Screening for potential targets for therapy in mesenchymal, clear cell, and dedifferentiated chondrosarcoma reveals Bcl-2 family members and TGFß as potential targets.

The mesenchymal, clear cell, and dedifferentiated chondrosarcoma subtypes are extremely rare, together constituting 10% to 15% of all chondrosarcomas. Their poor prognosis and lack of efficacious treatment emphasizes the need to elucidate the pathways playing a pivotal role in these tumors. We constructed tissue microarrays containing 42 dedifferentiated, 23 clear cell, and 23 mesenchymal chondrosarcomas and performed immunohistochemistry to study the expression of growth plate-signaling molecules and molecules shown to be involved in conventional chondrosarcoma. We observed high expression of SOX-9 and FGFR-3, as well as aberrant cellular localization of heparan sulfate proteoglycans, in all subtypes. TGFß signaling through p-SMAD2 and PAI-1 was highly active in all chondrosarcoma subtypes, which suggests that TGFß inhibitors as a possible therapeutic strategy in rare chondrosarcoma subtypes. As in conventional chondrosarcoma, antiapoptotic proteins (Bcl-2, and/or Bcl-xl) were highly expressed in all subtypes. Inhibition with the BH-3 mimetic ABT-737 rendered dedifferentiated chondrosarcoma cell lines sensitive to doxorubicin or cisplatin. Our data indicate that antiapoptotic proteins may play an important role in chemoresistance, suggesting a promising role for targeting Bcl-2 family members in chondrosarcoma treatment, irrespective of the subtype.

Is clear cell sarcoma a malignant form of psammomatous melanotic schwannoma? Case report.

The authors present a case of clear cell sarcoma (CCS) in which the tumor originated in the S-1 nerve root and had been previously diagnosed as psammomatous melanotic schwannoma (PMS). This is the third case of a spinal nerve root origin for CCS reported in the English-language literature. The similar histogenesis of CCS and malignant melanoma supports the hypothesis that biological agents or immunotherapy are potentially important areas of investigation. The patient underwent S1-3 laminectomy and gross-total resection of the mass lesion. The border of the resection was extended 1 cm distal to the tumor margin. The postoperative period was uneventful. The new histopathological diagnosis was CCS (malignant melanoma of soft tissue). Despite total resection, the patient returned with disseminated disease at the 18-month follow-up visit. His follow-up magnetic resonance image of the lumbar spine revealed sacral L5-S3 involvement of the vertebral bodies along with disseminated cauda equina seeding. A CCS originating from peripheral nerves is quite rare. The histopathological and immunohistochemical appearance of CCSs resembles those of PMSs. Surgery should be the first choice of treatment.

Fine-needle aspiration cytology of clear-cell sarcoma of the kidney: study of eight cases.

The largest series, to date, of fine-needle aspiration cytology (FNAC) findings in clear-cell sarcoma of the kidney (CCSK) is presented. All fine-needle aspirates of pediatric renal masses over a 17-yr period were reviewed. Eight out of 119 aspirates from late-stage childhood renal tumors (6.72%) were found to be CCSK. Ten aspirates from these eight patients and histopathological confirmation in six patients were available. Aspirates were cellular with three cell types: cord cells, septal cells, and small pyknotic cells. Cord cells, seen in all aspirates, were large polygonal cells with abundant eccentrically placed wispy cytoplasm, round to oval nuclei, and fine dusty chromatin. Occasional bare nuclei and frequent nuclear grooves were also seen. Small pyknotic cells were a degenerative change identified in 9 out of 10 aspirates. Stromal fragments with branching vascular cores were seen in 8 out of 10 aspirates, 6 of which had myxoid substance surrounding the vessel. Septal cells were spindle shaped and usually embedded in the stromal fragments. On the basis of cytology and histology, cases were classified into classical CCSK (5 cases), spindle-cell CCSK (1 case), and anaplastic CCSK (2 cases). Classical CCSK showed mostly cord cells with few stromal fragments. Spindle-cell CCSK showed preponderance of myxoid stromal fragments and septal cells. Anaplastic CCSK showed bizarre pleomorphic nuclei, coarse chromatin, and atypical mitosis. Cytology of CCSK is a spectrum with varying proportions of cord cells, septal cells, and mucopolysaccharide substance. Anaplastic CCSK is liable to misdiagnosis as Wilms tumor (WT) with unfavourable histology. Presence of eccentric cytoplasm in cord cells and nuclear grooves are the key to differentiation from Wilms tumor, including anaplastic variants.

A 71-year-old man with spindle-cell neoplasm of unknown origin: a difficult-to-diagnose clear-cell sarcoma.

A patient initially presented in 1988 with a solitary axillary mass, diagnosed as a high-grade neuroendocrine spindle-cell neoplasm; there was no history of a primary cutaneous malignancy. After subsequent development of a pulmonary nodule in 2001 (14-years post initial diagnosis), the case was reviewed and the possibility of metastatic melanoma was raised. The histopathologic and immunohistochemical profile of this melanocytic neoplasm was diagnostic of clear cell sarcoma (CCS) of tendons and aponeuroses, although the differential diagnosis included malignant melanoma, follicular dendritic and interdigitating cell tumors, malignant peripheral nerve sheath tumor, and a category of so-called PEComas. It is the role of pathologists, particularly dermatopathologists, to distinguish CCS from malignant melanoma, and to alert the clinician, because proper diagnosis ultimately influences treatment. We discuss the immunophenotype, differential diagnosis, and molecular signatures of these neoplasms, and review the pertinent literature on these entities.

