RESUMEN
Malignant peripheral nerve sheath tumors (MPNSTs) are soft tissue sarcomas that arise in connective tissue surrounding peripheral nerves. They occur sporadically in a subset of patients with neurofibromatosis type 1 (NF1). MPNSTs are highly aggressive, therapeutically resistant, and typically fatal. Using comparative transcriptome analysis, we identified CXCR4, a G-protein-coupled receptor, as highly expressed in mouse models of NF1-deficient MPNSTs, but not in nontransformed precursor cells. The chemokine receptor CXCR4 and its ligand, CXCL12, promote MPNST growth by stimulating cyclin D1 expression and cell-cycle progression through PI3-kinase (PI3K) and ß-catenin signaling. Suppression of CXCR4 activity either by shRNA or pharmacological inhibition decreases MPNST cell growth in culture and inhibits tumorigenesis in allografts and in spontaneous genetic mouse models of MPNST. We further demonstrate conservation of these activated molecular pathways in human MPNSTs. Our findings indicate a role for CXCR4 in NF1-associated MPNST development and identify a therapeutic target.
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Comunicación Autocrina , Quimiocina CXCL12/metabolismo , Neoplasias de la Vaina del Nervio/metabolismo , Neoplasias de la Vaina del Nervio/patología , Receptores CXCR4/metabolismo , Ciclo Celular , Proliferación Celular , Transformación Celular Neoplásica , Células Cultivadas , Técnicas de Silenciamiento del Gen , Humanos , Neurofibromatosis 1/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Transducción de SeñalRESUMEN
Undifferentiated pleomorphic sarcoma (UPS) and malignant peripheral nerve sheath tumor (MPNST) are aggressive soft tissue sarcomas that do not respond well to current treatment modalities. The limited availability of UPS and MPNST cell lines makes it challenging to identify potential therapeutic targets in a laboratory setting. Understanding the urgent need for improved treatments for these tumors and the limited cellular models available, we generated additional cell lines to study these rare cancers. Patient-derived tumors were used to establish 4 new UPS models, including one radiation-associated UPS-UPS271.1, UPS511, UPS0103, and RIS620, one unclassified spindle cell sarcoma-USC060.1, and 3 new models of MPNST-MPNST007, MPNST3813E, and MPNST4970. This study examined the utility of the new cell lines as sarcoma models by assessing their tumorigenic potential and mutation status for known sarcoma-related genes. All the cell lines formed colonies and migrated in vitro. The in vivo tumorigenic potential of the cell lines and corresponding xenografts was determined by subcutaneous injection or xenograft re-passaging into immunocompromised mice. USC060.1 and UPS511 cells formed tumors in mice upon subcutaneous injection. UPS0103 and RIS620 tumor implants formed tumors in vivo, as did MPNST007 and MPNST3813E tumor implants. Targeted sequencing analysis of a panel of genes frequently mutated in sarcomas identified TP53, RB1, and ATRX mutations in a subset of the cell lines. These new cellular models provide the scientific community with powerful tools for detailed studies of tumorigenesis and for investigating novel therapies for UPS and MPNST.
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Neurofibrosarcoma , Sarcoma , Neoplasias de los Tejidos Blandos , Animales , Humanos , Ratones , Modelos Teóricos , Mutación , Neurofibrosarcoma/genética , Sarcoma/genética , Sarcoma/patología , Neoplasias de los Tejidos Blandos/genéticaRESUMEN
BACKGROUND: Desmoid tumors (DTs) are rare and understudied fibroblastic lesions that are frequently recurrent and locally invasive. DT patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death. METHODS: Sorafenib has emerged as a promising therapeutic strategy, which has led to the first randomized phase 3 clinical trial devoted to DTs. Concurrently, we conducted a comprehensive analysis of sorafenib efficacy in a large panel of desmoid cell strains to probe for response mechanism. RESULTS: We found distinctive groups of higher- and lower-responder cells. Clustering the lower-responder group, we observed that CTNNB1 mutation was determinant of outcome. Our results revealed that a lower dose of sorafenib was able to inhibit cell viability, migration, and invasion of wild-type and T41A-mutated DTs. Apoptosis induction was observed in those cells after treatment with sorafenib. On the other hand, the lower dose of sorafenib was not able to inhibit cell viability, migration, or invasion or to induce apoptosis in the S45F-mutated DTs. The investigation of autophagy showed the dependency of S45F-mutated DTs on this pathway as a part of cell survival mechanism. Significantly, when autophagy was inhibited genetically or pharmacologically in the S45F mutant cell strains, sensitivity to sorafenib was restored. CONCLUSIONS: Our findings suggest that the response to sorafenib differs when comparing S45F-mutated DTs and T41A-mutated or wild-type DTs. Furthermore, the combination of hydroxychloroquine and sorafenib enhances the antiproliferative and proapoptotic effects in S45F-mutated DT cells, suggesting that profiling ß-catenin status could guide clinical management of desmoid patients who are considering sorafenib treatment.
