RESUMEN
Objective: To detect the expression of New York esophageal squamous cell carcinoma antigen 1 (NY-ESO-1) in common types of mesenchymal myxoid tumors, and to investigate its significance in the diagnosis and differential diagnosis of myxoid liposarcoma. Methods: A total of 43 formalin-fixed paraffin-embedded samples of mesenchymal myxoid tumors from the Affiliated Hospital of Qingdao University and Qingdao Municipal Hospital ranging between 2010 and 2017 were selected. NY-ESO-1 expression was detected by immunohistochemical staining. DDIT3 gene status was detected by fluorescence in situ hybridization (FISH). NY-ESO-1 mRNA was detected by reverse transcription-PCR (RT-PCR). Results: Histopathology and FISH results confirmed that there were 11 cases of myxoid liposarcoma and 32 other types (including 7 cases of well-differentiated liposarcoma, 1 dedifferentiated liposarcoma, 3 lipomas, 2 lipoblastomas and 19 non-adipocytic tumors). Immunohistochemical staining showed that the positive expression propotion of NY-ESO-1 in myxoid liposarcoma was 11/11, and the positive location was the cytoplasm and nucleus of lipoblast cells. The expression intensity is higher in regions with round cell differentiation. Among the 32 cases of other mesenchymal myxoid tumors, only one well-differentiated liposarcoma showed positive immunoreactivity for NY-ESO-1. RT-PCR confirmed that 7 cases of myxoid liposarcoma (7/11) and one well-differentiated liposarcoma (1/7) had NY-ESO-1 mRNA expression. Conclusions: NY-ESO-1 is positively expressed in myxoid liposarcoma. It can be served as a useful marker for the diagnosis and differential diagnosis of myxoid liposarcoma.
Asunto(s)
Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Liposarcoma Mixoide/química , Liposarcoma Mixoide/patología , Proteínas de la Membrana/análisis , Antígenos de Neoplasias/genética , Biomarcadores de Tumor/genética , Humanos , Hibridación Fluorescente in Situ , Lipoblastoma/química , Lipoblastoma/patología , Lipoma/química , Lipoma/patología , Liposarcoma/química , Liposarcoma/patología , Liposarcoma Mixoide/diagnóstico , Proteínas de la Membrana/genética , ARN Mensajero/análisis , Factor de Transcripción CHOP/análisis , Factor de Transcripción CHOP/genéticaRESUMEN
Lipoblastoma (LB) is a rare benign adipocytic tumor of childhood occasionally showing histological similarities to myxoid liposarcoma (ML) or well-differentiated liposarcoma (WDL). p16 immunohistochemistry has proved to be useful in distinguishing various types of liposarcomas, in particular WDL from lipoma, with higher sensitivity and specificity than MDM2 and CDK4 immunohistochemistry. In this study, we reported the histologic features of a series of 30 LB with emphasis on the potential diagnostic pitfalls and investigated the immunohistochemical expression of p16. Moreover, p16 immunostaining was performed in 16 liposarcomas (11 WDL and 5 ML), 16 lipomas, and 16 cases of liponecrosis in order to evaluate its usefulness in the differential diagnosis of challenging lesions occurring in older children. Overall, p16 immunostaining was positive in 3 LBs and in 12 out of 16 liposarcomas (10 WDL and 2 ML), with a sensitivity of 75%, a specificity of 90%, a positive predictive value of 80%, and a negative predictive value of 87%. All lipomas were p16 negative, whereas 5 liponecroses were positive. Accounting altogether the benign lesions versus liposarcomas, p16 showed a sensitivity of 75%, a specificity of 87%, a positive predictive value of 60%, and a negative predictive value of 93%. Our data suggest that a negative p16 immunostaining may be helpful in excluding a liposarcoma when occurring in unusual clinical contexts, such as in adolescence or late recurrence. However, such finding should be interpreted with caution since also some liposarcomas lack p16 and occasional LBs are positive.
