Sarcoma in neurofibromatosis 2: case report and review of the literature.

Neurofibromatosis type 2 (NF2) is associated with the development of several types of benign nervous system tumours, while malignancies are rare. We report a 22-year-old man who presented with retroperitoneal and spinal high-grade sarcomas with epithelial features. Samples showed a mixed epithelioid and spindled cell content with little associated matrix and inconclusive immunochemistry. Genetic analysis of a schwannoma and matched blood samples demonstrated a constitutional de novo substitution at the splice donor site of intron 8 of the NF2 gene and aa acquired large deletion of the entire NF2 gene as a second hit, with some loss of SMARCB1. The sarcoma also showed evidence of loss of SMARCB1 and NF2 with loss of INI1 staining. Unfortunately the mass was unresectable and the patient died 6 months after diagnosis. This malignancy was most consistent with SMARCB1-deficient epithelioid malignant peripheral nerve sheath tumour, although a significant differential was proximal-type epithelial sarcoma. Each differential has previously been reported only once with NF2. This demonstrates an extremely rare potential complication of the condition.

Subcutaneous and lung metastases from chondrosarcoma of the thumb.

We present a rare case of metacarpal chondrosarcoma with cutaneous metastases in the ipsilateral upper arm. Chondrosarcomas of the small bones of the hand rarely metastasise unlike chondrosarcomas elsewhere in the body. Excision/ray amputation rather than curettage may be preferable in the treatment of high-grade chondrosarcomas in the hand.

Osteoid osteoma and osteoblastoma: novel histological and immunohistochemical observations as evidence for a single entity.

AIMS: Osteoid osteoma and osteoblastoma have, in the past, been variously regarded as both similar and distinct entities. Currently, WHO classifies these tumours separately. We compared archetypal cases to identify novel histomorphological and immunohistochemical features attempting to clarify their mutual relationship. METHODS AND RESULTS: 10 osteoid osteomas and 20 osteoblastomas (10 spinal and 10 non-spinal) were retrieved and reviewed clinically, radiologically and histologically. Immunohistochemistry was performed for: desmin, SMA, neurofilament, S100, vimentin, PGP9.5, GFAP, EMA, caldesmon, CD34, broad-spectrum cytokeratins, claudin-1. We identified features, common to both osteoid osteoma and osteoblastoma, namely, areas of lesional non-osteoblastic stroma and the presence of scattered, large cells with smudged/degenerate nuclei. Immunohistochemically, we confirmed the innervated status of osteoid osteomas, and found that osteoblastomas were similarly innervated. The non-osteoblastic lesional stroma was distinctive owing to expression of EMA and NSE by the mesenchymal spindle cells and expression of desmin, PGP9.5 and S100 by the scattered, large cells with 'smudged' nuclei. CONCLUSIONS: Both osteoid osteoma and osteoblastoma are innervated bone-forming lesions which share novel histomorphological and immunohistochemical features supporting the view that separate classification is unjustified, and we offer a pathogenetic explanation for their apparent clinical and radiological variance.

Diffuse pigmented villonodular synovitis (diffuse-type giant cell tumour) of the foot and ankle.

Pigmented villonodular synovitis (PVNS) is a rare benign disease of the synovium of joints and tendon sheaths, which may be locally aggressive. We present 18 patients with diffuse-type PVNS of the foot and ankle followed for a mean of 5.1 years (2 to 11.8). There were seven men and 11 women, with a mean age of 42 years (18 to 73). A total of 13 patients underwent open or arthroscopic synovectomy, without post-operative radiotherapy. One had surgery at the referring unit before presentation with residual tibiotalar PVNS. The four patients who were managed non-operatively remain symptomatically controlled and under clinical and radiological surveillance. At final follow-up the mean Musculoskeletal Tumour Society score was 93.8% (95% confidence interval (CI) 85 to 100), the mean Toronto Extremity Salvage Score was 92 (95% CI 82 to 100) and the mean American Academy of Orthopaedic Surgeons foot and ankle score was 89 (95% CI 79 to 100). The lesion in the patient with residual PVNS resolved radiologically without further intervention six years after surgery. Targeted synovectomy without adjuvant radiotherapy can result in excellent outcomes, without recurrence. Asymptomatic patients can be successfully managed non-operatively. This is the first series to report clinical outcome scores for patients with diffuse-type PVNS of the foot and ankle.

