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1.
Clin Cancer Res ; 30(12): 2647-2658, 2024 Jun 14.
Article in English | MEDLINE | ID: mdl-38573684

ABSTRACT

PURPOSE: Tumor classification is a key component in personalized cancer care. For soft-tissue and bone tumors, this classification is currently based primarily on morphology assessment and IHC staining. However, these standard-of-care methods can pose challenges for pathologists. We therefore assessed how whole-genome and whole-transcriptome sequencing (WGTS) impacted tumor classification and clinical management when interpreted together with histomorphology. EXPERIMENTAL DESIGN: We prospectively evaluated WGTS in routine diagnostics of 200 soft-tissue and bone tumors suspicious for malignancy, including DNA and RNA isolation from the tumor, and DNA isolation from a peripheral blood sample or any non-tumor tissue. RESULTS: On the basis of specific genomic alterations or absence of presumed findings, WGTS resulted in reclassification of 7% (13/197) of the histopathologic diagnoses. Four cases were downgraded from low-grade sarcomas to benign lesions, and two cases were reclassified as metastatic malignant melanomas. Fusion genes associated with specific tumor entities were found in 30 samples. For malignant soft-tissue and bone tumors, we identified treatment relevant variants in 15% of cases. Germline pathogenic variants associated with a hereditary cancer syndrome were found in 22 participants (11%). CONCLUSIONS: WGTS provides an important dimension of data that aids in the classification of soft-tissue and bone tumors, correcting a significant fraction of clinical diagnoses, and identifies molecular targets relevant for precision medicine. However, genetic findings need to be evaluated in their morphopathologic context, just as germline findings need to be evaluated in the context of patient phenotype and family history.


Subject(s)
Genomics , Sarcoma , Humans , Sarcoma/genetics , Sarcoma/diagnosis , Sarcoma/pathology , Male , Female , Middle Aged , Adult , Aged , Genomics/methods , Bone Neoplasms/genetics , Bone Neoplasms/diagnosis , Bone Neoplasms/pathology , Young Adult , Gene Expression Profiling , Aged, 80 and over , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/pathology , Adolescent , Biomarkers, Tumor/genetics , Prospective Studies , Child , Whole Genome Sequencing/methods
2.
Am J Surg Pathol ; 44(9): 1213-1223, 2020 09.
Article in English | MEDLINE | ID: mdl-32427623

ABSTRACT

Dedifferentiated chordoma is a rare chordoma subtype characterized by a high-grade sarcoma juxtaposed to conventional chordoma. We identified a series of dedifferentiated chordomas, reviewed clinicopathologic features, performed next-generation sequencing in select cases, and analyzed all related English-language publications. Our series included 7 men and 3 women (age 15 to 80 y [median: 54 y]; <1% of >1000 chordomas surveyed). The tumor (2.8 to 24.5 cm [median: 5.8 cm] in size) presented de novo or as recurrence (including postradiotherapy) in sacrum (n=5), skull base (n=2), lumbar spine (n=1), thoracic/mediastinum (n=1), and lung (n=1; as metastasis). Histologically, the dedifferentiated component (3% to 95% [median: 60%]) was pleomorphic-to-fibrosarcomatous, juxtaposed to conventional (n=8) or chondroid (n=2) component. By immunohistochemistry, the conventional/chondroid component consistently expressed cytokeratin and brachyury, whereas the dedifferentiated component showed loss of both. We identified a sacral conventional chordoma with INI1 loss, with one of the lung metastases showing biphasic histology with loss of cytokeratin and brachyury in the dedifferentiated component. Sequencing identified tumor suppressor mutations in 4 tumors, including TP53 mutations in the dedifferentiated component in 3 tumors. Of 7 patients with follow-up, 6 developed metastases; 4 died at 15 to 99 months (median: 24 mo) after dedifferentiated chordoma diagnosis. Collectively, of 87 dedifferentiated chordoma patients described in 1913-2020 (including 10 herein), the median overall survival was 20 months. In summary, dedifferentiated chordoma involves diverse sites and presents de novo, postradiotherapy, or as recurrence/metastasis months-to-years after initial diagnosis. The dedifferentiated component shows loss of brachyury and cytokeratin staining and harbors recurrent TP53 mutations, implicating tumor suppressor dysregulation in chordoma dedifferentiation.


Subject(s)
Biomarkers, Tumor , Cell Dedifferentiation , Chordoma/classification , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/analysis , Biomarkers, Tumor/genetics , Boston , Chordoma/chemistry , Chordoma/genetics , Chordoma/secondary , Female , Florida , Genetic Predisposition to Disease , High-Throughput Nucleotide Sequencing , Humans , Immunohistochemistry , Male , Middle Aged , Mutation , Neoplasm Grading , Phenotype , SMARCB1 Protein/analysis , SMARCB1 Protein/genetics , Treatment Outcome , Tumor Suppressor Protein p53/genetics , Young Adult
3.
Cytopathology ; 30(5): 504-509, 2019 09.
Article in English | MEDLINE | ID: mdl-31161693

