Synovial chondrosarcoma: a single-institution experience with molecular investigations and review of the literature.

AIMS: To evaluate the available diagnostic histological criteria for synovial chondrosarcoma and to screen for the presence of IDH1/IDH2 mutations in a series of cases of this malignant cartilaginous neoplasm. METHODS AND RESULTS: Ten cases of synovial chondrosarcoma diagnosed at our institute were reviewed. At presentation, all tumours occurred in adults (median age, 62 years). The most common location was the knee joint (five cases), and the size at diagnosis ranged from 30 mm to 170 mm. Eight patients had secondary synovial chondrosarcomas associated with pre-existing/recurrent or concomitant synovial chondromatosis. Five patients had local recurrences and three had lung metastases. All patients with intralesional excisions developed local recurrences, whereas those who underwent wide resections did not. At last follow-up (mean, 91 months), available for nine patients, seven patients were alive and disease-free, one patient had died of disease, and one was alive with paravertebral metastases. Frequent histological features observed included loss of clustering of chondrocytes (nine cases), the presence of variable amounts of myxoid matrix (eight cases), peripheral hypercellularity (eight cases), tumour necrosis (six cases), and spindling of chondrocytes (four cases). Of the seven cases for which it was possible to evaluate bone permeation, six showed infiltration of bone marrow. All seven cases screened for mutations of exon 4 of IDH1 and IDH2 were found to be wild-type. CONCLUSIONS: Histological criteria in correlation with clinical and radiological features allow the recognition of synovial chondrosarcoma. IDH1/IDH2 mutations were not present in synovial chondrosarcoma. Adequate surgical margins are important for disease control.

Paediatric chondrosarcomas: a retrospective review of 17 cases.

AIMS: Chondrosarcoma is primarily a tumour of adulthood and old age. Some studies indicate that survival is worse in paediatric than in adult chondrosarcomas. In view of the rarity of paediatric chondrosarcoma, few large studies are currently available. METHODS AND RESULTS: We evaluated the clinical, radiological and pathological features of a single institution series of chondrosarcomas presenting in patients younger than 17 years between 1981 and 2014. Seventeen patients with central (10), peripheral (five) and periosteal (two) chondrosarcoma were retrieved. The patients received various treatments according to the dimension, stage and grading of the lesions. Only two tumours, treated with resection, recurred after the first diagnosis, at 11 and 108 months, respectively. All patients but one were alive without disease at the time of the last follow-up (median: 148 months). The one patient who died of disease 27 months after diagnosis had a grade 2 central chondrosarcoma of the metacarpal bone. He was affected by Maffucci syndrome and developed multiple bone and lung metastases. CONCLUSIONS: Chondrosarcoma in children is rare but does exist, and is not limited to the head and neck region. Our findings do not support the current view that chondrosarcomas are more aggressive in children than in adults.

Array CGH analysis identifies two distinct subgroups of primary angiosarcoma of bone.

Molecular genetic studies on vascular tumors are rare. Recently, possible involvement of MYC and KDR has been documented in a subset of angiosarcomas of soft tissue. We performed a cytogenetic analysis of primary angiosarcomas of bone (n = 13) and soft tissue (n = 5) using high density array-comparative genomic hybridization (array-CGH). Regions of interest were validated by fluorescence in situ hybridization (FISH). Antibodies for candidate genes (SKI, MYC, KDR, and MAPK9) were selected and immunohistochemistry was performed. Six angiosarcomas of bone and four angiosarcomas of soft tissue showed chromosomal losses, gains, and high level amplifications. Cluster analysis identified two groups: a group with a complex genetic profile and a group with only few genetic aberrations. Five regions of interest were selected, which were located at chromosome bands 1p36.23, 2q32-34, 5q35, 8q24, and 17q21.32-24.2. Interphase FISH confirmed the high-level amplifications. Immunohistochemical analysis showed high expression of MYC (16/60), MAPK9 (63/69), and SKI (52/62). There were no differences between the two groups with regards to location, immunohistochemical expression nor survival. In summary, we identified two subgroups of angiosarcoma: those with few or no gross aberrations and those which show numerous genetic aberrations consisting of chromosomal losses, gains and high level amplifications or complex aberrations. The most common finding was amplification of 2q and 17q in both angiosarcoma of bone and soft tissue, suggesting overlap in tumorigenesis irrespective of their location. We show MYC amplification in primary angiosarcoma indicating this is not entirely specific for radiation-induced angiosarcoma.