Bone healing response to a synthetic calcium sulfate/ß-tricalcium phosphate graft material in a sheep vertebral body defect model.

The introduction of a material able to promote osteogenesis and remodelling activity in a clinically relevant time frame in vertebroplasty and kyphoplasty procedures may have patient benefit. We report the in-vivo performance of a biphasic synthetic bone graft material (Genex Paste, Biocomposites, UK) [test material], composed of calcium sulfate and ß-tricalcium phosphate, implanted into a sheep vertebral defect model. Cavities drilled into 4 adjacent vertebrae (L2 to L5) of 24 skeletally mature sheep were; (1) filled with the test material; (2) filled with commercially available polymethylmethacrylate [PMMA] cement; (3) remained empty [sham]. Analysis was performed immediately after implantation and at 8, 16, and 36 weeks post implantation. Sites were evaluated for bone growth with microCT analysis, histological examination, and mechanical testing under compression. The test material exhibited an improved tissue response over the PMMA, indicating a superior biological tolerance. MicroCT and histology indicated marked osteoregenerative capacity of the test material when compared with sham and the PMMA. The percentage of new bone formation was higher for the test material than sham at 16 and 36 weeks post implantation, with bone regeneration almost complete at 36 weeks in this group. Resorption of test material and the integration into new bone tissue were demonstrated.

Fifty years of paediatric malignant bone tumours in the West Midlands, UK, 1957-2006: incidence, treatment and outcome.

Malignant bone tumours in the paediatric age group (0-14 years) are uncommon; various aetiological theories exist and few reports of incidence, age and sex distributions have been published. We examined the incidence of childhood malignant bone tumours in one large single region of the UK over an extended period of 50 years. The West Midlands specialist regional children's tumour registry holds data on all malignancies and benign brain tumours in children under 15 years in the West Midlands region, which has a population of around 1 million children. Demographic and clinical data have been abstracted and diagnoses reviewed by a panel of expert pathologists. During the period 1957-2006, 259 cases of malignant paediatric bone tumours were diagnosed. There were 153 osteosarcomas, 78 Ewing sarcomas and 28 other primary bone tumours. The overall age standardised rate was 4.66, with no increase over time, although there was a significant increase in the incidence of Ewing sarcomas in the period 1965-92. Sixty-eight per cent of tumours were in patients over 10 years, whereas the incidence in patients under 10 years showed a non-significant increase. Survival rates increased dramatically post-chemotherapy introduction, with Ewing sarcoma demonstrating better survival overall. This is a large study giving an overview of malignant bone tumours in the childhood population of a single region over an extended period, showing results consistent with national reports. It also examines late effects, which were mostly mobility/orthopaedic, although almost one-fifth of patients had cardiac problems and five went on to develop second malignancies.

Distal tibial giant cell tumour treated with curettage and stabilisation with an Ilizarov frame.

A 36-year-old man presented with a long history of pain in his left ankle. Imaging and biopsy confirmed this to be a giant cell tumour of bone. This was treated with curettage of the lesion and stabilisation with an Ilizarov frame. After a prolonged course of rehabilitation he has excellent function and has returned to hill walking and there is no evidence of recurrence of the giant cell tumour.

Sarcoma arising in Paget's disease of bone: declining incidence and increasing age at presentation.

