RESUMEN
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.
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Sarcoma/tratamiento farmacológico , Familia-src Quinasas/antagonistas & inhibidores , Adulto , Proteína Tirosina Quinasa CSK , Línea Celular Tumoral , Resistencia a Antineoplásicos , Femenino , Humanos , Masculino , Sarcoma/genética , Sarcoma/patologíaRESUMEN
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.
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Citodiagnóstico/métodos , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/genética , Adolescente , Adulto , Anciano , Biopsia con Aguja Fina , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Sarcoma Sinovial/patología , Adulto JovenRESUMEN
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.
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Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Condrosarcoma/genética , Condrosarcoma/mortalidad , Telomerasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mutación , Pronóstico , Regiones Promotoras Genéticas/genética , Adulto JovenRESUMEN
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.
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Neoplasias Gastrointestinales/cirugía , Tumores del Estroma Gastrointestinal/cirugía , Márgenes de Escisión , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Neoplasias Gastrointestinales/mortalidad , Neoplasias Gastrointestinales/patología , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/patología , Humanos , Masculino , Persona de Mediana Edad , Modelos de Riesgos ProporcionalesRESUMEN
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.
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Genómica , Sarcoma , Humanos , Sarcoma/genética , Sarcoma/diagnóstico , Sarcoma/patología , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Genómica/métodos , Neoplasias Óseas/genética , Neoplasias Óseas/diagnóstico , Neoplasias Óseas/patología , Adulto Joven , Perfilación de la Expresión Génica , Anciano de 80 o más Años , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/patología , Adolescente , Biomarcadores de Tumor/genética , Estudios Prospectivos , Niño , Secuenciación Completa del Genoma/métodosRESUMEN
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.
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Biomarcadores de Tumor , Desdiferenciación Celular , Cordoma/clasificación , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Boston , Cordoma/química , Cordoma/genética , Cordoma/secundario , Femenino , Florida , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Fenotipo , Proteína SMARCB1/análisis , Proteína SMARCB1/genética , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
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"
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Colitis/diagnóstico , Colágeno/metabolismo , Colon/patología , Colitis/patología , Colágeno/ultraestructura , Colon/ultraestructura , Errores Diagnósticos , Humanos , Mucosa Intestinal/patología , Mucosa Intestinal/ultraestructura , Estudios RetrospectivosRESUMEN
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.
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Biomarcadores de Tumor/análisis , Biopsia con Aguja Fina , Factor de Transcripción STAT6/análisis , Tumores Fibrosos Solitarios/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Masculino , Persona de Mediana Edad , Tumores Fibrosos Solitarios/química , Tumores Fibrosos Solitarios/diagnóstico , Adulto JovenRESUMEN
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.
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Variaciones en el Número de Copia de ADN , Dosificación de Gen , Mutación , Regiones Promotoras Genéticas , Tumores Fibrosos Solitarios/genética , Telomerasa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Análisis Mutacional de ADN , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Fenotipo , Factores de Riesgo , Tumores Fibrosos Solitarios/enzimología , Tumores Fibrosos Solitarios/secundario , Tumores Fibrosos Solitarios/cirugía , Suecia , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
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.
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Ácidos Grasos/química , Liposarcoma Mixoide/diagnóstico por imagen , Liposarcoma/diagnóstico por imagen , Imagen por Resonancia Magnética , Neoplasias de los Tejidos Blandos/diagnóstico por imagen , Biopsia , Diferenciación Celular , Femenino , Humanos , Lipoma/patología , Liposarcoma Mixoide/radioterapia , Masculino , Persona de Mediana Edad , Protones , Estudios Retrospectivos , Neoplasias de los Tejidos Blandos/radioterapia , Carga TumoralRESUMEN
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.
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Regulación Neoplásica de la Expresión Génica , Receptor IGF Tipo 1/biosíntesis , Sarcoma/diagnóstico , Sarcoma/metabolismo , Neoplasias de los Tejidos Blandos/diagnóstico , Neoplasias de los Tejidos Blandos/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Western Blotting , Proteínas de Ciclo Celular/biosíntesis , Línea Celular Tumoral , Niño , Preescolar , Estudios de Cohortes , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/biosíntesis , Masculino , Ratones , Microcirculación , Persona de Mediana Edad , Mitosis , Análisis Multivariante , Necrosis , Metástasis de la Neoplasia , Pronóstico , Unión Proteica , Proteínas Proto-Oncogénicas c-bcl-2/biosíntesis , Sarcoma/mortalidad , Neoplasias de los Tejidos Blandos/mortalidad , Factores de Tiempo , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/biosíntesis , Proteínas Supresoras de Tumor/biosíntesisRESUMEN
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.
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Neoplasias Abdominales/genética , Deleción Cromosómica , Cromosomas Humanos Par 13/genética , Sarcoma/genética , Adulto , Anciano , ADN/genética , Femenino , Inestabilidad Genómica/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-kit/genética , Factores Sexuales , Cariotipificación Espectral , Translocación Genética/genéticaRESUMEN
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.
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Neoplasias Renales/diagnóstico , Proteínas de Neoplasias/genética , Proteínas/genética , Proteínas Represoras/genética , Sarcoma Sinovial/diagnóstico , Adulto , Diagnóstico Diferencial , Femenino , Hemangiopericitoma/diagnóstico , Hemangiopericitoma/patología , Humanos , Inmunoquímica , Neoplasias Renales/patología , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Proteínas de Fusión Oncogénica/genética , Reacción en Cadena de la Polimerasa , Proteínas Proto-Oncogénicas , Sarcoma Sinovial/patologíaRESUMEN
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.
