCs. Immunohistochemistry for HS, HS proteoglycans, and HS-dependent signaling pathways (eg, TGF-β/BMP, Wnt, and PTHLH) also showed no differences. The cartilaginous cap of osteochondroma contained a mixture of HS-positive and HS-negative cells. Because a heterozygous EXT mutation does not affect chondrogenesis, EXT, HS, or downstream signaling pathways in MSCs, our results refute the haploinsufficiency theory. We found a second hit in 63% of analyzed osteochondromas, supporting the hypothesis that osteochondromas arise via loss of heterozygosity. The detection of the second hit may depend on the ratio of HS-positive (normal) versus HS-negative (mutated) cells in the cartilaginous cap of the osteochondroma.

Radiofrequency Ablation of Spinal Osteoid Osteoma : Clinical Outcome

Study Design. A prospective study on 24 patients with spinal osteoid osteoma treated with radiofrequency ablation (RFA). Objective. To determine if and when computed tomography (CT)-guided RFA is a safe and effective treatment for spinal osteoid osteomas. Summary of Background Data. Surgery has been considered the standard treatment for spinal osteoid osteomas. Surgery may cause spinal instability, infection, and nervous injury. We evaluated CT-guided RFA as an alternative treatment. Methods. A total of 28 RFA procedures in 24 patients with spinal osteoid osteoma were performed, using a 5-mm noncooled electrode. Clinical symptoms and spinal deformity were evaluated before and after the procedure. Unsuccessful treatment was defined as the presence of residual or recurrent symptoms. The mean follow-up was 72 months (range: 9–142 months). Results. Nineteen (79%) patients were successfully treated after 1 RFA, and all except one after repeat RFA. One patient with nerve root compression needed further surgery. No complications were observed. Spinal deformity persisted in 3 of 7 patients after successful RFA. Conclusion. CT-guided RFA is a safe and effective treatment for spinal osteoid osteoma. Surgery should be reserved for lesions causing nerve root compression.

Long-term results: adjuvant radiotherapy in en bloc resection of sacrococcygeal chordoma is advisable.

Study Design. A cross-sectional study. Objective. The purpose of this report is to define the role of postoperative radiotherapy in the prevention of local recurrence (LR). Summary of Background Data. Sacrococcygeal chordoma is a slow growing, malignant tumor with a clinical poor outcome due to a high LR rate. Several studies emphasize that margin-free tumor resection is the most important predictor of LR. However, even after extralesional resection a high LR up to 80% remains. Methods. A retrospective series of 15 patients who underwent surgical treatment for sacrococcygeal chordoma in one center between 1981 and 2003 was reviewed. Overall survival and continuous disease-free survival rates were compared between patients with intralesional resection with standard radiotherapy and patients with extralesional resection and no standard radiotherapy. Results. The median age at surgery was 53 years. The mean follow-up was 7 years or until death. Mean duration of preoperative complaints was 3 years. In 10 patients, an en bloc resection was (histologic resection margins were free) performed and in 5 patients, an intralesional resection was achieved. All but one patients with intralesional resection received radiotherapy (>50 Gy) and patients with extralesional resection only received radiotherapy in case of LR (6 of 10 patients). After extralesional resection (no initial radiotherapy), all 10 patients had LR of the tumor with a mean time to recurrence of 2 years. Six of these ten patients received radiotherapy after LR and had mean survival duration of 7 years. Only one (of five patients) in the group with intralesional resection and postoperative radiotherapy had LR after 11 years. The time to recurrence was significantly longer and we found a trend toward a longer overall survival in the group that received immediate radiotherapy after surgery. Conclusion. The results support the strategy to add radiotherapy as standard adjuvant therapy to sacrococcygeal chordoma tumor resection.

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.

The Value of Routinely Performing a Bone Biopsy During Percutaneous Vertebroplasty in Treatment of Osteoporotic Vertebral Compression Fractures

Study Design. A retrospective histologic evaluation of biopsies obtained during percutaneous vertebroplasty (PVP) procedures as treatment for presumed osteoporotic vertebral compression fractures. Objective. To determine the rate of unsuspected malignancy in bone biopsies of patients undergoing PVP for osteoporotic vertebral compression fractures. Summary of Background Data. Most vertebral compression fractures, which result from minimal, or no trauma have osteoporosis as underlying cause. The diagnosis osteoporosis is based on clinical and radiologic findings. Even in patients with proven osteoporosis it is not always the true cause of the fractures. In literature, outcomes of bone-biopsies obtained during vertebroplasty have been described with inconsistent percentages of unexpected malignancy. Methods. To determine the rate of unsuspected malignancy, 78 biopsies were obtained from 78 patients (18 male; 60 female; mean age, 73 years). The histologic diagnoses of vertebral body biopsy specimens were analyzed in a retrospective study. Results. Seventy-one biopsies (91%) obtained from 71 patients, were suitable for histologic evaluation. Seven biopsies (9.0%) could not be interpreted as a result of suboptimal quality biopsy material. The population included 10 patients (13%) with a history of malignancy, in this group no malignancy was found in the bone biopsies. In 3 patients (3.8% of all biopsies) previously undiagnosed malignancies, 2 multiple myeloma stage IIa and 1 chondrosarcoma grade I, were found. Conclusion. Obtaining bone biopsies during PVPs does not lead to increased morbidity and can verify the pathologic process underlying the vertebral compression fractures. Since this study showed an unsuspected malignancy rate of 3.8%, we recommend routine obtainment of a vertebral body bone biopsy, preferably using a biopsy needle with a diameter larger than 14 Gauge (>2.1 mm/0.083 inch), during every PVP procedure.

Current status and unanswered questions on the use of Denosumab in giant cell tumor of bone

Denosumab is a monoclonal antibody to RANK ligand approved for use in giant cell tumour (GCT) of bone. Due to its efficacy, Denosumab is recommended as the first option in inoperable or metastatic GCT. Denosumab has also been used pre-operatively to downstage tumours with large soft tissue extension to allow for less morbid surgery. The role of Denosumab for conventional limb GCT of bone is yet to be defined. Further studies are required to determine whether local recurrence rates will be decreased with the adjuvant use of Denosumab along with surgery. The long term use and toxicity of this agent is unknown as is the proportion of patients with primary or secondary resistance. It is advised that complicated cases of GCT requiring Denosumab treatment should be referred and followed up at expert centres. Collaborative studies involving further clinical trials and rigorous data collection are strongly recommended to identify the optimum use of this drug.