BACKGROUND: Paget's disease is presenting at older ages, with a trend to monostotic disease, associated with lower serum total alkaline phosphatase (serum total ALP) levels. Sarcomatous transformation is a rare complication, which only half a century ago had a median age of presentation of less than 60 years. We have investigated whether sarcomatous change exhibits increasing age at presentation, whether the trend to monostotic Paget's disease exists, whether male predominance in sarcoma still continues and explored factors that might affect survival. METHODS: Notes of all patients from the Royal Orthopaedic Hospital, Birmingham primary malignant bone tumour registry were reviewed and all cases of Pagetic sarcoma since 1975 extracted. In addition to basic demographic data, mode of presentation, skeletal involvement by Paget's disease, history of treatment, presence of pulmonary metastases, serum total ALP levels and survival were obtained. RESULTS: Unequivocal Pagetic sarcoma was identified in 32 patients (23 M, 9 F). Age at presentation was 73.8 years with no sex difference and with known pre-existing Paget's disease in 42%. Only 15% had received any specific Paget's disease treatment. Serum total ALP was not invariably markedly elevated (compared with non-sarcomatous disease) and was related to the number of skeletal sites, but not to the sarcoma histological subtype. Paget's disease was monostotic in 46%. Pagetic sarcoma fell from 23% to 8% of primary bone sarcoma referrals in patients aged over 50 years between the decades 1986-1995 and 1996-2005. Median survival remained poor at 0.66 years. Survival of greater than 2 years occurred in 4 patients, one of whom with a low grade Pagetic sarcoma being alive at 12 years follow up. CONCLUSIONS: The proportion of Paget's disease patients with sarcoma has fallen steadily since Paget's original report and is now about 0.3%, the decline predating availability of effective therapy. Sarcoma is not necessarily associated with very high serum total ALP. It is present amongst polyostotic cases in the expected proportion suggesting that more widespread skeletal involvement by Paget's disease is not a significant risk factor for malignant transformation. Sarcoma is presenting later concurrent with the advancing age of non-malignant disease, but male predominance continues. Pagetic sarcoma is now rare, continues to have a poor prognosis and is often the presenting feature of the disease.

Hibernoma--correlation of histopathology and magnetic-resonance-imaging features in 10 cases.

UNLABELLED: OBJECTIVE, DESIGN AND PATIENTS: Hibernoma is an uncommon, slow-growing, benign soft-tissue tumour resembling brown adipose tissue. The histological appearances are well-documented, but there are relatively few descriptions of the magnetic resonance (MR) imaging features. We report a retrospective comparison of the histological and MR appearances of ten hibernomas of the extremities, classified histologically into lipoma-like [<70% multivacuolated adipocytes (MVAs)] and non-lipoma-like hibernomas (>70% MVAs). RESULTS: The lipoma-like hibernomas measured 4-27 cm in maximum size. All were well-defined on MR imaging and histology except for one subcutaneous lesion that blended in with surrounding fat histologically. All lesions were isointense with subcutaneous fat on T1- and T2-weighting apart from one lesion that was predominantly slightly hypointense on T1-weighting and predominantly slightly hyperintense on T2-weighting and STIR. Two slightly inhomogeneous lesions contained thin (<5 mm thickness) tortuous vessels. One patient received intravenous contrast, but the lesion did not enhance. The six non-lipoma-like hibernomas measured 2.5-15.5 cm in maximum size and all were unencapsulated. Three were well-defined and three partly ill-defined on MR imaging. There were no significant differences in the MR characteristics of the non-lipoma-like variants. On T1-weighting, the non-lipoma-like hibernomas that contained >90% MVAs were predominantly slightly hypointense to subcutaneous fat. One lesion was isointense with subcutaneous fat, but this lesion only contained from 80-90% MVAs. All non-lipoma-like lesions were slightly hyperintense on STIR but so too were two of the four lipoma-like lesions. Four of the six non-lipoma-like lesions showed marked or moderate inhomogeneity due to thick septa and prominent vessels. Of the two cases that received intravenous contrast, both showed enhancement corresponding to regions of >90% MVAs or prominent vessels within fibrous septa. CONCLUSIONS: MR imaging has shown some distinguishing features between lipoma-like and non-lipoma-like hibernomas. Lipoma-like hibernomas are usually isointense with subcutaneous fat on T1-weighting, are either homogeneous or slightly inhomogeneous and may contain thin tortuous vascular structures. Non-lipoma-like hibernomas are pre-dominantly slightly hypointense to subcutaneous fat on T1-weighting, often display marked or moderate inhomogeneity with prominent septa and vessels and enhancement is typical. The appearances of non-lipoma-like hibernomas are not diagnostic and may be mimicked by lipoma variants and by well-differentiated liposarcoma or atypical lipoma.

