Edward F. McCarthy

Heterotopic ossification: a review

Heterotopic ossification is the formation of bone in the soft tissues. Soft tissue bone deposition may range from the minimal and inconsequential to massive and clinically significant. In some clinical settings it is a predictable finding with an unpredictable course and in other settings it may be diagnostically confounding. Heterotopic ossification may be encountered in clinically disparate disease processes and circumstances. We review the genetic, neurogenic, post-traumatic, post-surgical and “reactive” causes of heterotopic ossification and discuss some current concepts of its pathogenesis.

Localisation of mesenchymal tumours by somatostatin receptor imaging

Oncogenic osteomalacia, an acquired hypophosphataemic syndrome associated with mesenchymal tumours, is characterised by hypophosphataemia secondary to inappropriate phosphaturia, reduced concentrations of serum calcitriol, and defective bone mineralisation. Removal of these tumours results in complete reversal of these biochemical defects. However, because these tumours are small, slow-growing, and frequently situated in unusual anatomical sites, conventional imaging techniques often fail to detect them. Since mesenchymal tumours express somatostatin receptors, we postulated that somatostatin analogues would be able to detect these tumours. We did Indium-111 labeled pentetreotide imaging in seven patients with oncogenic osteomalacia. In five patients, we identified a mesenchymal tumour, and clinical improvement occurred after tumour resection. Our findings suggest that 111In-pentetreotide imaging effectively detects occult mesenchymal tumours and facilitates surgical treatment of oncogenic osteomalacia.

Brachyury expression in extra-axial skeletal and soft tissue chordomas: A marker that distinguishes chordoma from mixed tumor/myoepithelioma/parachordoma in soft tissue

Axial chordoma represents approximately 1% of malignant bone tumors. This tumor expresses cytokeratins, specifically cytokeratin 19, and commonly S100. More recently brachyury, a transcription factor important in mesodermal differentiation, including notochord development, has been detected by immunohistochemistry in axial chordomas and hemangioblastomas but not chondrosarcomas or other neoplasms. In this report, we describe 10 cases (6 men, 4 women: age 18 to 68 y; mean 44.6) of extra-axial tumors, 8 in bone and 2 in soft tissue, with morphologic and immunohistochemical features identical to those of axial chordoma. Imaging excluded metastases from axial chordoma. Three tumors occurred in the tibia, the others in the rib, metatarsal, ulna, femur, pubis: 2 intracortical, 6 intramedullary. Both soft tissue brachyury-positive tumors, one involving the thumb the other the wrist, were sited in the juxta-articular region. Seven of the tumors were widely excised and these patients are disease-free but of the 3 tumors that recurred, 1 was curetted, 1 was marginally excised, and 1 had a pathologic fracture on presentation. Metastases have not occurred in any of the patients. We also confirm the expression of brachyury in hemangioblastomas, and for the first time demonstrates its expression in spermatogonia and testicular germ cell tumors by immunohistochemistry. Brachyury was not detected in a wide range of tumors including carcinomas, lymphomas, and sarcomas. In conclusion, we describe the first series of extra-axial skeletal chordomas bringing the total number of such cases reported in the literature to 11, and present the first report of 2 soft tissue chordomas as defined by brachyury expression.

Osteosarcoma of the head and neck: A review of the johns hopkins experience

Objective: To determine factors including treatment modalities which influence survival in patients with osteosarcoma of the head and neck. Study Design: Retrospective clinicopathologic study of 27 patients with osteosarcoma of the head and neck. Methods: The clinical charts and pathology slides were reviewed on 27 patients who had osteosarcoma of the head and neck between 1946 and 1998. The following variables were examined for their effect on survival: age of diagnosis, site of tumor, presentation, race, sex, prior radiation exposure, retinoblastoma history, margin status, and method of treatment. Results: The average age at the time of diagnosis of the patients was 37.6 years (range, 7–82 y). The sex distribution was similar with 14 male and 13 female patients. Eight of 27 patients had osteosarcoma of the mandible, 9 of 27 had osteosarcoma of the maxilla and paranasal sinuses, and in 10 of 27 patients osteosarcoma occurred elsewhere, including the temporal bones, occipital bones, and orbit. The overall 2‐year survival was 66% with a 5‐year survival rate of 55%. Conclusions: Positive surgical margins and a high tumor grade were found to have a statistically deleterious effect on overall survival. There was no detectable effect on survival of age, race, sex, prior radiation exposure, tumor site, and tumor cell type. It was not possible to differentiate between the different adjuvant treatment modalities because of the small numbers in the study. Key Words: Bone, malignancy, osteogenic sarcoma, radiation therapy, surgery.