Asunto(s)
Biomarcadores de Tumor/análisis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Inmunohistoquímica , Lipoblastoma/química , Liposarcoma Mixoide/química , Anciano , Biomarcadores de Tumor/genética , Diferenciación Celular , Niño , Preescolar , Proteínas de Unión al ADN/genética , Diagnóstico Diferencial , Femenino , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Lipoblastoma/genética , Lipoblastoma/patología , Liposarcoma Mixoide/patología , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Reproducibilidad de los ResultadosRESUMEN
The atypical lipomatous tumor (ALT)/well-differentiated liposarcoma (WDLS) and the de-differentiated liposarcoma (DDLS) represent the most common category of liposarcomas. ALT/WDLSs and DDLSs are often difficult to distinguish from other tumors with similar morphological characteristics. In this study, we investigated whether the detection of amplified or overexpressed murine double-minute 2 (MDM2) can be a useful diagnostic ancillary aid. We used fluorescent in situ hybridization (FISH) and immunohistochemistry (IHC) to detect MDM2 amplification and protein overexpression, respectively, in 49 WDLSs, 5 DDLSs, 23 myxoid liposarcomas, 25 benign lipomatous tumors, and 75 spindle and pleomorphic sarcomas. MDM2 amplification was detected in 48 of 49 WDLSs, 5 of 5 DDLSs, 2 of 9 malignant peripheral nerve sheath tumors, and 2 of 10 myxofibrosarcomas. We did not detect MDM2 amplification in any of the benign lipomatous tumors. FISH-mediated detection of MDM2 amplification was the most valuable diagnostic aid for ALT/WDLS, as determined by using the Fisher exact test to compare two different diagnoses of 19 biopsies. On the contrary, unequivocal nuclear overexpression of MDM2 was found in only 10 of 50 ALT/WDLSs. The sensitivity and specificity of MDM2 amplification in distinguishing a DDLS from spindle and pleomorphic sarcomas were 100% and 95%, respectively, while those of MDM2 overexpression were 100% and 87%, respectively. In conclusion, our results indicate that FISH-mediated detection of MDM2 amplification is the most useful adjunct in the diagnosis of both ALT/WDLS and DDLS. However, IHC-mediated detection of MDM2 protein is useful only for the diagnosis of DDLS.
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Biomarcadores de Tumor/genética , Amplificación de Genes , Hibridación Fluorescente in Situ , Lipoma/genética , Liposarcoma/genética , Proteínas Proto-Oncogénicas c-mdm2/genética , Biomarcadores de Tumor/análisis , Biopsia , Diferenciación Celular , Distribución de Chi-Cuadrado , Diagnóstico Diferencial , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Lipoma/química , Lipoma/patología , Liposarcoma/química , Liposarcoma/patología , Liposarcoma Mixoide/química , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/patología , Fenotipo , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas c-mdm2/análisis , Regulación hacia ArribaRESUMEN
A 70-year-old woman visited a local hospital complaining of a nodulein the right breast, present since 1 month. She was referred to our hospital for further evaluation. Following mammotome (MMT) biopsy, the nodule was diagnosed as myxoid/round cell liposarcoma. She underwent total mastectomy of the right breast. Histological analysis indicated that the tumor was almost entirely composed of proliferating small round mesenchymal cells in amyxoid matrix background with capillary-like vessels with partial necrosis (<10%). Immunohistochemically, p53 positive cells were seen focally (<1%) only, and the Ki-67 labeling index was approximately 20%. Since the surgical margin was histologically positive despite pathologic findings of high-grade malignancy, adjuvant treatment involving local radiation therapy (60Gy) was administered. The patient was free from any symptoms of local recurrence and metastases 1 year and 8 months after surgery.
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Neoplasias de la Mama/patología , Liposarcoma Mixoide/patología , Anciano , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia , Neoplasias de la Mama/química , Neoplasias de la Mama/genética , Neoplasias de la Mama/cirugía , Femenino , Humanos , Inmunohistoquímica , Antígeno Ki-67/análisis , Liposarcoma Mixoide/química , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/cirugía , Imagen por Resonancia Magnética , Mastectomía , Neoplasia Residual , Valor Predictivo de las Pruebas , Radioterapia Adyuvante , Resultado del Tratamiento , Proteína p53 Supresora de Tumor/análisis , Ultrasonografía MamariaRESUMEN
Myxoid and round cell liposarcomas constitute approximately one-third of all liposarcomas, a relatively common group of fat-derived soft tissue sarcomas. The histomorphology is a continuum between highly differentiated myxoid and poorly differentiated round cell components. The gold standard of diagnosis is dependent on histomorphology and/or identification of t(12;16)(q13;p11) translocation by cytogenetics or demonstration of DDIT3 rearrangements by fluorescence in situ hybridization. There are currently no diagnostic immunohistochemical stains available. The broad range of myxoid neoplasms in the differential diagnosis includes a variety of sarcomas. Given the notable differences in disease biology among myxoid neoplasms, which range from benign to aggressive, an accurate diagnosis is imperative for proper treatment and prognostication. Prompted by our recent study showing frequent expression of the cancer testis antigen NY-ESO-1 in myxoid and round cell liposarcomas, we sought to evaluate the utility of NY-ESO-1 as an immunohistochemical marker for myxoid and round cell liposarcoma among mesenchymal myxoid neoplasms within the differential diagnosis. Formalin-fixed, paraffin-embedded blocks were obtained for the following mesenchymal myxoid neoplasms (n=138): myxoid and round cell liposarcoma (n=38); well-differentiated liposarcoma (n=12); lipoma (n=20; 4 with myxoid change); extra-cardiac soft tissue myxoma (n=39); extraskeletal myxoid chondrosarcoma (n=12); myxofibrosarcoma (n=10: 5 low grade, 2 intermediate grade, 3 high grade); and low-grade fibromyxoid sarcoma (n=7). Utilizing standard immunohistochemistry protocols, full sections were stained with NY-ESO-1 (clone E978), and staining was assessed for intensity (1-2+), percentage of tumor positivity, and location. In all, 36/38 (95%) of the myxoid and round cell liposarcomas demonstrated NY-ESO-1 immunoreactivity. The majority of the positive cases (34/36; 94%) showed strong, homogenous staining (>50% tumor positivity), and two cases (6%) showed weak (1+ intensity), patchy staining (20-30% tumor positivity). Immunoreactivity was predominantly cytoplasmic. All the other neoplasms evaluated were negative for NY-ESO-1. NY-ESO-1 appears to be a sensitive and a specific marker for myxoid and round cell liposarcoma among mesenchymal myxoid neoplasms. The assessment of NY-ESO-1 expression by immunohistochemistry in the appropriate setting provides a cheaper, faster, and more accessible confirmatory test.