Ewing's sarcoma of bone: the detection of specific transcripts in a large, consecutive series of formalin-fixed, decalcified, paraffin-embedded tissue samples using the reverse transcriptase-polymerase chain reaction.

AIMS: (i) To report on the routine use of the reverse transcriptase-polymerase chain reaction (RT-PCR) technique on decalcified or non-decalcified, formalin-fixed, paraffin-embedded tissue (FFPET) for translocation detection, with particular emphasis on improved RNA extraction methodology and the use of PCR primers designed to generate small amplicons. (ii) To report on the relative incidences of translocation types and transcript variants in a large, single institution series of Ewing's sarcoma of bone. METHODS AND RESULTS: Using RT-PCR to detect specific transcript variants, we analysed FFPET from 54 consecutive cases of Ewing's sarcoma of bone. We used 'gold standard' detection methods on corresponding fresh and fresh frozen tissue to validate the technique. We have demonstrated the effective use of RT-PCR on decalcified and non-decalcified FFPET samples for sarcoma-specific translocation detection (96% sensitivity, 100% specificity). Tissue decalcification did not affect the detection rate. The relative incidence of Ewing's sarcoma-specific translocation types and transcript variants was entirely consistent with previously published data. CONCLUSIONS: With equal effectiveness, RT-PCR can be applied to both acid decalcified and non-decalcified FFPET for (Ewing's sarcoma) translocation detection and the technique can be introduced into routine practice in histopathology departments.

Primary synovial osteochondromatosis presenting as constrictive capsulitis.

Primary synovial chondromatosis of the joints can present as capsular constriction with peri-articular osteopenia. This rare presentation is highlighted in three cases (two hips and one shoulder). The diagnosis in all the patients was made on arthrography and/or MRI/CT and was confirmed histologically. Synovial chondromatosis should be considered in patients with this presentation. Arthrography is the best imaging modality to confirm the cause (synovial chondromatosis) and effect (constrictive capsulitis).

Giant lipomatous tumours of the hand and forearm.

This study examines the presentation, management and outcomes of a series of 10 patients with giant lipomatous tumours (defined as greater than 5 cm diameter) of the hand and forearm who presented to our orthopaedic oncology service. All patients underwent local staging and were discussed at our multidisciplinary tumour meeting prior to definitive surgery. In all cases, neurovascular structures required mobilization in order to excise the tumour. Seven of the tumours were benign lipomas and one was a neural fibrolipoma. The other two were well differentiated lipoma-like liposarcomas/atypical lipomatous tumours. Giant lipomas and well differentiated lipoma-like liposarcomas/atypical lipomatous tumours of the hand and forearm present infrequently and a multidisciplinary approach is recommended in the investigation and surgical management of these patients.

Microvessel density does not predict outcome in high grade soft tissue sarcoma.