ABSTRACT

OBJECTIVE: Synovial sarcomas (SS) are rare soft tissue tumours defined by the SYT-SSX fusion gene. The tumours are composed of mesenchymal cells with varying degrees of epithelial differentiation. Cytomorphological descriptive studies are limited to small series and single cases. In this study we systematically examined the cytological features of SS diagnosed at our institution. METHODS: SS diagnosed by fine-needle aspiration (FNA) cytology at our institution between 2006 and 2018 were reviewed by a panel of senior cytopathologists. Clinical and cytopathological characteristics were categorised and described. RESULTS: A total of 38 SS FNAs were identified from 35 patients. The cytomorphology was uniform, presenting as highly cellular smears of clusters and individual cells with mixed round, oval and spindle cells. We frequently observed pericapillary arrangement and occasionally pink background stroma was seen. Glandular formation or epithelial components were identified in the majority of cases which on histology were subtyped as biphasic SS. Pleomorphism and mitoses were rare. Immunocytochemical analysis was frequently positive for vimentin, epithelial membrane antigen, Bcl2 and, in recent cases, TLE1. Pan-cytokeratins and CK7 could occasionally be positive in biphasic cases. The diagnostic SYT-SSX fusion gene was detected in all FNA specimens using polymerase chain reaction or fluorescence in situ hybridisation. CONCLUSIONS: SS have distinct and uniform cytopathological features. Molecular genetic analysis for SYT-SSX are invaluable for diagnosing SS with FNA and should be implemented in cytopathological laboratories that routinely perform soft tissue diagnostics.


Subject(s)
Cytodiagnosis/methods , Sarcoma, Synovial/diagnosis , Sarcoma, Synovial/genetics , Adolescent , Adult , Aged , Biopsy, Fine-Needle , Female , Humans , Immunohistochemistry , Male , Middle Aged , Sarcoma, Synovial/pathology , Young Adult
4.
Br J Cancer ; 120(4): 435-443, 2019 02.
Article in English | MEDLINE | ID: mdl-30745580

ABSTRACT

BACKGROUND: Heterogeneity and low incidence comprise the biggest challenge in sarcoma diagnosis and treatment. Chemotherapy, although efficient for some sarcoma subtypes, generally results in poor clinical responses and is mostly recommended for advanced disease. Specific genomic aberrations have been identified in some sarcoma subtypes but few of them can be targeted with approved drugs. METHODS: We cultured and characterised patient-derived sarcoma cells and evaluated their sensitivity to 525 anti-cancer agents including both approved and non-approved drugs. In total, 14 sarcomas and 5 healthy mesenchymal primary cell cultures were studied. The sarcoma biopsies and derived cells were characterised by gene panel sequencing, cancer driver gene expression and by detecting specific fusion oncoproteins in situ in sarcomas with translocations. RESULTS: Soft tissue sarcoma cultures were established from patient biopsies with a success rate of 58%. The genomic profile and drug sensitivity testing on these samples helped to identify targeted inhibitors active on sarcomas. The cSrc inhibitor Dasatinib was identified as an active drug in sarcomas carrying chromosomal translocations. The drug sensitivity of the patient sarcoma cells ex vivo correlated with the response to the former treatment of the patient. CONCLUSIONS: Our results show that patient-derived sarcoma cells cultured in vitro are relevant and practical models for genotypic and phenotypic screens aiming to identify efficient drugs to treat sarcoma patients with poor treatment options.


Subject(s)
Sarcoma/drug therapy , src-Family Kinases/antagonists & inhibitors , Adult , CSK Tyrosine-Protein Kinase , Cell Line, Tumor , Drug Resistance, Neoplasm , Female , Humans , Male , Sarcoma/genetics , Sarcoma/pathology
5.
Mod Pathol ; 31(12): 1834-1841, 2018 12.
Article in English | MEDLINE | ID: mdl-30065261

ABSTRACT

Chondrosarcomas are malignant skeletal tumors with chondroid differentiation. Prognosis is largely dependent on histological grading, which suffer from significant interobserver variability. Telomerase activity and abundant telomerase reverse transcriptase (hTERT) expression has previously been associated with chondrosarcoma grade and metastasis. We therefore analyzed the hTERT promoter in clinicopathologically well-characterized chondrosarcomas (grade 1-3) from 87 patients. Using Sanger sequencing we identified an activating -124 C > T mutation in 23 cases (26%). Promoter mutations were significantly associated with increased histological grade (8% of grade 1, 32% of grade 2 and 46% of grade 3, P = 0.002), suggesting a role in tumor progression. In four chondrosarcomas where the histopathological grade was heterogenous, the hTERT mutation was only identified in the higher-grade areas. Additionally, hTERT promoter mutations were significantly associated with worse metastasis-free survival (P = 0.018), chondrosarcoma-specific survival (P = 0.022) and older patient age (P = 0.003). These data suggest that hTERT promoter mutations are common in high grade conventional chondrosarcomas. Granted that additional studies can confirm these findings; hTERT promoter analysis could potentially serve as an adjuvant prognostic marker in routine chondrosarcoma grading. This study reinforces the rationale of telomerase targeted therapy in a subset of chondrosarcomas.