Active TGF-ß signaling and decreased expression of PTEN separates angiosarcoma of bone from its soft tissue counterpart.

Angiosarcomas constitute a heterogeneous group of highly malignant vascular tumors. Angiosarcoma of bone is rare and poorly characterized. For angiosarcoma of soft tissue, some pathways seem to be involved in tumor development. Our aim was to evaluate the role of these pathways in angiosarcoma of bone. We collected 37 primary angiosarcomas of bone and used 20 angiosarcomas of soft tissue for comparison. Immunohistochemistry was performed on constructed tissue microarrays to evaluate expression of CDKN2A, TP53, PTEN, BCL2, CDK4, MDM2, cyclin D1, ß-catenin, transforming growth factor-ß (TGF-ß), CD105, phospho-Smad1, phospho-Smad2, hypoxia-inducible factor-1α, plasminogen activator inhibitor type 1 (PAI-1), VEGF, CD117 and glucose transporter--1. PIK3CA was screened for hotspot mutations in 19 angiosarcomas. In nearly 55% of the angiosarcoma of bone, the retinoblastoma (Rb) pathway was affected. Loss of CDKN2A expression was associated with a significantly worse prognosis. No overexpression of TP53 or MDM2 was found, suggesting that the TP53 pathway is not important in angiosarcoma of bone. Angiosarcoma of bone showed highly active TGF-ß signaling with immunoreactivity for phospho-Smad2 and PAI-1. Although the phosphatidylinositol 3-kinase (PI3K)/Akt pathway seems to be active in both tumor groups, different mechanisms were involved: 41% of angiosarcoma of bone showed a decrease in expression of PTEN, whereas in angiosarcoma of soft tissue overexpression of KIT was found (90%). PIK3CA hotspot mutations were absent. In conclusion, the Rb pathway is involved in tumorigenesis of angiosarcoma of bone. The PI3K/Akt pathway is activated in both angiosarcoma of bone and soft tissue, however, with a different cause; PTEN expression is decreased in angiosarcoma of bone, whereas angiosarcomas of soft tissue show overexpression of KIT. Our findings support that angiosarcomas are a heterogeneous group of vascular malignancies. Both angiosarcoma of bone and soft tissue may benefit from therapeutic strategies targeting the PI3K/Akt pathway. However, interference with TGF-ß signaling may be specifically relevant in angiosarcoma of bone.

Distinct histological features characterize primary angiosarcoma of bone.

AIMS: To define the histological criteria of primary angiosarcoma of bone. METHODS AND RESULTS: Forty-two angiosarcomas of bone in 23 males and 15 females were studied. Histological criteria were related to patients' outcome. Eleven patients had multifocal lesions. Lesions were located in the long and short tubular bones followed by the pelvis, spine and trunk. Tumour cells were positive for CD31 in 38 of 40, von Willebrand Factor in 21 of 35, CD34 in 15 of 38, smooth muscle actin in 22 of 36, D2-40 in 11 of 35 and keratin AE1AE3 in 27 of 39. Thirty-nine tumours showed an epithelioid phenotype. One- and 5-year survival rates were 55% and 33%, respectively. Survival analysis showed that a macronucleolus, three or more mitoses per 10 high-power field (HPF) and fewer than five eosinophilic granulocytes per 10 HPF within a tumour was associated with an even worse survival compared to the overall group. CONCLUSIONS: Because keratin positivity is seen in the majority of cases, pathologists should avoid misinterpretation as metastatic carcinoma. A macronucleolus, three or more mitoses per 10 HPF and fewer than five eosinophilic granulocytes per 10 HPF can be used to further define angiosarcoma of bone.

Osteosarcoma of the Jaws: A Literature Review.