UNLABELLED: The induction of new blood vessel growth into tumours from a pre-existing vascular bed (angiogenesis) is a characteristic of virtually all malignant tumours studied. Previous studies have demonstrated a consistent correlation between the extent of angiogenesis and disease prognosis for a wide range of carcinomas, but not for sarcomas. AIMS: To investigate the most appropriate method for assessment of microvessel density (MVD) using a cohort of patients with large (>5 cm), deep (intramuscular), high grade soft tissue sarcoma and investigate any relationship between MVD, vascular endothelial growth factor (VEGF) expression and prognosis. METHODS: Forty-two patients were included in the study. MVD was evaluated in peripheral, central, necrotic and hotspot areas within the tumour by either Chalkley count or total count of immunostained vessels in five high power (x 200) visual fields. RESULTS: Hot spots of angiogenesis were only present in 33% of specimens. There was a strong correlation p<0.001 between the two methods of quantification with Chalkey method being recommended. VEGF expression evaluated by immunohistochemistry was seen in all but one tumour with strong diffuse cytoplasmic staining within tumour cells, which was not correlated with microvessel density, metastasis or survival. There was a positive correlation between MVD and histological subtype (p<0.01), and primary tumour size and the development of metastasis (p=0.049) but MVD was not predictive of metastasis or overall survival. CONCLUSIONS: Unlike the majority of previous studies involving various types of carcinoma, there was no correlation between microvessel density and metastasis or survival in a group of patients with large (>5 cm), deep, high grade soft tissue sarcoma.

Percutaneous radiofrequency thermocoagulation of osteoid osteomas: factors affecting therapeutic outcome.

OBJECTIVE: To examine factors which affect local recurrence of osteoid osteomas treated with percutaneous CT-guided radiofrequency thermocoagulation. DESIGN AND PATIENTS: A prospective study was carried out on 45 patients with osteoid osteoma who underwent percutaneous radiofrequency thermocoagulation with a minimum follow-up of 12 months. RESULTS: There were seven local recurrences (16%); all occurred within the first year. Local recurrence was significantly related to a non-diaphyseal location (P<0.01). There was no significant relationship (P=0.05) between local recurrence and age of the patient, duration of symptoms, previous treatment, size of the lesion, positive biopsy, radiofrequency generator used or the number of needle positions. There were no complications. CONCLUSIONS: Osteoid osteomas in a non-diaphyseal location are statistically more likely to recur than those in a diaphyseal location when treated with CT-guided percutaneous radiofrequency thermocoagulation. This relationship between local recurrence and location has not been previously reported.

TP53 mutations and outcome in osteosarcoma: a prospective, multicenter study.

PURPOSE: Mutations of the TP53 gene have been associated with resistance to chemotherapy as well as poor prognosis in many different malignancies. This is the first prospective study of the prognostic value of somatic TP53 mutations in patients with newly diagnosed extremity osteosarcoma. PATIENTS AND METHODS: One hundred ninety-six patients with high-grade, nonmetastatic osteosarcoma of the extremities were enrolled from seven tertiary care institutions and observed prospectively for tumor recurrence (median follow-up duration, 44 months). All patients received neoadjuvant or adjuvant chemotherapy and surgery. Tumors were analyzed for the presence of TP53 mutations by polymerase chain reaction single-strand conformation polymorphism analysis and direct DNA sequencing. The association of the status of the TP53 gene with the risk of systemic recurrence was examined using survival analyses with traditional and histologic markers as prognostic factors. RESULTS: Patient age was the only factor that varied with TP53 gene status (P = .05). No relationship was identified between TP53 status and systemic relapse (relative risk, 1.24; P = .41). Analyses based on missense or nonsense mutations gave similar results (P > .10). In multivariate analysis, large (> 9 cm) tumor size (relative risk, 1.9; P = .006) and poor histologic response (< or = 90% necrosis) to chemotherapy (relative risk, 2.14; P = .02) were the only significant independent predictors of systemic outcome. CONCLUSION: We found no evidence that TP53 mutations predict for development of metastases in patients with high-grade osteosarcoma. Identification of other genes that influence chemotherapy response and clinical outcome in osteosarcoma is needed to facilitate further improvements in patient outcomes.

Calcific myonecrosis: a report of ten new cases with an emphasis on MR imaging.