Subject(s)
Bone Neoplasms/genetics , Bone Neoplasms/mortality , Chondrosarcoma/genetics , Chondrosarcoma/mortality , Telomerase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biomarkers, Tumor/genetics , Disease Progression , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Prognosis , Promoter Regions, Genetic/genetics , Young Adult
6.
J Clin Pathol ; 71(9): 832-839, 2018 Sep.
Article in English | MEDLINE | ID: mdl-29703757

ABSTRACT

AIMS: Solitary fibrous tumour (SFT) is an infrequently metastasising mesenchymal tumour defined by the NAB2-STAT6 fusion gene. Activating mutations in the telomerase reverse transcriptase (hTERT) gene promoter has been reported to associate with adverse patient outcome in SFTs. METHODS: We analysed the hTERT gene for promoter mutations and copy number alterations in 43 primary extrameningeal SFTs (9 malignant and 34 benign tumours according to WHO 2013 criteria), six local recurrences and three metastatic lesions. RESULTS: Activating -124 C>T (n=12) or -148 C>T (n=2) mutations were found in 33% of the tumours and associated with older age (P=0.006), necrosis (P=0.009), higher mitotic rate (P=0.003), nuclear atypia (P=0.002), malignant histological diagnosis (P=0.04) and worse progression-free survival (P=0.023). We also observed frequent (24%) hTERT promoter mutations in histologically benign tumours without metastasis (mean follow-up >9 years), and in 14%-18% of low-risk SFTs as determined by three risk-stratification models. Mutations were seen in 2/6 metastatic tumours and metastatic lesions. hTERT copy number gain was seen in 11/28 hTERT promoter wild-type cases. CONCLUSIONS: Activating hTERT promoter mutations associate with aggressive histopathological features, indicating a role in tumour progression. Given the comparatively high prevalence of hTERT promoter mutations in low-risk and non-metastasising lesions, further studies are required to clarify the prognostic value of hTERT promoter analysis before implementing the analysis in clinical diagnostics.


Subject(s)
DNA Copy Number Variations , Gene Dosage , Mutation , Promoter Regions, Genetic , Solitary Fibrous Tumors/genetics , Telomerase/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Biopsy , DNA Mutational Analysis , Disease Progression , Disease-Free Survival , Female , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Neoplasm Recurrence, Local , Phenotype , Risk Factors , Solitary Fibrous Tumors/enzymology , Solitary Fibrous Tumors/secondary , Solitary Fibrous Tumors/surgery , Sweden , Time Factors , Treatment Outcome , Young Adult
7.
World J Surg ; 42(8): 2512-2521, 2018 08.
Article in English | MEDLINE | ID: mdl-29435627

ABSTRACT

BACKGROUND: Surgical resection is still the main treatment for gastrointestinal stromal tumor (GIST), and R0 excision, regardless of surgical margins, is considered sufficient. METHODS: A cohort of 79 consecutive GIST cases treated at the Karolinska University Hospital, who were without metastasis at diagnosis and who had not received any pre-or postoperative treatment with tyrosine kinase inhibitors, was included. Surgical margins were evaluated at the time of surgery and classified as wide, marginal or intralesional. Time to local/peritoneal recurrence, distant metastasis, and survival were recorded. Cox regression analysis was used to investigate the association between surgical margin, and recurrence and survival. RESULTS: Local/peritoneal recurrence was diagnosed in 2/39 cases with wide margins, in 7/22 cases with marginal margins, and in 13/18 cases with intralesional surgery. Compared to wide margins this gives a hazard ratio of 6.8 (confidence interval 1.4-32.7) for marginal margins and 13.5 (3-61) for intralesional margins. In multivariate analysis, adjusting for size, site, and mitotic index, surgical margin remained an independent significant predictor of risk for recurrence. When classifying patients according to R0/R1 surgery, patients with R0 surgery showed longer time to peritoneal recurrence and better recurrence-free and disease-specific survival as compared to those with R1 resection. However, when excluding patients operated with wide surgical margin, no significant difference was observed. CONCLUSION: Wide surgical margins are of significant prognostic importance, supporting the strategy of en bloc resection with good margin and careful handling of the tumor to avoid damaging the peritoneal surface in surgical resection of GIST.


Subject(s)
Gastrointestinal Neoplasms/surgery , Gastrointestinal Stromal Tumors/surgery , Margins of Excision , Adolescent , Adult , Aged , Aged, 80 and over , Child , Female , Gastrointestinal Neoplasms/mortality , Gastrointestinal Neoplasms/pathology , Gastrointestinal Stromal Tumors/mortality , Gastrointestinal Stromal Tumors/pathology , Humans , Male , Middle Aged , Proportional Hazards Models
8.
Cancer Cytopathol ; 126(1): 36-43, 2018 01.
Article in English | MEDLINE | ID: mdl-28914981