Osteosarcoma of the jaws (OSJ) is a relatively rare disease, accounting for between 2% and 10% of all cases of osteosarcoma. It is morphologically and radiologically identical to the trunk and extremity variant, but distinct in several crucial aspects. The lesion is characterized by sarcomatous cells which produce a variable amount of osteoid bone. It arises centrally within the bone and can be subdivided into osteoblastic, chondroblastic and fibroblastic subtype, depending on the predominant cell type. Radiographically, these tumors display a spectrum of bone changes from well-demarcated borders to lytic bone destruction with indefinite margins and variable cortical bone erosion or, in some cases, images of sclerotic bone. Therapeutic options for OSJ include surgery, chemotherapy and radiotherapy, which are employed according to age of the patient, histological classification and localization of the tumor. Today, there is no general consensus in the treatment guidelines for the OSJ though surgery represents the key to the treatment. The main prognostic factor deeply influencing the patient's prognosis remains the complete tumor resection with negative surgical margins. The aim of the present review is to describe state of the art regarding diagnostic and surgical treatment aspects of the primary osteosarcoma of the jaws.

Surgical treatment of grade I central chondrosarcoma.

UNLABELLED: The grade of chondrosarcoma relates to the likelihood of local recurrence and metastases. Many Grade I chondrosarcomas behave benignly if aggressively, and the question arises regarding whether wide resection is essential to control the disease. We therefore asked whether intralesional surgery also could be extended to Grade I chondrosarcomas without an increase in recurrence. We retrospectively reviewed 31 patients with Grade I chondrosarcomas of the limbs. The minimum followup was 66 months (mean, 157 months; range, 66-296 months). None of the 16 patients treated by resection had recurrences during the followup and two of the 15 patients with intralesional excision had recurrences, both of which resolved with resection of the site involved by the recurrence without progression of the disease. The Musculoskeletal Tumor Society scores averaged 72% in patients treated with wide resection compared with 89% in the 15 patients treated by intralesional surgery. The two recurrences occurred in patients whose radiographs showed thinning of the cortex combined with bone enlargement and marked endosteal scalloping; histologic examination in these two patients also showed a correlation between radiographic aggressiveness and the presence of myxoid areas and hypercellularity. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Dedifferentiated peripheral chondrosarcomas: regulation of EXT-downstream molecules and differentiation-related genes.

Dedifferentiated peripheral chondrosarcoma is a rare subtype of chondrosarcoma arising superimposed on the cartilage cap of a preexisting osteochondroma. It consists of two clearly defined components, a low-grade malignant, well-differentiated cartilage component and a high-grade non-cartilaginous sarcoma. Signaling pathways having a role in normal cartilage development were analyzed in these tumors, and compared with available data of other cartilaginous tumors. Sixteen well-characterized dedifferentiated peripheral chondrosarcomas were immunohistochemically analyzed for parathyroid hormone-like hormone (PTHLH)-BCL-2, fibroblastic growth factor (FGF), and transforming growth factor-beta signaling molecules, as well as matrix molecules and p53, comparing the chondrogenic component of dedifferentiated peripheral chondrosarcomas with the anaplastic component and with previously published data obtained from conventional grade I and II secondary peripheral chondrosarcomas. Results were correlated with clinical outcome. In the anaplastic component, various lines of differentiation could be found (collagen I (6/16), CD31 (1/16), smooth muscle actin (12/16), muscle-specific actin (12/16) and desmin (2/9)). Compared with the anaplastic component, the chondrogenic component of dedifferentiated peripheral chondrosarcomas shows more often expression of cyclin D1 (P=0.05), p53 (P=0.008), plasminogen activator inhibitor 1 (PAI-1) (P=0.005), and CD44 (P=0.030). Compared with secondary peripheral chondrosarcomas, more samples were positive in the chondrogenic component of dedifferentiated peripheral chondrosarcomas for FGF signaling (FGF receptor 3 P=0.000; bFGF P=0.003) and CD44 (P=0.000). Lower expression of BCL-2 (P=0.025) and absence of CD44v3 (P=0.000), a splice variant of CD44, was observed in the chondrogenic component of dedifferentiated peripheral chondrosarcomas compared with secondary peripheral chondrosarcomas. With regard to clinical data, PAI-1 expression in the chondrogenic component of dedifferentiated peripheral chondrosarcomas correlated with better survival (P=0.019). In conclusion, in the chondrogenic component of dedifferentiated peripheral chondrosarcomas, FGF signaling pathway is active, whereas PTHLH signaling seems to be low/downregulated. Interestingly, although the chondrogenic component of dedifferentiated peripheral chondrosarcoma is CD44+/CD44v3-, secondary peripheral chondrosarcomas is CD44-/CD44v3+, which suggest different splicing (preference). The prognostic value of PAI-1 in dedifferentiated peripheral chondrosarcomas might also be of interest for the more common dedifferentiated central chondrosarcomas.