Asunto(s)
Antígenos de Neoplasias/análisis , Biomarcadores de Tumor/análisis , Inmunohistoquímica , Liposarcoma Mixoide/química , Proteínas de la Membrana/análisis , Biopsia , Diferenciación Celular , Condrosarcoma/química , Condrosarcoma/patología , Diagnóstico Diferencial , Fibroma/química , Fibroma/patología , Humanos , Liposarcoma Mixoide/patología , Clasificación del Tumor , Neoplasias de los Tejidos Conjuntivo y Blando/química , Neoplasias de los Tejidos Conjuntivo y Blando/patología , Adhesión en Parafina , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Fijación del TejidoRESUMEN
BACKGROUND: Myxoid liposarcoma (MLPS), a disease especially of young adults with potential for local recurrence and metastasis, currently lacks solid prognostic factors and therapeutic targets. The authors of this report evaluated the natural history and outcome of patients with MLPS and commonly deregulated protein biomarkers. METHODS: Medical records were retrospectively reviewed for patients who presented to the authors' institution with localized (n = 207) or metastatic (n = 61) MLPS (1990 to 2010). A tissue microarray of MLPS patient specimens (n = 169) was constructed for immunohistochemical analysis of molecular markers. RESULTS: The 5-year and 10-year disease-specific survival rates among patients with localized disease were 93% and 87%, respectively; male gender, age >45 years, and recurrent tumor predicted poor outcome. The local recurrence rate was 7.4%, and the risk of local recurrence was associated with recurrent tumors and nonextremity disease location. Male gender was the main risk factor for metastatic disease, which occurred in 13% of patients. Forty percent of patients who had localized disease received chemotherapy, mostly in the neoadjuvant setting. Immunohistochemical analysis revealed significantly higher expression of C-X-C chemokine receptor type 4 (CXCR4) and platelet-derived growth factor beta (PDGFR-ß) in metastatic lesions versus localized lesions. Tumors with a round cell phenotype expressed increased levels of CXCR4, p53, adipophilin, PDGFR-α, PDGFR-ß, and vascular endothelial growth factor relative to myxoid phenotype. Only the receptor tyrosine kinase encoded by the AXL gene (AXL) was identified as a prognosticator of disease-specific survival in univariate analysis. CONCLUSIONS: In this study, the authors identified clinical and molecular outcome prognosticators for patients with MLPS as well as several potential therapeutic targets.
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Biomarcadores de Tumor/análisis , Liposarcoma/química , Liposarcoma/patología , Adolescente , Adulto , Factores de Edad , Anciano , Análisis de Varianza , Quimioterapia Adyuvante , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Liposarcoma/mortalidad , Liposarcoma/terapia , Liposarcoma Mixoide/química , Liposarcoma Mixoide/patología , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/epidemiología , Radioterapia Adyuvante , Estudios Retrospectivos , Factores de Riesgo , Factores Sexuales , Análisis de Matrices Tisulares , Resultado del TratamientoAsunto(s)
Liposarcoma Mixoide/patología , Liposarcoma/patología , Biomarcadores de Tumor , Diferenciación Celular , Desmina/análisis , Diagnóstico Diferencial , Humanos , Queratinas/análisis , Liposarcoma/química , Liposarcoma/clasificación , Liposarcoma/diagnóstico , Liposarcoma Mixoide/química , Liposarcoma Mixoide/diagnóstico , Liposarcoma Mixoide/genética , Pronóstico , Proteínas Proto-Oncogénicas c-mdm2/análisis , Translocación GenéticaRESUMEN
Almost all primary retroperitoneal liposarcomas can be classified as well-/dedifferentiated liposarcoma. Rarely, however, primary retroperitoneal liposarcoma is classified as myxoid/round cell liposarcoma, based on the presence of myxoid areas and vascular crow's feet pattern, which has resulted in a debate on the classification of liposarcoma in the retroperitoneum. Genetically, myxoid/round cell liposarcoma and well-/dedifferentiated liposarcoma are different diseases. Myxoid/round cell liposarcoma is characterized by a translocation causing FUS-CHOP or EWSR1-CHOP fusion, whereas well-/dedifferentiated liposarcoma is characterized by an amplification of the 12q13-15 region, including MDM2 and CDK4 genes. As myxoid/round cell liposarcoma is highly radio- and chemosensitive, differentiation between subtypes is important to optimize treatment. We studied whether primary retroperitoneal liposarcomas diagnosed as myxoid/round cell liposarcoma represent molecularly true myxoid/round cell liposarcoma or are histopathological mimics and represent well-/dedifferentiated liposarcoma. Primary retroperitoneal myxoid/round cell liposarcoma (n=16) were compared to primary extremity myxoid/round cell liposarcoma (n=20). Histopathological and immunohistochemical features were studied. Amplification status of the 12q13-15 region was studied using a multiplex