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Aberraciones Cromosómicas , Marcadores Genéticos , Histiocitoma Fibroso Benigno/genética , Hibridación de Ácido Nucleico/métodos , Sarcoma/genética , Cariotipificación Espectral/métodos , Bandeo Cromosómico , Cromosomas Humanos Par 12/genética , Cromosomas Humanos Par 6/genética , Cromosomas Humanos Par 8/genética , Histiocitoma Fibroso Benigno/diagnóstico , Humanos , Análisis de Secuencia por Matrices de Oligonucleótidos , Sarcoma/diagnósticoRESUMEN
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.
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Neoplasias Óseas/genética , Proteínas de Unión a Calmodulina/genética , Hemangioma/genética , Factores de Transcripción NFATC/genética , Proteínas de Fusión Oncogénica , Proteínas de Unión al ARN/genética , Adulto , Neoplasias Óseas/patología , Neoplasias Óseas/cirugía , Bandeo Cromosómico , Cromosomas Humanos Par 22 , Supervivencia sin Enfermedad , Hemangioma/patología , Hemangioma/cirugía , Humanos , Hibridación Fluorescente in Situ , Masculino , Hueso Occipital/patología , Proteína EWS de Unión a ARN , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
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.
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Regulación Neoplásica de la Expresión Génica , Leiomiosarcoma/genética , Disomía Uniparental , Adulto , Cromosomas Humanos Par 20 , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 5 , Análisis por Conglomerados , Femenino , Perfilación de la Expresión Génica , Humanos , Inflamación/patología , Leiomiosarcoma/patología , Pérdida de Heterocigocidad , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple , Adulto JovenRESUMEN
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.
RESUMEN
Soft tissue and skeletal chondromas are rare entities, and only 21 cases with abnormal karyotypes have been reported. A survey of these, and 10 new cases reported herein, showed that the 12q13-15 segment is nonrandomly involved in structural rearrangements in chondromas. The HMGA2 (HMGI-C) locus in 12q15 is frequently rearranged in other benign mesenchymal tumors, and this study aimed at characterizing the expression of HMGA2 in chondromatous tumors. The material consisted of 8 soft tissue and 6 skeletal chondromas, as well as of 14 skeletal chondrosarcomas. All cases had been cytogenetically analyzed. Expression of HMGA2 could be assessed by RT-PCR in 8 chondromas and 13 chondrosarcomas. HMGA2 was expressed in 4 of six soft tissue chondromas, all displaying 12q-rearrangements at cytogenetic analysis. A truncated transcript (exons 1-3), but not a full-length (exons 1-5) transcript, was detected in three of them, suggesting activation through an intragenic rearrangement. One soft tissue chondroma had a t(3;12)(q27;q15), and the RT-PCR analysis revealed an HMGA2-LPP fusion transcript, composed of HMGA2 exons 1-3 and LPP exons 9-11. An identical fusion transcript previously has been identified in lipoma and pulmonary chondroid hamartoma. In the fourth soft tissue chondroma, a full-length transcript was detected, indicating expression of at least one intact allele. Both skeletal chondromas expressed HMGA2. In one of them, a full-length transcript was detected, even though 12q was cytogenetically unaffected. A truncated or full-length transcript was found in 8 of 13 chondrosarcomas, 4 of which displayed 12q rearrangements. Possibly, cryptic rearrangements were present among the many complex marker chromosomes in the remaining 4 cases.
Asunto(s)
Neoplasias Óseas/metabolismo , Condroma/metabolismo , Proteína HMGA2/genética , Proteína HMGA2/metabolismo , Proteínas Recombinantes de Fusión/metabolismo , Neoplasias de los Tejidos Blandos/metabolismo , Adolescente , Adulto , Anciano , Secuencia de Aminoácidos , Secuencia de Bases , Condrosarcoma/metabolismo , Proteínas del Citoesqueleto/genética , Femenino , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Proteínas con Dominio LIM , Masculino , Persona de Mediana Edad , Datos de Secuencia MolecularRESUMEN
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.
Asunto(s)
Imagen de Difusión por Resonancia Magnética , Neoplasias de los Tejidos Blandos/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Sarcoma/diagnóstico , Sarcoma/radioterapia , Neoplasias de los Tejidos Blandos/radioterapiaRESUMEN
The FUS gene at 16p11 fuses with DDIT3 and ATF1 as the result of translocations with chromosome band 12q13 in myxoid liposarcoma and angiomatoid fibrous histiocytoma, respectively, and with ERG as the result of a t(16;21)(p11;q22) in acute myeloid leukemia. We here show that a t(7;16)(q33;p11) in two cases of low grade fibromyxoid sarcoma fuses the FUS gene to BBF2H7, a previously uncharacterized gene that is homologous to the Drosophila Bbf-2 gene. BBF2H7 spans more than 120 kbp genomic DNA, is composed of 12 exons and contains a 1560 bp open reading frame. It codes for a 519 amino acid protein that contains a basic DNA binding and leucine zipper dimerization (B-ZIP) motif, highly similar to that in the OASIS, CREB-H, CREB4 and CREB3 transcription factors, followed by a hydrophobic region predicted to be an alpha-helical transmembrane domain. Reverse transcription-polymerase chain reaction (RT-PCR), using FUS forward and BBF2H7 reverse primers, amplified FUS/BBF2H7 chimeric transcripts composed of the first five exons and part of exon 6 of FUS and part of exon 5 and exons 6-12 of BBF2H7. The FUS/BBF2H7 chimera codes for a protein containing the N-terminus of FUS and the B-ZIP domain and the C-terminus of BBF2H7.