New approaches in the diagnosis of small-cell round tumors of bone and soft tissue.

The diagnosis of 17 small-cell round tumors of the bone and soft tissue, which were histologically similar to Ewing's sarcoma (EWS), was verified on paraffin sections, by using tissue microarray (TMA) technology, immunohistochemistry, cytogenetic (FISH) and molecular biological (RT-PCR) methods. Classical EWS was found to be in 8 patients, large-cell EWS in 1 patient; atypical EWS in 1, and endothelial ESW in 1. Two patients were diagnosed as having primitive neuroectodermal tumor (PNET), synovial sarcoma was present in 1 patient, embryonic rhabdomyosarcoma in 1, high-grade undifferentiated sarcoma in 1 and diffuse B-cell large-cell lymphoma in 1. TMA makes it possible to perform a number of diagnostic procedures on the same block containing a copious number of tumor samples and to assess the results of their use. It is emphasized that the diagnosis of small-cell round tumors requires the use of a package of the currently available methods providing the qualitative characteristics of each neoplasm.

18F-FDG PET/CT in the evaluation of cartilaginous bone neoplasms: the added value of tumor grading.

OBJECTIVES: Cartilaginous bone tumors represent a wide variety of neoplasms ranging from benign to extremely aggressive malignant lesions. Unlike other tumors, the biopsy cannot easily predict the histological grade, sometimes not allowing choosing the best therapeutic approach. The aim of the study was to evaluate the ability of 18F-FDG PET/CT to differentiate enchondroma from chondrosarcoma and to predict the histological grade as compared to biopsy. METHODS: 18F-FDG PET/CT of 95 patients with chondroid lesions were retrospectively evaluated. The best SUVmax cutoff to predict the post-surgical histological grade were correlated to those of biopsy and to several radiologic aggressiveness features, which were summarized in the parameter "Radiologic Aggressiveness Score" (AgSCORE). RESULTS: A concordance between the preoperative biopsy and the definitive histological grade was observed overall in 78.3% of patients, the lowest accuracy (58.6%) being in the identification of intermediate/high-grade chondrosarcoma (G2/G3). The best SUVmax cutoff was 2.6 to discriminate enchondroma vs. low-grade chondrosarcoma (sensitivity 0.68, specificity 0.86), 3.7 to differentiate low-grade vs. intermediate/high-grade chondrosarcoma (sensitivity 0.83, specificity 0.84) and 7.7 to differentiate intermediate/high-grade vs. dedifferentiated chondrosarcoma (sensitivity 0.92, specificity 0.9). The AgSCORE also showed a high accuracy to differentiate between G1 and G2/G3 chondrosarcoma (cutoff = 4; sensitivity 0.76; specificity 0.89). An even higher accuracy was observed in those cases in which both SUVmax and AgSCORE cutoff were concordant. CONCLUSIONS: Results in this large series of patients suggest a potential role of 18F-FDG PET/CT for histological grading of cartilaginous tumors, thus helping the orthopedic surgeon towards the most appropriate surgical procedure.

Increased osteoclast activity is associated with aggressiveness of osteosarcoma.

Osteosarcoma (OS) is a highly malignant primary skeletal tumor with a striking tendency to rapidly destroy the surrounding bone and metastasize, since metastases are frequently present at clinical onset. The basis for the aggressiveness of this tumor is largely unknown. However, recent studies in in vivo models indicate that the anti-osteolytic drugs, bisphosphonates, can inhibit the tumor local expansion and the formation of metastases. We further investigated the association between the presence of active osteoclasts and the aggressiveness of OS. We evaluated the presence of osteoclasts and the mRNA of different osteoclast-related genes in tumor biopsies from 16 OS patients and in three OS cell lines and the serum levels of bone resorption markers in the same series and in 28 other patients. Tumor-associated osteoclasts were found in 63 and 75% of cases by histological and mRNA analysis. Among different serum markers, only MMP-9 was significantly higher in OS cases (p=0.0001), whereas TRACP 5b was significantly higher in metastatic patients compared to nonmetastatic patients (p=0.0509). Serum TRACP 5b was significantly correlated to serum NTX (p<0.0001) and cathepsin K mRNA in tumor tissues (p=0.0153). In 8 patients we also analyzed TRACP 5b serum level at follow-up and we verified a significant decrease of TRACP 5b after primary tumor removal (p=0.0117). In conclusion, tumor-infiltrating osteoclasts are frequently found in OS and increased serum TRACP 5b levels and the presence of active osteoclast at primary sites were positively associated with tumor aggressiveness.