ligation-dependent probe amplification analysis, and FUS-CHOP or EWS-CHOP translocations were studied using RT-PCR. In primary retroperitoneal myxoid/round cell liposarcoma, MDM2 and CDK4 staining was both positive in 12 of 15 cases. In primary extremity myxoid/round cell liposarcoma, MDM2 was negative in 18/20 and CDK4 was negative in all cases. Multiplex ligation-dependent probe amplification showed the amplification of 12q13-15 region in 16/16 primary retroperitoneal myxoid/round cell liposarcomas and in 1/20 primary extremity myxoid/round cell liposarcomas. Translocation was present in all (18/18) primary extremity myxoid/round cell liposarcomas, but absent in all primary retroperitoneal myxoid/round cell liposarcomas. On the basis of immunohistochemical and molecular characteristics, apparent primary retroperitoneal myxoid/round cell liposarcoma can be recognized as well-/dedifferentiated liposarcoma with morphological features mimicking myxoid/round cell liposarcoma. In these cases, treatment should probably be specifically designed as for well-/dedifferentiated liposarcoma. Moreover, finding of myxoid/round cell liposarcoma translocations in a retroperitoneal localization is highly suggestive of metastasis and should prompt search for a primary localization outside the retroperitoneum.
Asunto(s)
Inmunohistoquímica , Liposarcoma Mixoide/patología , Reacción en Cadena de la Polimerasa , Neoplasias Retroperitoneales/patología , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Unión a Calmodulina/genética , Diferenciación Celular , Cromosomas Humanos Par 12 , Quinasa 4 Dependiente de la Ciclina/análisis , Quinasa 4 Dependiente de la Ciclina/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Liposarcoma Mixoide/química , Liposarcoma Mixoide/clasificación , Liposarcoma Mixoide/genética , Liposarcoma Mixoide/terapia , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-mdm2/análisis , Proteínas Proto-Oncogénicas c-mdm2/genética , Proteína EWS de Unión a ARN , Proteína FUS de Unión a ARN/genética , Proteínas de Unión al ARN/genética , Neoplasias Retroperitoneales/química , Neoplasias Retroperitoneales/clasificación , Neoplasias Retroperitoneales/genética , Neoplasias Retroperitoneales/terapia , Terminología como Asunto , Factor de Transcripción CHOP/genética , Translocación GenéticaRESUMEN
A rare case of mixed-type liposarcoma arising in deep soft tissue of the right thigh of a 45-year-old female patient is reported. The neoplasm was completely excised and was composed of an irregular admixture of areas of atypical lipomatous tumor/well-differentiated liposarcoma of the lipoma-like subtype with areas of myxoid/round cell liposarcoma. An amplification of the MDM2 and CDK4 genes respectively in the atypical lipomatous tumor/well-differentiated liposarcoma areas was detected by fluorescence in situ hybridization (FISH) analysis, and translocations of the CHOP and FUS genes were detected by FISH analysis in the myxoid/round cell liposarcoma areas.
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Liposarcoma Mixoide/patología , Liposarcoma/patología , Quinasa 4 Dependiente de la Ciclina/metabolismo , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Liposarcoma/química , Liposarcoma Mixoide/química , Persona de Mediana Edad , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteína FUS de Unión a ARN/genética , Muslo , Factor de Transcripción CHOP/genética , Translocación GenéticaRESUMEN
Several previous studies have demonstrated the lack of SMARCB1/INI1 protein expression in only the malignant rhabdoid tumor (MRT). Several sarcoma groups are associated with a tumor-specific translocation involving EWS. Moreover, the EWS and SMARCB1/INI1 genes are located on the same 22q chromosome. We analyzed the status of SMARCB1/INI1 protein expression in 93 cases of sarcomas associated with chromosomal translocation involving EWS, comprising 52 Ewing's sarcoma/primitive neuroectodermal tumors, 24 extraskeletal myxoid chondrosarcomas (EMCS), 14 clear cell sarcomas of soft tissue, 2 desmoplastic small round cell tumors, and 1 myxoid/round cell liposarcoma. In addition, we analyzed the detailed SMARCB1/INI1 gene alteration in cases, which lacked its protein expression. Consequently, 4 EMCS showed no SMARCB1/INI1 expression, and 2 of these 4 cases revealed homozygous deletion and frameshift mutation of the SMARCB1/INI1 gene, respectively. These cases showed histologic findings compatible with EMCS, according to the most recent WHO classification, but no major fusion gene transcripts were detected. Moreover, 3 out of 4 SMARCB1/INI1 negative variant EMCS disclosed rhabdoid features. Therefore, the lack of SMARCB1/INI1 protein expression may be associated with rhabdoid features. The immunohistochemical result of the SMARCB1/INI expression is not an absolute diagnostic criteria for MRT and careful histologic evaluation is required to make a precise diagnosis of MRT.