ABSTRACT

BACKGROUND: Solitary fibrous tumors (SFTs) are rare mesenchymal tumors commonly located in the pleura, soft tissues, or meninges and are characterized by the NGFI-A-binding protein 2 (NAB2)-signal transducer and activator of transcription 6 (STAT6) fusion gene. Recent studies have indicated that nuclear STAT6 immunohistochemistry is a specific marker for SFTs. METHODS: The authors reviewed fine-needle aspiration (FNA) specimens from extracranial SFTs diagnosed at their institution between 1993 and 2017. Histologic blocks and available formalin-fixed smears of FNA specimens from SFTs were investigated for STAT6 immunoreactivity using a monoclonal antibody. STAT6 immunocytochemistry was also investigated in schwannomas and spindle cell lipomas. Cytopathologic and clinical characteristics were described. RESULTS: Nineteen benign and 9 malignant SFTs were identified. Both benign and malignant SFTs had a female predominance (female-to-male ratio, 2.8:1 and 1.25, respectively). Localization varied, and approximately one-half of the extrapleural tumors were located in the extremities and frequently were intramuscular. Benign and malignant primary tumors had limited differences in cytologic presentation, the most notable feature being nuclear pleomorphism. Cytomorphologic features included low-to-moderate cellularity of mixed oval, elongated, round, and stellate cells with pink collagenous stroma and hypercellular clusters with infrequent atypia. In metastatic SFTs, the cytopathology was suggestive of sarcoma. Immunohistochemistry revealed nuclear STAT6 immunoreactivity in SFTs (n = 5) with cytoplasmic reactivity in cytologic mimickers. CONCLUSIONS: Benign and malignant SFTs have common cytopathologic features, and the ability to distinguish between them is limited. Nuclear STAT6 immunoreactivity is a valuable cytologic marker for SFTs. Cancer Cytopathol 2018;126:36-43. © 2017 American Cancer Society.


Subject(s)
Biomarkers, Tumor/analysis , Biopsy, Fine-Needle , STAT6 Transcription Factor/analysis , Solitary Fibrous Tumors/pathology , Adolescent , Adult , Aged , Aged, 80 and over , Female , Humans , Immunohistochemistry , Ki-67 Antigen/analysis , Male , Middle Aged , Solitary Fibrous Tumors/chemistry , Solitary Fibrous Tumors/diagnosis , Young Adult
9.
Magn Reson Imaging ; 43: 37-41, 2017 11.
Article in English | MEDLINE | ID: mdl-28698004

ABSTRACT

BACKGROUND: Myxoid liposarcomas are highly radiosensitive. Consequently radiotherapy is often used pre-operatively to reduce tumor volume and lessen the post-operative deficit. In soft-tissue sarcomas therapy response is mainly evaluated using magnetic resonance imaging (MRI) and the fundamental criterion for a positive response is decreased tumor size. In myxoid liposarcomas an increased fat content is also known to occur as a response to radiotherapy. OBJECTIVE: To highlight the difficulties of MRI for therapy response evaluation in irradiated myxoid liposarcomas, by using MRI Dixon techniques enabling objective quantification of proton density fat fraction (%) and the number of double bonds (ndb; unsaturation degree) of fatty acids. Secondly, to compare quantitative fat fraction measurements versus visual grading of fat content on T1-weighted images. CASE DESCRIPTIONS: Prior to surgery, two patients with myxoid liposarcoma were treated with 50Gy. Following radiotherapy, both tumors on MRI showed reduced size, elevated fat fraction and transformed fat fraction histograms with diverse changes of ndb, while histopathological specimens showed discordant treatment effects; one case having good response and the other having poor response. CONCLUSIONS: A decrease in tumor size and increase in fat content on MRI cannot be interpreted as positive therapy response in radiotherapy of myxoid liposarcomas. Our data also give further supporting evidence that differentiation and maturation of tumor cells is the cause for the lipoma-like areas seen after radiotherapy. Finally, quantitative MRI Dixon techniques are preferable to visual grading for estimating the fat content in lipomatous tumors.


Subject(s)
Fatty Acids/chemistry , Liposarcoma, Myxoid/diagnostic imaging , Liposarcoma/diagnostic imaging , Magnetic Resonance Imaging , Soft Tissue Neoplasms/diagnostic imaging , Biopsy , Cell Differentiation , Female , Humans , Lipoma/pathology , Liposarcoma, Myxoid/radiotherapy , Male , Middle Aged , Protons , Retrospective Studies , Soft Tissue Neoplasms/radiotherapy , Tumor Burden
10.
Am J Surg Pathol ; 37(4): 613-6, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23480895

ABSTRACT

The EWSR1 gene in chromosome band 22q12 is a promiscuous fusion partner involved in a vast array of tumors characterized by gene fusions. In this study, we report the finding of a new fusion gene, EWSR1-NFATC1, in a hemangioma of the bone; genetic rearrangements have not previously been described in this tumor type. Chromosome banding analysis showed a t(18;22)(q23;q12) translocation as the sole change. Fluorescence in situ hybridization mapping suggested the involvement of each of the 2 partner genes, and reverse transcriptase polymerase chain reaction revealed an in-frame EWSR1-NFATC1 transcript. NFATC1 has not previously been shown to be involved in a fusion chimera. However, NFATC2, encoding another member of the same protein family, is known to be a fusion partner for EWSR1 in a subgroup of Ewing sarcoma. Thus, our findings further broaden the spectrum of neoplasms associated with EWSR1 fusion genes, add a new partner to the growing list of EWSR1 chimeras, and suggest that chromosomal rearrangements of pathogenetic, and possibly also diagnostic, significance can be present in benign vascular bone tumors.