Malignant fibrous histiocytoma of bone: A study of 35 cases

Thirty-five cases of primary malignant fibrous histiocytoma of bone are reported. Twenty of these cases were collected from a retrospective analysis of other malignant bone tumors. The age range was from 11 to 69 years; the average age was 34 years. The tumor occurred most commonly in the distal femur and proximal tibia. The distinguishing histologic feature was a storiform arrangement of spindle cells. The differential diagnosis included fibrosarcoma, osteogenic sarcoma, malignant giant cell tumor, malignant lymphoma, and metastatic carcinoma. Follow-up of at least three years was available in 21 cases. Of these, nine patients were alive and free of metastases three and one-half to 12 years after treatment. Two were alive with solitary metastases at three years, and 10 patients died between three months and three years after treatment. In four cases the lesions were multicentric at the time of diagnosis and in four cases were associated with bone infarction. This tumor must be recognized as an important complication of bone infarction and should be suspected when a patient with a known history of bone infarction develops a change in symptoms. Because the prognosis of this tumor is significantly better than that in those tumors with which it had been previously grouped, and in view of its association with bone infarction, it deserves to be maintained as a distinct clinicopathologic entity. Amputation is the treatment of choice.

Chondrosarcoma of bone with dedifferentiation: A study of eighteen cases

Eighteen patients with chondrosarcomas showing dedifferentiation were reviewed. Thirteen of the 14 patients in whom there was follow-up died of their tumors, with an average survival of six months. The average age was 61, and the most common location was the distal femur. Eight patients presented with pathologic fractures. Radiographically the tumor appeared as a destructive are with an associated heavily calcified lesion. This corresponded to combined histologic patterns of high grade sarcoma, usually with features of a malignant fibrous histiocytoma, and a low grade chondrosarcoma. This lesion must be distinguished from a primary malignant fibrous histiocytoma of bone in view of the different prognostic implications.

Magnetic resonance imaging of soft-tissue tumors : Determinate and indeterminate lesions

The evaluation of patients with soft-tissue masses must be done in a systematic fashion to prevent management errors. Although most soft-tissue masses (approximately 99%) are benign, an error in the management of a soft-tissue sarcoma can lead to limb loss or adversely affect survival1. Before magnetic resonance imaging became easily available, physicians relied on the patients history, physical examination, conventional radiographs, and computed tomography scans for decision-making. These modalities often were insufficient for establishing a definitive diagnosis. The patients history alone cannot provide enough information for a diagnosis and, in fact, may be misleading. For example, lesions identified after a traumatic episode are not necessarily traumatic in origin; only half of soft-tissue sarcomas are painful at presentation2, and the growth rate may not assist in the diagnosis (slow-growing lesions can be malignant or benign). Similarly, although a patient may present with systemic symptoms, the lack of systemic symptoms does not exclude malignancy. Physical examination may provide some clues that may suggest malignancy, but none are pathognomonic. Conventional radiography and computed tomography are not specific enough in differentiating benign and malignant soft-tissue masses. If one relies solely on these modalities, biopsy often is necessary for diagnosis and management. Biopsy is associated with several hazards, including neurovascular injury, hematoma formation, and delayed wound-healing. The use of magnetic resonance imaging to identify soft-tissue lesions has markedly altered the treatment algorithm for a number of lesions3,4. In contrast to conventional radiography and computed tomography, magnetic resonance imaging provides clear advantages in terms of diagnosis: the spatial resolution of the images is excellent; the images can be reconstructed in multiple planes; lesions can be identified more readily, and the lesions signal characteristics can help to narrow the differential diagnosis; areas of hemorrhage, cysts, and vascular structures are …

Mechanisms responsible for longitudinal growth of the cortex: Coalescence of trabecular bone into cortical bone

BACKGROUND The purpose of the present study was to determine whether longitudinal growth of the cortex occurs through intramembranous bone formation involving the periosteum or through endochondral bone formation involving the growth plate and to explore the cellular and biochemical mechanisms responsible for this process. METHODS Cortical bone formation was studied in the metaphyses of growing New Zealand White rabbits by means of (1) oxytetracycline labeling and fluorescence microscopy, (2) computer-assisted histomorphometry, (3) osteoblast culture and [(3) H]-thymidine incorporation in the presence of periosteum or periosteum-conditioned medium, and (4) surgical insertion of membranes between the periosteum and the underlying spongiosa. RESULTS Within the metaphyseal cortex, oxytetracycline labeling produced fluorescent closed curves outlining enlarging trabeculae derived from coalescing endochondral trabecular bone. In this region of coalescing trabeculae close to the periosteum, osteoblast surface was increased compared with trabeculae farther from the periosteum (p < 0.001). The osteoclast surface did not differ. In vitro, osteoblast proliferation was increased in the presence of periosteum (p < 0.001) or periosteum-conditioned medium (p < 0.001). Surgical insertion of permeable or impermeable membranes between the periosteum and the spongiosa did not prevent cortex formation. CONCLUSIONS These observations demonstrate that metaphyseal cortical bone is formed by coalescence of endochondral trabecular bone. This coalescence is associated with increased osteoblast surface in the peripheral spongiosa. The increased osteoblast surface could be due to inductive effects of periosteum; in the present study, periosteum stimulated osteoblast proliferation in vitro but was not required for metaphyseal cortical bone formation in vivo. CLINICAL RELEVANCE Understanding metaphyseal cortical growth may help to elucidate the pathophysiology of osseous growth disorders in children.