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Condrosarcoma/química , Proteínas Cromosómicas no Histona/análisis , Proteínas de Unión al ADN/análisis , Regulación Neoplásica de la Expresión Génica , Proteínas de Fusión Oncogénica/genética , Proteína EWS de Unión a ARN/genética , Tumor Rabdoide/química , Sarcoma/química , Factores de Transcripción/análisis , Translocación Genética , Condrosarcoma/genética , Condrosarcoma/mortalidad , Condrosarcoma/patología , Proteínas Cromosómicas no Histona/genética , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Humanos , Inmunohistoquímica , Liposarcoma Mixoide/química , Liposarcoma Mixoide/genética , Tumores Neuroectodérmicos Primitivos/química , Tumores Neuroectodérmicos Primitivos/genética , Pronóstico , Reproducibilidad de los Resultados , Tumor Rabdoide/genética , Tumor Rabdoide/mortalidad , Tumor Rabdoide/patología , Proteína SMARCB1 , Sarcoma/genética , Sarcoma/mortalidad , Sarcoma/patología , Sarcoma de Células Claras/química , Sarcoma de Células Claras/genética , Sarcoma de Ewing/química , Sarcoma de Ewing/genética , Factores de Transcripción/genéticaAsunto(s)
Liposarcoma Mixoide/patología , Neoplasias de los Tejidos Blandos/patología , Adulto , Biomarcadores de Tumor/análisis , Biopsia con Aguja Fina , Femenino , Humanos , Inmunohistoquímica , Liposarcoma Mixoide/química , Liposarcoma Mixoide/cirugía , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Neoplasias de los Tejidos Blandos/química , Neoplasias de los Tejidos Blandos/cirugía , MusloRESUMEN
AIM: Liposarcoma is common soft tissue sarcoma that is sometimes difficult to treat, besides its good prognosis. The inter-alpha-trypsin inhibitor heavy chains (HCs) has been reported to be linked to hyaluronan, which play important roles in tumour progression and metastasis. In this study, clinical significance of HCs in patients with liposarcoma was investigated. METHODS: HC expression was studied by immunohistochemistry on resected specimens of 33 liposarcoma patients and 10 lipoma patients. The expression of HC mRNA was analyzed by reverse transcription polymerase chain reaction (RT-PCR). Serum concentration of HC was determined with enzyme-linked immunosorbent assay (ELISA). RESULTS: Prominent positive staining of HC was observed in extracellular matrix of pleomorphic and myxoid liposarcoma. In well-differentiated liposarcoma and lipoma, faint staining was seen with HC. No products of HC could be detected by RT-PCR. Serum concentration of HC was not up-regulated in any subtypes of liposarcoma. HC expression was not significantly correlated with tumour subtypes and prognosis. CONCLUSION: HC was strongly accumulated in pleomorphic and myxoid liposarcoma, however, was not locally synthesized in liposarcoma. HC might play roles in stabilizing extracellular matrix, such as hyaluronan (HA), in liposarcoma.
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alfa-Globulinas/análisis , Biomarcadores de Tumor/análisis , Liposarcoma/química , alfa-Globulinas/genética , Biomarcadores de Tumor/genética , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Humanos , Lipoma/química , Liposarcoma Mixoide/química , Valor Predictivo de las Pruebas , ARN Neoplásico/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Inhibidores de Tripsina/análisisRESUMEN
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.
Asunto(s)
Fusión Artificial Génica , Liposarcoma Mixoide/genética , Proteína FUS de Unión a ARN/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Secuencia de Bases , Cromosomas Humanos Par 16 , Cromosomas Humanos Par 7 , Dimerización , Exones , Femenino , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Hibridación Fluorescente in Situ , Leucina Zippers , Liposarcoma Mixoide/química , Masculino , Datos de Secuencia Molecular , Sistemas de Lectura Abierta , Estructura Secundaria de Proteína , Estructura Terciaria de Proteína , Proteínas Recombinantes de Fusión/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Homología de Secuencia de Aminoácido , Translocación GenéticaRESUMEN
AIMS: To determine the relation between clinical outcome and tumour grade defined by a MIB-1 (Ki-67) score based grading system. METHOD: The clinical and pathological features of 50 patients with myxoid liposarcoma were evaluated, and MIB-1 immunostaining was performed to grade these patients' tumours. Univariate and multivariate analyses were conducted to evaluate survival. Clinical follow up details were available for all patients (median, 46.5 months; range, 9-408). RESULTS: Univariate analysis revealed that the tumour site (p < 0.05), round cell component content (p < 0.01), necrosis (p < 0.01), mitosis (p < 0.01), MIB-1 labelling index (p < 0.001), and tumour grade (p < 0.001) had a significant impact on overall survival. Multivariate analysis showed that, of the variables evaluated, the tumour grade defined by a MIB-1 score based grading system was the most significant adverse prognostic factor. CONCLUSION: Tumour grade determined by the grading system using the MIB-1 score (MIB-1 system) is a very strong prognostic factor in patients with myxoid liposarcoma.