Expression of embryonic lethal abnormal vision (ELAV)-like protein HuR and cyclooxygenase-2 (COX-2) in Ewing sarcoma.

AIMS AND BACKGROUND: HuR is a member of the family of ELAV (embryonic lethal abnormal vision)-like proteins that stabilize several cellular mRNAs by binding to AU-rich elements in the 3' untranslated region of the mRNA. Cyclooxygenase-2 (COX-2) is a well known enzyme that promotes tumor growth and metastasis. Recent studies have shown that HuR can stabilize the mRNA of COX-2, and cytoplasmic expression of HuR is associated with increased COX-2 expression in some cancers. The aim of this study was to investigate the correlation between COX-2 and HuR in Ewing sarcoma. METHODS: The expression patterns for HuR and COX-2 were assessed via immunochemical analysis of 70 Ewing sarcoma samples. RESULTS: Nuclear HuR expression was observed in 12 of 70 (17.1%) cases, but cytoplasmic expression was not observed. COX-2 expression was seen in 25 of 70 (35.7%) samples. Nuclear HuR and COX-2 were simultaneously expressed in 8 of 70 (11.4%) samples. The expression of nuclear HuR was significantly associated with COX-2 expression (P = 0.014). Neither HuR nor COX-2 expression showed a correlation with age or sex. CONCLUSIONS: COX-2 expression in Ewing sarcoma may not be directly related to mRNA stabilization by HuR. However, a correlation between COX-2 expression and nuclear HuR expression through indirect mRNA stabilization can be suggested.

Management of pelvic giant cell tumours involving the acetabular bone.

The purpose of this study was to establish the optimal surgical treatment in patients with a Giant Cell Tumour (GCT) involving the acetabular bone. The surgical outcome in 10 patients with GCT involving the acetabular bone was reviewed. Patients were divided into two groups: group 1 in which 5 patients were primarily treated by curettage, and group 2, in which 5 patients were treated by resection and pelvic reconstruction. In group 1, local recurrence occurred in two cases. The functional outcome was excellent or good in 4, and poor in one case. There were no recurrences in group 2, in which the functional outcome was excellent or good in 4 and poor in one patient. The optimal surgical treatment modality should be based upon the tumour extension. Tumours located primarily in the ischiopubic region and not extending proximally beyond the supra-acetabular line can be adequately treated by extended curettage while those with further proximal extension are better treated by en-bloc resection. However, the possible complications of the different methods of pelvic reconstruction should always be considered.

Charcot's joint secondary to neurologic complications of epidural anaesthesia: a case report.

Neurogenic arthropathy or Charcot's Joint is an articular pathology that can strike patient with neurological effects or can be the result of a neurological lesion with deficit of the superficial and deep sensitivity. In this article we introduce one case Charcot's Joint of the hip, caused by an epidural anaesthesia performed for a surgery of the other hip.

Vancomycin and meropenem in acrylic cement: elution kinetics of in vitro bactericidal action.

The Authors present a paper with a dual goal: in vitro evaluation of the elution of vancomycin and monitoring of its bactericidal action when the antibiotic is used in acrylic cement. Discs of cement with different concentrations of vancomycin alone or combined with meropenem were prepared. To assess the elution of vancomycin the discs were kept in physiological solution and periodically sampled for five weeks. The bactericidal action was assessed by putting the antibiotic discs in contact with colonies of Staphylococcus, Enterococcus, Pseudomonas and Escherichia coli. Two combinations of antibiotic-loaded cement were tested: the first one to act as a spacer and the second to stabilise the revision prosthesis.

Severe suppression of Frzb/sFRP3 transcription in osteogenic sarcoma.