The effect of low intensity pulsed ultrasound applied to rabbit tibiae during the consolidation phase of distraction osteogenesis

The purpose of this study was to determine if low intensity pulsed ultrasound (LIPU) accelerated the maturation of regenerate bone when applied after distraction in a rabbit model. A mid‐tibial osteotomy was performed in 26 New Zealand white rabbits and an external fixator applied anteromedially. After a seven day latency period, the tibiae were distracted 0.5 mm every 12 h for 10 days. Thirteen of the rabbits received LIPU for 20 min/day (treatment group) and 13 received sham LIPU (control group) from day 17 until sacrifice on day 37. Radiographs were taken weekly after distraction and the total and mineralized areas of the callus were measured. After sacrifice, dual‐energy X‐ray absorptiometry, torsional testing to failure, and histomorphometry were performed. Ultrasound‐treated tibiae were a mean of 68.8 ± 3.8% as stiff as and 68.2 ± 6.0% as strong as the contralateral tibiae. Control tibiae were 78.7 ± 7.0% as stiff as and 70.2 ± 7.9% as strong as the contralateral tibiae. The differences in stiffness and strength were not significant (p = 0.39 and 0.81, respectively) with the number of the animals tested in the study. The treatment group was 91.6% as dense as the contralateral side and the control group was 88.5% as dense as the contralateral side (p = 0.84). Radiographs revealed a significantly larger callus in the LIPU‐treated tibiae at 1, 2 and 3 weeks after distraction compared to control tibiae (p < 0.01, 0.008 and 0.05, respectively). Histomorphometry revealed significantly less fibrous tissue in the LIPU‐treated tibiae (p < 0.05) and a strong trend towards more bone in the LIPU‐treated tibiae compared to controls (p = 0.06). LIPU was found to increase the size of the distraction callus and it might alter the composition of regenerate bone but it did not have a positive effect on the mechanical properties or density of regenerate bone when applied during the consolidation phase of distraction osteogenesis. Published by Elsevier Science Ltd. on behalf of Orthopaedic Research Society.

Generation of chordoma cell line JHC7 and the identification of Brachyury as a novel molecular target: Laboratory investigation

OBJECT Chordoma is a malignant bone neoplasm hypothesized to arise from notochordal remnants along the length of the neuraxis. Recent genomic investigation of chordomas has identified T (Brachyury) gene duplication as a major susceptibility mutation in familial chordomas. Brachyury plays a vital role during embryonic development of the notochord and has recently been shown to regulate epithelial-to-mesenchymal transition in epithelial-derived cancers. However, current understanding of the role of this transcription factor in chordoma is limited due to the lack of availability of a fully characterized chordoma cell line expressing Brachyury. Thus, the objective of this study was to establish the first fully characterized primary chordoma cell line expressing gain of the T gene locus that readily recapitulates the original parental tumor phenotype in vitro and in vivo. METHODS Using an intraoperatively obtained tumor sample from a 61-year-old woman with primary sacral chordoma, a chordoma cell line (JHC7, or Johns Hopkins Chordoma Line 7) was established. Molecular characterization of the primary tumor and cell line was conducted using standard immunostaining and Western blotting. Chromosomal aberrations and genomic amplification of the T gene in this cell line were determined. Using this cell line, a xenograft model was established and the histopathological analysis of the tumor was performed. Silencing of Brachyury and changes in gene expression were assessed. RESULTS The authors report, for the first time, the successful establishment of a chordoma cell line (JHC7) from a patient with pathologically confirmed sacral chordoma. This cell line readily forms tumors in immunodeficient mice that recapitulate the parental tumor phenotype with conserved histological features consistent with the parental tumor. Furthermore, it is demonstrated for the first time that silencing of Brachyury using short hairpin RNA renders the morphology of chordoma cells to a more differentiated-like state and leads to complete growth arrest and senescence with an inability to be passaged serially in vitro. CONCLUSIONS This report represents the first xenograft model of a sacral chordoma line described in the literature and the first cell line established with stable Brachyury expression. The authors propose that Brachyury is an attractive therapeutic target in chordoma and that JHC7 will serve as a clinically relevant model for the study of this disease.