Subject(s)
Bone Neoplasms/genetics , Calmodulin-Binding Proteins/genetics , Hemangioma/genetics , NFATC Transcription Factors/genetics , Oncogene Proteins, Fusion , RNA-Binding Proteins/genetics , Adult , Bone Neoplasms/pathology , Bone Neoplasms/surgery , Chromosome Banding , Chromosomes, Human, Pair 22 , Disease-Free Survival , Hemangioma/pathology , Hemangioma/surgery , Humans , In Situ Hybridization, Fluorescence , Male , Occipital Bone/pathology , RNA-Binding Protein EWS , Reverse Transcriptase Polymerase Chain Reaction
11.
Neoplasia ; 14(9): 807-12, 2012 Sep.
Article in English | MEDLINE | ID: mdl-23019412

ABSTRACT

Inflammatory leiomyosarcoma (ILMS) is a soft tissue tumor that morphologically resembles conventional leiomyosarcoma (LMS) admixed with a prominent inflammatory infiltrate. Genetic data on ILMS are still limited but have suggested that this entity is characterized by hyperhaploidy (24-34 chromosomes). This low chromosome number is otherwise uncommon in neoplasia and has been found only in 0.2% to 0.3% of cytogenetically investigated tumors. Here, three ILMS were investigated using cytogenetic, single-nucleotide polymorphism (SNP) array, and global gene expression analyses. All cases displayed a hyperhaploid origin. Combined with previously reported cases, hyperhaploidy has been found in six of seven cytogenetically investigated ILMS. The copy number distribution of individual chromosomes is clearly nonrandom; the hyperhaploid clones of all six cases displayed disomy for chromosomes 5 and 20, and two copies of chromosomes 18, 21, and 22 were also common. All chromosomes identified as disomic showed a biparental origin by SNP array analysis; whether this is of pathogenetic importance is not known. Compared with conventional LMS, ILMS had a distinct gene expression signature. Furthermore, the number of chromosome copies correlated well with gene expression levels; disomic chromosomes showed higher gene expression levels than monosomic chromosomes, a finding that has not previously been reported for hyperhaploid tumors. Taken together, our findings suggest that disomy for some chromosomes, notably 5 and 20, as well as distorted gene expression achieved through massive loss of other chromosomes are essential features of ILMS.


Subject(s)
Gene Expression Regulation, Neoplastic , Leiomyosarcoma/genetics , Uniparental Disomy , Adult , Chromosomes, Human, Pair 20 , Chromosomes, Human, Pair 22 , Chromosomes, Human, Pair 5 , Cluster Analysis , Female , Gene Expression Profiling , Humans , Inflammation/pathology , Leiomyosarcoma/pathology , Loss of Heterozygosity , Male , Middle Aged , Neoplasm Staging , Polymorphism, Single Nucleotide , Young Adult
12.
Am J Clin Pathol ; 130(3): 375-81, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18701410

ABSTRACT

The thickness of eosinophilic band in collagenous colitis (CC) was assessed by 3 methods: histologic estimates (22 observers), conventional measurements using a calibrated micrometric scale (1 observer), and semiautomatic micrometric measurements (1 observer). By the histologic estimate technique, 7.4% of the results failed to diagnose CC; by calibrated micrometry, the failure was 6% and by semiautomatic micrometry, 6%. The main difficulty in measuring the thickness of the CC band is that the deeper border of the band appears fuzzy and hairy-irregular. CC should be defined not exclusively on the basis of the thickness of the collagen table, but as a microscopic constellation characterized by a distorted superficial cell arrangement, with areas of epithelial denudation and inflammatory cells in the superficial epithelium and the lamina propria. In agreement with Lazenby's statement: "Focusing solely on the collagen band can result in both over- and underdiagnosis"


Subject(s)
Colitis/diagnosis , Collagen/metabolism , Colon/pathology , Colitis/pathology , Collagen/ultrastructure , Colon/ultrastructure , Diagnostic Errors , Humans , Intestinal Mucosa/pathology , Intestinal Mucosa/ultrastructure , Retrospective Studies
13.
Onco Targets Ther ; 1: 67-78, 2008 Nov 01.
Article in English | MEDLINE | ID: mdl-21127754

ABSTRACT

The growth of many soft tissue sarcomas is dependent on aberrant growth factor signaling, which promotes their proliferation and motility. With this in mind, we evaluated the effect of sorafenib, a receptor tyrosine kinase inhibitor, on cell growth and apoptosis in sarcoma cell lines of various histological subtypes. We found that sorafenib effectively inhibited cell proliferation in rhabdomyosarcoma, synovial sarcoma and Ewing's sarcoma with IC(50) values <5 µM. Sorafenib effectively induced growth arrest in rhabdomyosarcoma cells, which was concurrent with inhibition of Akt and Erk signaling. Studies of ligand-induced phosphorylation of Erk and Akt in rhabdomyosarcoma cells showed that insulin-like growth factor-1 is a potent activator, which can be blocked by treatment with sorafenib. In vivo sorafenib treatment of rhabdomyosarcoma xenografts had a significant inhibitory effect on tumor growth, which was associated with inhibited vascularization and enhanced necrosis in the adjacent tumor stroma. Our results demonstrate that in vitro and in vivo growth of rhabdomyosarcoma can be suppressed by treatment with sorafenib, and suggests the possibilities of using sorafenib as a potential adjuvant therapy for the treatment of rhabdomyosarcoma.