Clear cell chondrosarcoma: radiographic, computed tomographic, and magnetic resonance findings in 34 patients with pathologic correlation.

OBJECTIVE: To describe the radiographic features of clear cell chondrosarcoma (CCCS), including the computed tomographic (CT) and magnetic resonance (MR) findings, and to correlate them with the histopathologic findings. DESIGN AND PATIENTS: A retrospective review was carried out of 72 patients with histopathologically confirmed CCCS. Imaging studies were available for 34 patients: conventional radiographs (n=28), CT scans (n=14), and MR images (n=15). Radiographic studies were reviewed by three radiologists who rendered a consensus opinion; the studies were correlated with the histopathologic findings. RESULTS: Of the 34 patients with imaging studies, 30 were male and 4 were female (mean age 38.6 years; range 11-74 years). Twenty-two lesions were in long bones (15, proximal femur; 1, distal femur; 1, proximal tibia; 5, proximal humerus) and 11 were in flat bones (5, vertebra; 4, rib; 1, scapula; 1, innominate). One lesion occurred in the tarsal navicular bone. Typically, long bone lesions were located in the epimetaphysis (19/22) and were lucent with a well-defined sclerotic margin and no cortical destruction or periosteal new bone formation. More than one-third of the long bone lesions contained matrix mineralization with a characteristic chondroid appearance. Pathologic fractures were present in six long bone lesions (4, humerus; 2, femur). Lesions in the proximal humerus were more likely to have indistinct margins (4/5) and extend into the diaphysis. Flat bone lesions were typically lytic and expansile and occasionally demonstrated areas of cortical disruption. Typically, matrix mineralization, when present, was amorphous. MR imaging, when available, was superior to conventional radiographs for demonstrating the intramedullary extent of a lesion as well as soft tissue extension. CT images better delineated the presence of cortical destruction and the character of matrix mineralization patterns. CCCS lesions were typically low signal intensity on T1-weighted images and moderately or significantly bright on T2-weighted images. Areas of lesion heterogeneity on T1- and T2-weighted images and on post-gadolinium T1-weighted images corresponded pathologically to areas of mineralization, intralesional hemorrhage, and cystic changes. Adjacent bone marrow edema was typically absent (12/15) or only minimally observed in a few cases (3/15). No cases examined with MR imaging demonstrated periosteal new bone formation. CONCLUSIONS: CCCS typically presents radiographically as a geographic lytic lesion located in the epimetaphyseal region of long bones. Most commonly lesions are found in the proximal femur, followed by the proximal humerus. Lesions within the proximal humerus may exhibit more aggressive features. Lesions in the axial skeleton are typically expansile and destructive, often with soft tissue extension and lack of mineralization. MR imaging may show the presence or absence of bone marrow edema.

Classification of clear-cell sarcoma as a subtype of melanoma by genomic profiling.

PURPOSE: To develop a genome-based classification scheme for clear-cell sarcoma (CCS), also known as melanoma of soft parts (MSP), which would have implications for diagnosis and treatment. This tumor displays characteristic features of soft tissue sarcoma (STS), including deep soft tissue primary location and a characteristic translocation, t(12;22)(q13;q12), involving EWS and ATF1 genes. CCS/MSP also has typical melanoma features, including immunoreactivity for S100 and HMB45, pigmentation, MITF-M expression, and a propensity for regional lymph node metastases. MATERIALS AND METHODS: RNA samples from 21 cell lines and 60 pathologically confirmed cases of STS, melanoma, and CCS/MSP were examined using the U95A GeneChip (Affymetrix, Santa Clara, CA). Hierarchical cluster analysis, principal component analysis, and support vector machine (SVM) analysis exploited genomic correlations within the data to classify CCS/MSP. RESULTS: Unsupervised analyses demonstrated a clear distinction between STS and melanoma and, furthermore, showed that CCS/MSP cluster with the melanomas as a distinct group. A supervised SVM learning approach further validated this finding and provided a user-independent approach to diagnosis. Genes of interest that discriminate CCS/MSP included those encoding melanocyte differentiation antigens, MITF, SOX10, ERBB3, and FGFR1. CONCLUSION: Gene expression profiles support the classification of CCS/MSP as a distinct genomic subtype of melanoma. Analysis of these gene profiles using the SVM may be an important diagnostic tool. Genomic analysis identified potential targets for the development of therapeutic strategies in the treatment of this disease.

Risk assignment in pediatric soft-tissue sarcomas: an evolving molecular classification.

Pediatric soft-tissue sarcomas are increasingly being defined by both histologic appearance and underlying chromosomal abnormalities to determine their biologic behavior. Most sarcomas of this type have specific chromosomal translocations that create unique fusion genes. Expression of such fusion genes may have diagnostic, prognostic, and surveillance implications for the patient. This review analyzes the fusion gene expressions seen with seven of the major types of pediatric soft-tissue tumors and their impact on biologic behavior. In nearly 50% of the malignancies discussed, the diagnostic, prognostic, and surveillance implications of their specific fusion gene expressions are already defined or becoming established (alveolar rhabdomyosarcoma, Ewing sarcoma/primitive neuroectodermal tumor, and synovial sarcoma). In the remainder of the tumors, these questions are rapidly being addressed. To facilitate future fusion gene studies, pediatric surgeons, pathologists, and oncologists need to work as a coordinated team to ensure proper tumor procurement. Large clinical cooperative trials involving biologic studies of pediatric soft-tissue sarcomas could facilitate advancement of knowledge in this area of pediatric oncology.