Deciphering the molecular basis of cancer is critical for developing novel diagnostic and therapeutic strategies. To better understand the early molecular events involving osteogenic sarcoma (OGS), we have initiated a program to identify potential tumor suppressor genes. Expression profiling of total RNA from ten normal bone cell lines and eleven OGS-derived cell lines by microarray showed 135-fold lower expression of FRZB/sFRP3 mRNA in OGS cells compared to bone cells; this down-regulation of Frzb/sFRP3 mRNA expression was found to be serum-independent. Subsequently, fourteen OGS biopsy specimens showed nine-fold down-regulation of Frzb/sFRP3 mRNA expression compared to expression in eight normal bone specimens as determined by microarray. FRZB /sFRP3 protein level was also found to be at a very low level in 4/4 OGS cell lines examined. Quantitation by RT-PCR indicated approximately 70% and approximately 90% loss of Frzb/sFRP3 mRNA expression in OGS biopsy specimens and OGS-derived cell lines respectively, compared to expression in bone (p<0.0001). Hybridization experiments of a cDNA microarray containing paired normal and tumor specimens from nineteen different organs did not show any significant difference in the level of Frzb/sFRP3 mRNA expression between the normal and the corresponding tumor tissues. Exogenous expression of FRZB/sFRP3 mRNA in two OGS-derived cell lines lacking endogenous expression of the mRNA produced abundant mRNA from the exogenous gene, eliminating degradation as a possibility for very low level of FRZB/sFRP3 mRNA in OGS specimens. Results from PCR-based experiments suggest that the FRZB/sFRP3 gene is not deleted in OGS cell lines, however, karyotyping shows gross abnormalities involving chromosome 2 (location of the FRZB gene) in five of twelve OGS-derived cell lines. Together, these data suggest a tumor-suppressive potential for FRZB/sFRP3 in OGS.

Epithelioid variant of myxofibrosarcoma: expanding the clinicomorphologic spectrum of myxofibrosarcoma in a series of 17 cases.

Myxofibrosarcoma (MFS) is one of the most common soft tissue sarcomas of elderly patients and has a predilection for the limbs. Herein, we report a previously undescribed variant of MFS showing epithelioid morphology. Seventeen cases diagnosed as epithelioid MFS were retrieved from the authors' files from among 570 cases of MFS. Hematoxylin and eosin-stained sections were reexamined and immunostains for pan-keratin (15 cases), S-100 protein (15), desmin (15), and alpha-smooth muscle actin (13) were performed. Nine patients were men and 8 were women (age range 43 to 89 y; median 63.5). Fifteen patients presented with a mass, and in 2 of these there was also pain. Duration of symptoms varied from 1 to 24 months (median 3). Tumor size ranged from 2 to 15 cm (median 6.75). In 10 cases, the tumor was located in subcutaneous tissue and in 6 cases it was subfascial. The majority of the tumors were located on the limbs (8 lower extremities and 6 upper extremities) followed by neck (1), scalp (1), and trunk (1). Follow-up was available for 14 patients (range 2 to 240 mo; median 16). Twelve patients were treated by surgery followed by chemotherapy and/or radiation (8 cases). One patient received chemotherapy after an incisional biopsy and 1 patient was treated by surgery alone. Ten patients (71.4%) developed local recurrences. Seven patients (50%) developed metastases to lungs or retroperitoneum. Five patients (35.7%) have died of disease so far. Two patients were lost to follow-up. Morphologically, 14 cases were high grade, 2 were intermediate, and 1 was low grade. Tumors were characterized by a multinodular, infiltrating growth pattern with alternation of hypercellular and hypocellular myxoid areas; the latter showed prominent curvilinear vessels. Neoplastic cells were arranged singly and in small clusters in the myxoid areas or formed sheets in the hypercellular areas, where they showed epithelioid morphology with round nuclei, vesicular chromatin, prominent nucleoli, and moderate amounts of eosinophilic cytoplasm. The epithelioid areas were generally multifocal with admixed areas of conventional MFS. Immunostains were negative for all markers studied. Differential diagnosis included carcinoma, melanoma, myoepithelial carcinoma, pleomorphic liposarcoma, and pleomorphic rhabdomyosarcoma. In conclusion, epithelioid MFS is a rare variant of MFS, accounting for <3% of MFS in consultation material. Its natural history seems more aggressive than usual high-grade MFS, with approximately 70% local recurrence and 50% metastases, even within a relatively short follow-up period.