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Anticuerpos Antinucleares/análisis , Anticuerpos Monoclonales/análisis , Biomarcadores de Tumor/análisis , Liposarcoma Mixoide/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Liposarcoma Mixoide/química , Liposarcoma Mixoide/mortalidad , Masculino , Persona de Mediana Edad , Necrosis , Pronóstico , Modelos de Riesgos Proporcionales , Tasa de SupervivenciaRESUMEN
Dendritic fibromyxolipoma (DFML) is an uncommon, recently described, benign soft tissue lesion that shares many clinical and pathological features with myxoid variants of spindle cell lipoma (SCL). As described, DFML is distinguished from SCL by the presence of dendritic cytoplasmic processes, abundant keloidal collagen and a prominent, often plexiform vascular pattern. We describe the first known reported case of an intramuscular DFML that occurred in the right shoulder region of a 73-year-old man. The tumor displayed the typical histopathological features of DFML but also included foci of chondroid metaplasia, a previously unreported finding. This report also discusses the differential diagnosis, particularly distinguishing DFML from SCL and myxoid liposarcoma. In view of the similarities in many clinical and pathological features between SCL and DFML, we speculate that DFML probably represents an unusual variant of myxoid SCL.
Asunto(s)
Células Dendríticas/patología , Fibroma/patología , Lipoma/patología , Liposarcoma Mixoide/patología , Neoplasias de los Músculos/patología , Anciano , Biomarcadores de Tumor , Células Dendríticas/química , Diagnóstico Diferencial , Supervivencia sin Enfermedad , Fibroma/química , Fibroma/cirugía , Humanos , Técnicas para Inmunoenzimas , Lipoma/química , Lipoma/cirugía , Liposarcoma Mixoide/química , Imagen por Resonancia Magnética , Masculino , Neoplasias de los Músculos/química , Neoplasias de los Músculos/cirugíaRESUMEN
Angiogenesis is an important factor in the morphological progression and metastasis of many solid tumours. We studied two homogeneous series of myxofibrosarcoma (MFS) and myxoid/round liposarcoma (MRLS), characterised by distinct vascular patterns and correlated the intratumoral microvessel density (IMD) with morphologic progression in both types of sarcoma. In our study, 43 cases of MFS and 42 cases of MRLS were graded according to established diagnostic criteria. For evaluation of IMD, representative sections were stained immunohistochemically for CD31. After selection of "neovascular hot spots", IMD was calculated by measuring the endothelial surface within twenty 200x fields in relation to the total analysed area. In addition to the correlation of IMD with histological grades of malignancy, a correlation of IMD with the inflammatory infiltrate in MFS was done. To determine whether vascular endothelial growth factor (VEGF) and its receptors, KDR and flt-1, may play a role in the progression of both types of sarcomas, we used mRNA in situ hybridisation (ISH) to study VEGF, KDR and flt-1 expression in selected cases. In addition, the expression of thrombospondin-1, which has been reported to inhibit angiogenesis, and of collagen type I was studied using mRNA ISH. Cases of MFS varied histologically from hypocellular, mainly myxoid, neoplasms (low-grade malignant, 18 cases) to intermediate-grade malignant lesions with increased cellularity and mitotic activity (13 cases), and high-grade malignant cases with marked pleomorphism, high proliferative activity and areas of necrosis in many cases (12 cases). Cases of purely low-grade myxoid liposarcoma (16 cases) were characterised by low-cellularity, mucin pooling and plexiform vasculature. In combined MRLS, these hypocellular areas were admixed with hypercellular, round cell areas (5-80% of the analysed tumour area; 23 cases), and in round cell liposarcoma (three cases) rounded tumour cells predominated (>80% of the analysed tumour area). The average IMD in intermediate and high-grade malignant MFS (4.03 and 4.09, respectively) was significantly higher than in low-grade malignant MFS (2.73). Correlation of vascularity with the inflammatory infiltrate in MFS showed increased IMD only in cases with abundant neutrophils; most of these cases were high-grade malignant neoplasms. In contrast, no statistical correlation between morphological progression and IMD was seen in myxoid liposarcoma (6.08), MRLS (6.57) and round cell liposarcoma (4.07). VEGF mRNA was expressed by tumour cells in all histological grades of MFS and MRLS. VEGF receptor mRNA was weakly expressed by endothelia of newly formed blood vessels in both entities. Interestingly, tumour cells of all analysed cases of MFS strongly expressed collagen type I and thrombospondin-1, while these proteins were not detected in tumour cells of MRLS. In conclusion, morphologic tumour progression in MFS is associated with increased IMD, whereas, in MRLS, no such correlation is seen. Whereas VEGF and VEGF receptor mRNA were expressed in both entities, a characteristic expression profile of collagen type I and thrombospondin-1 in MFS emerged. Further studies are necessary to correlate vascularity and clinical course in MFS and MRLS.