The aim of this study is to report the typical radiographic and MR imaging features of calcific myonecrosis, which help to distinguish this rare entity from other causes of a calcifying calf mass. Ten patients with a final diagnosis of calcific myonecrosis were referred to a specialist orthopaedic oncology service in a 5-year period with the presumptive diagnosis of malignancy based on recent clinical presentation and imaging findings. Radiographs were available for retrospective review in all ten cases and MR imaging in six. All patients presented with a slow-growing painless calf mass. All gave a history of major trauma to the lower leg many years before, but in only two cases did the referring clinician query whether trauma might be a contributory factor. Radiographs showed well-defined fusiform mineralised masses up to 25 cm in length arising within the calf. The calcification was consistently peripheral and plaque-like. Ossification was not present. MR imaging showed the anterior compartment to be involved in four cases and all compartments in two. T1- and T2-weighted images showed peripheral low signal intensity, more prominent on the T2-weighted images, because of the peripheral mineralization. The contents of the masses were variable on T1-weighted images depending on the differing amounts of blood breakdown products and were heterogeneous on T2-weighted images. The latter may be explained by a combination of the mineralisation and T2 shortening due to blood breakdown products. A gadolinium chelate, administered in two cases, failed to show any appreciable enhancement. Calcific myonecrosis has characteristic clinical, radiographic and MR features that should make the condition easy to recognise. Despite its rarity, it should be included in the differential diagnosis of focal mineralisation of the calf.

Imaging features of intraosseous ganglia: a report of 45 cases.

The aim of this study is to report the spectrum of imaging findings of intraosseous ganglia (IG) with particular emphasis on the radiographic and magnetic resonance (MR) features. Forty-five patients with a final diagnosis of IG were referred to a specialist orthopaedic oncology service with the presumptive diagnosis of either a primary or secondary bone tumour. The diagnosis was established by histology in 25 cases. In the remainder, the imaging features were considered characteristic and the lesion was stable on follow-up radiographic examination. Radiographs were available for retrospective review in all cases and MR imaging in 29. There was a minor male preponderance with a wide adult age range. Three quarters were found in relation to the weight-bearing long bones of the lower limb, particularly round the knee. On radiographs all were juxta-articular and osteolytic; 74% were eccentric in location, 80% had a sclerotic endosteal margin and 60% of cases showed a degree of trabeculation. Periosteal new bone formation and matrix mineralization were not present. Of the 29 cases that underwent MR imaging, 66% were multiloculated. On T1-weighted images the IG contents were isointense or mildly hypointense in 90% cases. Forty-one per cent of the cases showed a slightly hyperintense rim lining that enhanced with a gadolinium chelate. Thirty-eight per cent were associated with soft tissue extension and 17% with a defect of the adjacent articular cortex. Fifty-five per cent showed surrounding marrow oedema on T2-weighted or STIR images and two cases (7%) a fluid-fluid level prior to any surgical intervention. The authors contend that it is semantics to differentiate between an IG and a degenerate subchondral cyst as, while the initial pathogenesis may vary, the histological endpoint is identical, as are the imaging features apart from the degree of associated degenerative joint disease. IGs, particularly when large, may be mistaken for a bone tumour. Correlation of the typical radiographic and MR imaging features will indicate the correct diagnosis and obviate the need for biopsy.

Calcific haemorrhagic bursitis anterior to the knee mimicking a soft tissue sarcoma: report of two cases.

We describe the radiological and pathological findings of two cases of calcific haemorrhagic bursitis, one involving the superficial infrapatellar bursa and the other the prepatellar bursa. It was the presence of dystrophic calcification within the lesion that suggested a mineralizing soft tissue sarcoma such as synovial sarcoma. As the radiographic and MR features of the two conditions can be similar but the appropriate management very different, rare calcifying haemorrhagic bursitis needs to be included in the differential diagnosis of masses adjacent to the knee joint showing calcification.

Pencil-core granuloma of the distal radio-ulnar joint: an unusual presentation as soft-tissue sarcoma after 45 years.

A case of pencil-gore granuloma occurring 45 years after he initial injury is described. The clinical and radiological presentation was suggestive of a soft-tissue sarcoma. The diagnosis was confirmed by biopsy, which also revealed foreign body fragments which, on spectometric analysis, had high concentrations of carbon and aluminium.