14.
Clin Cancer Res ; 11(1): 206-16, 2005 Jan 01.
Article in English | MEDLINE | ID: mdl-15671548

ABSTRACT

PURPOSE: To evaluate known and suggested prognostic markers, especially insulin-like growth factor type 1 receptor (IGF-1R), in highly malignant soft tissue sarcomas (STS). EXPERIMENTAL DESIGN: A cohort of 101 patients with primary STS of high malignancy grade was studied with respect to development of metastasis, local recurrence, and survival during a minimum of 5 years follow-up. All tumors were analyzed by immunohistochemistry for expression of Ki-67, p53, p27, Bcl-2, IGF-1R, and microvessel density. The traditional clinical variables size, malignancy grade (3 or 4), necrosis, mitotic frequency, infiltrative tumor growth, vascular invasion, depth, and surgical margins were also evaluated. RESULTS: A significant association was shown between high expression of IGF-1R and favorable outcome. Among STS with positive IGF-1R immunoreactivity, cases with high expression (76-100% positive cells) had the best outcome, whereas cases with the lowest expression (1-25% positive cells) had the worst. As expected, large tumor size (>11 cm), presence of necrosis, high mitotic count, intralesional surgery, and deep location were all significantly associated with poor outcome, both in univariate and multivariate analyses. No difference in outcome was observed between cases of malignancy grade 3 versus 4, whereas the included and more objective variables necrosis and mitotic count were found to be reliable prognostic markers. CONCLUSION: IGF-1R expression is a common feature of highly malignant STS. Further elucidation of the role of IGF-1R and the IGF system in STS may both provide a basis for development of new prognostic tools in STS, as well as shed light on the basic mechanisms of the STS development.


Subject(s)
Gene Expression Regulation, Neoplastic , Receptor, IGF Type 1/biosynthesis , Sarcoma/diagnosis , Sarcoma/metabolism , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/metabolism , Adolescent , Adult , Aged , Aged, 80 and over , Animals , Blotting, Western , Cell Cycle Proteins/biosynthesis , Cell Line, Tumor , Child , Child, Preschool , Cohort Studies , Cyclin-Dependent Kinase Inhibitor p27 , Female , Humans , Immunohistochemistry , Ki-67 Antigen/biosynthesis , Male , Mice , Microcirculation , Middle Aged , Mitosis , Multivariate Analysis , Necrosis , Neoplasm Metastasis , Prognosis , Protein Binding , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Sarcoma/mortality , Soft Tissue Neoplasms/mortality , Time Factors , Treatment Outcome , Tumor Suppressor Protein p53/biosynthesis , Tumor Suppressor Proteins/biosynthesis
15.
Int J Oncol ; 26(1): 5-16, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15586219

ABSTRACT

Soft tissue sarcomas (STSs) arising in the abdominal cavity constitute a group of aggressive tumours, typically of very large size and with a high recurrence rate in the affected patients. While some distinct genetic etiologies have been described, the genetic background of this tumour group is not well characterised. Here we have assessed gross chromosomal alterations in a series of such tumours obtained from 26 patients. CGH alterations were found in tumours from 23 of the patients (88%), the most frequent being loss of 13q21 (46%) and gain of 17p and/or q (46%). Furthermore, mutations of C-KIT exon 11 were demonstrated in five tumours from four patients, and the two myxoid liposarcomas exhibited a translocation t(12;16)(q13;p11). From the pattern of chromosomal alterations detected, a genetic progression of events was clearly evident in the tumours. Taken together with analysis of subsequent relapses from the same patients, the common CGH alteration +12q13 was suggested to be a relatively early event in the genetic progression, similar to t(12;16)(q13;p11) and C-KIT mutations. Moreover, -1p21-22, -13q21, -14q, -Xp22, +9q34, +17p, +17q, and +20q13 would all represent relative later events. The most consistent alteration was loss of 13q, that was found to target the 13q14-21 and 13q34 regions as determined by CGH and Southern blot analyses. Loss of 13q was identified independently of +12q13 and C-KIT mutation and the patient's sex, and was observed in all common subtypes of STS, suggesting that it is a general and late event in the genetic progression. The findings provide a starting point for further dissection of the target genes involved in development of STSs in the abdominal cavity.