Asunto(s)
Fibrosarcoma/irrigación sanguínea , Fibrosarcoma/patología , Liposarcoma Mixoide/irrigación sanguínea , Liposarcoma Mixoide/patología , Neovascularización Patológica , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Colágeno/genética , Progresión de la Enfermedad , Factores de Crecimiento Endotelial/genética , Femenino , Fibrosarcoma/química , Humanos , Hibridación in Situ , Liposarcoma Mixoide/química , Linfocinas/genética , Masculino , Microcirculación/patología , Persona de Mediana Edad , Metástasis de la Neoplasia , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Proteínas Proto-Oncogénicas/genética , ARN Mensajero/análisis , Proteínas Tirosina Quinasas Receptoras/genética , Receptores de Factores de Crecimiento/genética , Receptores de Factores de Crecimiento Endotelial Vascular , Trombospondina 1/genética , Factor A de Crecimiento Endotelial Vascular , Receptor 1 de Factores de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
We examined the cell/extracellular-matrix interface in 13 myxoid liposarcomas by determining the distribution of collagen and reticular fibers in the myxoid matrix, the presence of adhesion proteins and the morphological features of the cytoplasmic border. Adhesion proteins (fibronectin, integrin alpha3) and the cytoplasmic border were examined by immunofluorescence and a differential interference-contrast image analysis respectively. A network of reticular fibers and collagen fibers was present in the myxoid matrix of 11 cases (85%) and 3 cases (23%) respectively. Tumor cells with dendritic cytoplasmic processes were observed in 8 cases (62%). Adhesion proteins were sparsely present in tumor cells and there was no correlation between those proteins and collagen fibers, reticular fibers or cytoplasmic processes. Collagen fibers, dense reticular fibers or well-developed cytoplasmic processes were more frequently observed in the cases of long-term-surviving patients than those with recently developed tumors or patients who died. All 3 cases positive for collagen fibers also contained both dense reticular fibers and cytoplasmic processes. Our findings suggest that the fibrous components in the myxoid matrix and the well-developed cytoplasmic processes may limit the invasiveness of malignant cells. This peculiar architecture may also explain the slowly progressive nature of myxoid liposarcomas.
Asunto(s)
Antígenos CD/análisis , Moléculas de Adhesión Celular/análisis , Colágeno/análisis , Fibronectinas/análisis , Integrinas/análisis , Liposarcoma Mixoide/patología , Proteínas de Neoplasias/análisis , Reticulina/análisis , Adulto , Citoplasma/química , Matriz Extracelular/química , Femenino , Técnica del Anticuerpo Fluorescente Indirecta , Humanos , Integrina alfa3 , Liposarcoma Mixoide/química , Masculino , Persona de Mediana EdadRESUMEN
The cytogenetic hallmark of myxoid liposarcoma is the chromosomal aberration t(12;16)(q13;p11), which is pathognomonic for this tumor type. The translocation results in the hybrid gene FUS/CHOP, where the central and C-terminal parts of FUS, coding for the RNA binding domain and the RGG triplet motif, are replaced by the full length CHOP protein. Thus, CHOP is under the control of the FUS promoter and the FUS/CHOP chimera contains the 5'-terminal part of FUS which provides a transcriptional activation function. Although different structural variations of the FUS/CHOP chimeric transcript have been reported, none of them contains the parts of FUS encoding the RNA binding properties. An explanation is the location of the genomic breakpoint in FUS, which frequently occurs in the region spanning exon 5 to intron 8. We describe here a case of myxoid liposarcoma containing two novel FUS/CHOP chimeric transcripts and with the breakpoint occurring in intron 14 of FUS. Reverse transcription-polymerase chain reaction, using FUS forward and CHOP reverse primers, amplified strongly a 2.1-kbp DNA fragment and weakly a 0.9-kbp DNA fragment. Direct sequencing showed that in the 2.1-kbp transcript nt 1474, which corresponds to the third nucleotide of exon 14 of FUS, was in-frame fused to exon 2 of CHOP. In the 0.9-kbp DNA fragment, exon 3 of FUS was in-frame fused to exon 2 of CHOP. Genomic analyses revealed that the breaks were located at the end of exon 14/beginning of intron 14 of FUS and in intron 1 of CHOP and that microdeletions had occurred in the close vicinity of the breakpoints.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/genética , Liposarcoma Mixoide/genética , Proteínas de Fusión Oncogénica/genética , Ribonucleoproteínas/genética , Factores de Transcripción/genética , Translocación Genética , Secuencia de Aminoácidos , Secuencia de Bases , ADN Complementario/análisis , Genoma Humano , Ribonucleoproteínas Nucleares Heterogéneas , Humanos , Liposarcoma Mixoide/química , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Oncogenes , Proteína FUS de Unión a ARN , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción CHOPRESUMEN