Dedifferentiated chondrosarcomas arising in preexisting osteochondromas.

BACKGROUND: Dedifferentiated chondrosarcomas that arise in osteochondromas are extremely rare lesions for which very little information on treatment and outcome is available in the literature. The purpose of the present study was to describe the specific clinical, radiographic, and histologic features of this lesion and to evaluate the oncologic outcome after different treatment strategies. METHODS: We reviewed the files of the Rizzoli Institute between 1970 and 2002 and identified eighteen patients for whom adequate records and histologic images were available and in whom a high-grade sarcoma had been diagnosed at the same location as a preexisting osteochondroma. Radiographic studies, histologic slides, and clinical records were reviewed, the features of those studies were tabulated, and prognostic features and the results of treatment were identified. RESULTS: The patients included twelve men and six women with an average age of forty-six years (range, twenty-two to seventy-four years). Eight lesions occurred in patients with multiple osteochondromas, and ten occurred in patients with solitary lesions. The most common locations were the pelvis (six lesions) and the femur (five lesions). Symptoms included pain, swelling, and a growing mass; the average duration of symptoms was eighteen months. Radiographically, ten lesions appeared as a conventional secondary chondrosarcoma arising in an exostosis, whereas eight showed typical signs of dedifferentiation. Histologic evaluation of the cartilage component demonstrated thirteen grade-1 and two grade-2 chondrosarcomas. In three cases, no cartilage component was recognized. The dedifferentiated component was considered to be an osteosarcoma in nine cases (including six cases in which it was osteoblastic and three in which it was fibroblastic), a malignant fibrous histiocytoma in eight, and a fibrosarcoma in one. The dedifferentiated component represented an average of 59% (range, 20% to 100%) of the lesion. For the fifteen patients who were managed at the authors' institution, the two and five-year survival rates were 47% and 29%, respectively; the median survival time was fourteen months. Patients who were managed with a combination of surgery and chemotherapy had a better overall survival rate than did those who were managed with surgery alone (p = 0.03). CONCLUSIONS: Dedifferentiated chondrosarcoma arising in a preexisting osteochondroma is an extremely rare lesion with a poor prognosis. In the present small series, overall survival was better when wide surgical resection was combined with adjuvant chemotherapy.

Protein expression of KIT and gene mutation of c-kit and PDGFRs in Ewing sarcomas.

Ewing sarcoma is a highly malignant tumor of bone preferentially arising in children and young adults. Its 5-year survival rate is only 50% despite the use of multimodal therapeutic approaches, requiring a search for new therapeutic targets and the development of novel therapeutic modalities. KIT and PDGFRs are type III receptor tyrosine kinases, and activating mutations in c-kit (which encodes KIT) and PDGFRs have been reported as oncogenic events in many malignancies. Imatinib is a selective inhibitor of KIT, PDGFR, and ABL tyrosine kinase activity and exerts different anti-tumor effects according to the regions of mutations in c-kit and PDGFR genes. Thus, we evaluated the immunohistochemical expression of KIT protein and the mutational status of exons 9, 11, 13, and 17 of the c-kit gene, exons 12 and 18 of the PDGFRA gene, and exon 12 of the PDGFRB gene in 71 formalin-fixed, paraffin-embedded Ewing sarcomas to increase our understanding of the potential, if any, of imatinib treatment for this malignancy. Of the 71 samples, 27 (38%) were immunohistochemically positive for KIT; however, activating mutations in c-kit were found in only 2 of 71 Ewing sarcomas (2.6%) within exon 9. No activating mutations in the PDGFRA and PDGFRB genes were found, but pleomorphism was identified in exon 18 of the PDGFRA gene. Our results for KIT protein expression agree with those of previous studies. This is the largest series of c-kit mutational analysis in Ewing sarcoma to date, and the results definitively show that c-kit activating mutations are not coincident with KIT protein expression in Ewing sarcoma in most samples. These findings imply other mechanisms for KIT activity and leave open the question of whether imatinib would be efficacious in the treatment of Ewing sarcoma.