Subject(s)
Abdominal Neoplasms/genetics , Chromosome Deletion , Chromosomes, Human, Pair 13/genetics , Sarcoma/genetics , Adult , Aged , DNA/genetics , Female , Genomic Instability/genetics , Humans , Male , Middle Aged , Proto-Oncogene Proteins c-kit/genetics , Sex Factors , Spectral Karyotyping , Translocation, Genetic/genetics
16.
Genes Chromosomes Cancer ; 40(3): 218-28, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15139001

ABSTRACT

Low-grade fibromyxoid sarcoma (LGFMS) is a variant of fibrosarcoma that was recognized as a distinct tumor entity only quite recently. We previously described a translocation, t(7;16)(q33;p11), that resulted in a fusion of the FUS and CREB3L2 (also known as BBF2H7) genes in two soft tissue tumors that fulfilled morphologic criteria for LGFMS. To delineate the spectrum of tumors that may harbor the FUS/CREB3L2 gene, we selected 45 low-grade spindle cell sarcomas for reverse transcriptase polymerase chain reaction (RT-PCR) and/or fluorescence in situ hybridization (FISH) analyses; none of these tumors had originally been diagnosed as LGFMS. Furthermore, also included were two benign soft tissue tumors and nine high-grade sarcomas with supernumerary ring chromosomes or 7q3 rearrangement and three tumors diagnosed as LGFMS prior to the genetic analysis. Of the 59 tumors analyzed, 12 were FUS/CREB3L2-positive, all of which were diagnosed at histopathologic re-examination as being LGFMS, of both the classical subtype and the subtype with giant collagen rosettes. The breakpoints in the fusion transcripts were always in exons 6 or 7 of FUS and exon 5 of CREB3L2. The results indicated that FUS/CREB3L2 is specifically associated with LGFMS and that RT-PCR or FISH analysis may be useful for the differential diagnosis.


Subject(s)
Biomarkers, Tumor , Fibrosarcoma/diagnosis , RNA-Binding Protein FUS/genetics , Recombinant Fusion Proteins , Transcription Factors/genetics , Adolescent , Adult , Aged , Aged, 80 and over , Amino Acid Sequence/genetics , Base Sequence/genetics , Biomarkers, Tumor/genetics , Chromosome Mapping/methods , Cyclic AMP Response Element-Binding Protein , Cytogenetic Analysis/methods , Female , Fibrosarcoma/classification , Fibrosarcoma/genetics , Humans , In Situ Hybridization, Fluorescence/methods , Male , Middle Aged , Molecular Sequence Data , Recombinant Fusion Proteins/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , Sarcoma/diagnosis , Sarcoma/genetics , Soft Tissue Neoplasms/diagnosis , Soft Tissue Neoplasms/genetics
17.
Diagn Mol Pathol ; 13(1): 47-51, 2004 Mar.
Article in English | MEDLINE | ID: mdl-15163009

ABSTRACT

We report a new case of synovial sarcoma of the kidney. The patient underwent nephrectomy because of a large tumor in the right kidney. The histologic diagnosis was hemangiopericytoma. Less than 1 year after primary surgery the patient was reoperated due to massive local recurrence. Histology now revealed a poorly differentiated tumor tissue with hemangiopericytoma-like features. Immunostainings showed immunoreactivity to cytokeratin, epithelial membrane antigen, and vimentin. The tumor was negative to CD34 and factor VIII. The tumor cell proliferation, assessed by Ki-67, was high. RT-PCR analysis and sequence analysis demonstrated the presence of SS18/SSX2 fusion gene. Review of the histologic specimens from the original tumors confirmed hemangiopericytoma-like morphology. The new diagnosis was poorly differentiated synovial sarcoma. At the time of reoperation, lung metastases were detected radiologically, reflecting a very aggressive phenotype. To our knowledge, this is the third case of poorly differentiated synovial sarcoma of the kidney. Common for all these three cases is the hemangiopericytoma-like histology and a very aggressive clinical behavior. These circumstances accentuate the impact of SS18/SSX analysis in diagnosis of renal hemangiopericytoma-like tumors.


Subject(s)
Kidney Neoplasms/diagnosis , Neoplasm Proteins/genetics , Proteins/genetics , Repressor Proteins/genetics , Sarcoma, Synovial/diagnosis , Adult , Diagnosis, Differential , Female , Hemangiopericytoma/diagnosis , Hemangiopericytoma/pathology , Humans , Immunochemistry , Kidney Neoplasms/pathology , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/pathology , Oncogene Proteins, Fusion/genetics , Polymerase Chain Reaction , Proto-Oncogene Proteins , Sarcoma, Synovial/pathology
18.
Am J Pathol ; 164(5): 1645-53, 2004 May.
Article in English | MEDLINE | ID: mdl-15111311