Subcutaneous myxoid liposarcoma (ML) is exceedingly rare, with only two or three cases having been reported. Lipoblastoma (LB), a rare fatty tumor that arises in infants and children, is unknown after adolescence. In contrast to ML, LB is often superficial. The two tumors can be difficult to distinguish due to many histologic similarities. We examined a 0.9 cm superficial subcutaneous nodule from the dorsal neck of a 48 year old man that had been growing slowly. Three and one half years later, a 0.4 cm palpable recurrent nodule was excised from the scar. The patient is now free of disease at 7.5 years. Because of these unusual features, we performed clinicopathologic, immunohistochemical and molecular analysis of this unusual tumor to decide if this represented a rare cutaneous ML or an unprecedented example of LB in an adult. The primary featured a thick fibrous pseudocapsule with foci of lymphocytes and infiltrating nests of semi-mature fetal-appearing adipocytic tissue. This surrounded a more immature cellular-but-cytologically-bland myxoid tissue featuring stellate cells and signet lipoblasts. There were fibrous sep at the periphery and the vasculature was rather inconspicuous. The 0.4 cm diameter recurrence was distinctly lobular and had minute satellite nodules. It was composed of uniform fetal-appearing bland myxoid lipoblastic tissue featuring signet ring lipoblasts surrounded by a few spindle cells. In both tumors, lipoblasts expressed S-100 protein. In the primary, 5% of the lesional cells were FXIIIa+ dendritic stromal histiocytes while in the recurrence, 15% of the lesional cells were FXIIIa+ dendritic cells. CD34 stained only scattered small capillaries. The Ki67 proliferation index was 1% in the primary and 3% in the recurrence. RT-PCR assay for TLS/FUS-CHOP fusion transcripts was negative despite three repeat tests performed on paraffin sections of the primary tumor in the presence of good m-RNA internal controls. We reviewed the clinicopathologic and cytogenetic features of ML and LB. Based on this review and on the growth pattern, anatomic features and molecular data from the present case, we conclude that this tumor may represent the first reported case of adult LB.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT , Lipoma/patología , Liposarcoma Mixoide/patología , Proteína FUS de Unión a ARN , Neoplasias de los Tejidos Blandos/patología , Antígenos CD34/análisis , Biomarcadores de Tumor/análisis , ADN de Neoplasias/análisis , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Lipoma/química , Lipoma/genética , Liposarcoma Mixoide/química , Liposarcoma Mixoide/genética , Masculino , Persona de Mediana Edad , Proteínas Nucleares/análisis , Proteínas de Fusión Oncogénica/análisis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas S100/análisis , Neoplasias de los Tejidos Blandos/química , Neoplasias de los Tejidos Blandos/genética , Factor de Transcripción CHOPRESUMEN
To broaden the knowledge of myxoid morphology in liposarcoma, eight cases of unusual liposarcoma with combined well-differentiated and myxoid malignant fibrous histiocytoma (MFH)-like myxoid areas are reported. The tumors arose as huge retroperitoneal masses in elderly patients, except for one that occurred in the spermatic cord. Three cases had local recurrences, and one of the seven patients who were followed up had died of the tumor. Grossly, the tumors were mostly confluent and multinodular and showed a glistening myxoid appearance in variable proportions, which merged gradually into or were juxtaposed to yellow fatty or sclerotic whitish areas. Microscopically, in addition to areas of well-differentiated lipoma-like or sclerosing liposarcoma, all the tumors contained myxoid portions characterized by scattered multinucleated or bizarre giant cells and a prominent plexiform vascular pattern that resembled myxoid MFH or myxofibrosarcoma. The myxoid areas were associated with discernible lipogenesis. High-grade dedifferentiation was present in one tumor. Cytogenetically, in one case, the myxoid lesion had nonrandom chromosomal aberrations, such as ring and marker chromosomes, characteristic of a well-differentiated variant of liposarcoma. In a nested reverse transcription-polymerase chain reaction analysis using archival paraffin-embedded tissue, it was seen that none of the eight tumors with myxoid MFH-like features had TLS/FUS-CHOP fusion transcripts characteristic of myxoid and round cell liposarcomas. These clinicopathologic and molecular features suggest that the current myxoid tumors are more closely related to well-differentiated liposarcoma rather than to ordinary myxoid liposarcoma despite their unequivocal myxoid morphology. Missense point mutations of the p53 gene were detected in two (25%) cases by single-strand conformation polymorphism and sequence analyses. Immunohistochemical expressions of p53 and mdm2 were observed in 75% of the cases, in which immunoreactive tumor cells were seen more often in the myxoid MFH-like areas. Thus, altered p53 pathways, such as p53 gene mutation and mdm2-mediated inactivation of p53, may play a pathogenetic role in this form of tumor progression showing myxoid MFH-like morphology in liposarcoma, as has been suggested in dedifferentiated liposarcoma.