ABSTRACT

Activation of the GLI oncogene is an important step in the sonic hedgehog signaling pathway, and leads to, eg, tissue-specific cell proliferation during embryogenesis. GLI activity in adult tissues is restricted, but has been identified in various neoplasms, as a result of mutations in the PTCH (patched) or SMOH (smoothened) genes, encoding components of the sonic hedgehog pathway, or by amplification of GLI. Herein, we present a new mechanism of GLI activation through fusion with the beta-actin gene (ACTB) in five histologically distinctive soft tissue tumors showing a t(7;12)(p21-22;q13-15) and a pericytic phenotype. Each was composed of a perivascular proliferation of monomorphic short spindle cells that stained positively for smooth muscle actin and laminin and that showed pericytic features by electron microscopy. To date, with a median follow-up of 24 months, none has behaved in an aggressive manner. Molecular genetic analysis showed that the translocation in all cases resulted in a fusion transcript including the 5'-part of ACTB and the 3'-part of GLI. The DNA-binding zinc finger domains of GLI were retained in the fusion transcripts and it is likely that the replacement of the promoter region of GLI with that of the ubiquitously expressed ACTB gene leads to deregulation of GLI expression and its downstream target genes.


Subject(s)
Actins/metabolism , Chromosomes, Human, Pair 12 , Chromosomes, Human, Pair 7 , Oncogene Proteins/metabolism , Pericytes/pathology , Soft Tissue Neoplasms/classification , Soft Tissue Neoplasms/genetics , Soft Tissue Neoplasms/metabolism , Transcription Factors/metabolism , Translocation, Genetic , Adolescent , Adult , Aged , Amino Acid Sequence , Artificial Gene Fusion , Base Sequence , Cell Division , Child , DNA/metabolism , Female , Humans , In Situ Hybridization, Fluorescence , Laminin/metabolism , Male , Middle Aged , Models, Genetic , Molecular Sequence Data , Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Sequence Analysis, DNA , Signal Transduction , Time Factors , Trans-Activators , Zinc Finger Protein GLI1
19.
Cancer Genet Cytogenet ; 150(1): 27-32, 2004 Apr 01.
Article in English | MEDLINE | ID: mdl-15041220

ABSTRACT

In this study, we characterized the chromosomal composition of an intra-abdominal soft tissue sarcoma diagnosed as a malignant fibrous histiocytoma (MFH). By applying a combination of spectral karyotyping, G-banding, and comparative genomic hybridization (CGH), this case was shown to carry large chromosome markers with material mainly from chromosomes 6 and 8. Further characterization of this unique tumor revealed high-level amplifications at the 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 regions. Using array CGH, these amplified regions were found to include MASL1 in 8p, as well s MDM2 and CDK4 in 12q, which have been shown to be amplified in MFH. Similarly, gains of 6q and 8q have also been seen in MFH. In conclusion, our study demonstrates the occurrence of large chromosome markers in MFH and suggests that the regions 6q21 approximately q23, 8p21 approximately pter, 8q24 approximately qter, and 12q13 approximately q21 might harbor oncogenes that could play a role in MFH's tumorigenesis. In addition, gain of 12q13 approximately q21, which is typical of well-differentiated liposarcoma, may also occur in MFH, supporting the previously suggested overlap in genetic etiologies between these two tumor types.


Subject(s)
Chromosome Aberrations , Genetic Markers , Histiocytoma, Benign Fibrous/genetics , Nucleic Acid Hybridization/methods , Sarcoma/genetics , Spectral Karyotyping/methods , Chromosome Banding , Chromosomes, Human, Pair 12/genetics , Chromosomes, Human, Pair 6/genetics , Chromosomes, Human, Pair 8/genetics , Histiocytoma, Benign Fibrous/diagnosis , Humans , Oligonucleotide Array Sequence Analysis , Sarcoma/diagnosis
20.
Eur Radiol ; 14(6): 959-63, 2004 Jun.
Article in English | MEDLINE | ID: mdl-14767604

ABSTRACT

The purpose of this study was to evaluate the clinical utility of a multi-shot spin-echo echo-planar (SE-EPI) diffusion-weighted sequence in the diagnostic work-up of soft tissue tumours. There were 29 patients, 16 with a benign lesion and 13 with a sarcoma. Four of the sarcomas were examined both before and after radiation therapy. Diffusion-weighted imaging was performed with a multi-shot SE-EPI sequence. The b values were 0 and 600 s/mm(2). Phase navigation and pulse trigging were applied. The apparent diffusion constant (ADC) value of a large region of interest (ROI) representing the lesion was measured and compared to diagnosis and treatment. The ADC values of the benign lesions (mean 1.8 x 10(-3) mm(2)/s) overlapped with non-treated sarcomas (mean 1.7 x 10(-3) mm(2)/s). The ADC value increased in all radiated sarcomas. A multi-shot SE-EPI diffusion imaging sequence of less than 2-min duration is technically feasible in soft tissue tumours of the extremities and the trunk. The ADC values of benign soft tissue tumours and sarcomas overlapped and could not be used to differentiate between the bulk of benign and malignant tumours. However, the increase in ADC values of soft tissue sarcomas after radiotherapy warrants further studies of diffusion imaging for evaluating therapy response.


Subject(s)
Diffusion Magnetic Resonance Imaging , Soft Tissue Neoplasms/diagnosis , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Sarcoma/diagnosis , Sarcoma/radiotherapy , Soft Tissue Neoplasms/radiotherapy
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