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Antineoplásicos/uso terapéutico , Autofagia/efectos de los fármacos , Fibromatosis Agresiva/tratamiento farmacológico , Sorafenib/uso terapéutico , Antineoplásicos/farmacología , Femenino , Humanos , Masculino , Sorafenib/farmacologíaRESUMEN
BACKGROUND: Sarcomas are malignant heterogeneous tumors of mesenchymal derivation. Dedifferentiated liposarcoma (DDLPS) is aggressive with recurrence in 80% and metastasis in 20% of patients. We previously found that miR-133a was significantly underexpressed in liposarcoma tissues. As this miRNA has recently been shown to be a tumor suppressor in many cancers, the objective of this study was to characterize the biological and molecular consequences of miR-133a underexpression in DDLPS. METHODS: Real-time PCR was used to evaluate expression levels of miR-133a in human DDLPS tissue, normal fat tissue, and human DDLPS cell lines. DDLPS cells were stably transduced with miR-133a vector to assess the effects in vitro on proliferation, cell cycle, cell death, migration, and metabolism. A Seahorse Bioanalyzer system was also used to assess metabolism in vivo by measuring glycolysis and oxidative phosphorylation (OXPHOS) in subcutaneous xenograft tumors from immunocompromised mice. RESULTS: miR-133a expression was significantly decreased in human DDLPS tissue and cell lines. Enforced expression of miR-133a decreased cell proliferation, impacted cell cycle progression kinetics, decreased glycolysis, and increased OXPHOS. There was no significant effect on cell death or migration. Using an in vivo xenograft mouse study, we showed that tumors with increased miR-133a expression had no difference in tumor growth compared to control, but did exhibit an increase in OXPHOS metabolic respiration. CONCLUSIONS: Based on our collective findings, we propose that in DDPLS, loss of miR-133a induces a metabolic shift due to a reduction in oxidative metabolism favoring a Warburg effect in DDLPS tumors, but this regulation on metabolism was not sufficient to affect DDPLS.
RESUMEN
Myxoid liposarcoma has the pathognomonic fusion oncogene FUS-DDIT3 encoding a chimeric transcription factor. Metastatic risk is higher with an increased round cell component and has been linked to aberrations involving the IGFR/PI3K/AKT pathway. These molecular insights have yet to translate to targeted therapies, and the lack of experimental models is a major hindrance. We describe the initial in-depth characterization of a new cell line (DL-221) and establishment of a mouse xenograft model. The cell line DL-221 was derived from a metastatic pleural lesion showing myxoid and round cell histology. This newly established cell line was characterized for phenotypic properties and molecular cytogenetic profile, using PCR, COBRA-FISH, and western blot. Next-generation whole-exome sequencing was performed to further characterize the cell line and the parent tumor. NOD-SCID-IL2R gamma knockout mice were xenograft hosts. DL-221 cells grew an adhering monolayer and COBRA-FISH showed an aneuploid karyotype with t(12;16)(q13;p11) and several other rearrangements; RT-PCR demonstrated a FUS-DDIT3 fusion transcript type 1. Both the cell line and the original tumor harbored a TP53 compound heterozygous mutation in exon 4 and 7, and were wild-type for PIK3CA. Moreover, among the 1254 variants called by whole-exome sequencing, there was 77% concordance between the cell line and parent tumor. The recently described hotspot mutation in the TERT promoter region in myxoid liposarcomas was also found at C228T in DL-221. Xenografts suitable for additional preclinical studies were successfully established in mice after subcutaneous injection. The established DL-221 cell line is the only published available myxoid liposarcoma cell line that underwent spontaneous immortalization, without requiring SV40 transformation. The cell line and its xenograft model are unique and helpful tools to study the biology and novel potential-targeted treatment approaches for myxoid liposarcoma.
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Liposarcoma Mixoide/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Animales , Línea Celular Tumoral , Análisis Mutacional de ADN , Femenino , Xenoinjertos , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Hibridación Fluorescente in Situ , Liposarcoma Mixoide/patología , Liposarcoma Mixoide/secundario , Masculino , Ratones , Ratones Endogámicos NOD , Ratones Noqueados , Ratones SCID , Neoplasias Pleurales/genética , Neoplasias Pleurales/patología , Neoplasias Pleurales/secundarioRESUMEN
Dedifferentiated liposarcomas (DDLPS) are highly resistant to conventional chemo- and radiotherapies, with surgical resection remaining the classic treatment strategy; therefore, there is a pressing need for novel anti-DDLPS-targeted chemotherapeutics. Hepatocyte growth factor receptor (Met) expression is elevated in DDLPS, but the functional role of Met signaling in this disease is not known. We found that the in vitro stimulation of DDLPS cells with hepatocyte growth factor (HGF) elevated the degree of PI3K/AKT and MAPK pathway signaling, and that pro-tumorigenic phenotypes such as cell proliferation, invasion, and migration were significantly enhanced. Conversely, Met knockdown using shRNA-mediated interference decreased HGF-induced Met signaling, the invasive and migratory nature of DDLPS cells in vitro, and the tumorigenicity of DDLPS cells in vivo. These data strongly support the role for Met as a DDLPS therapeutic target. To that end, using EMD1214063, an ATP-competitive kinase inhibitor that targets Met more specifically than other kinases, inhibited Met-dependent signaling, reduced the oncogenicity of DDLPS cells in vitro, and significantly increased the survival of nude mice bearing subcutaneous DDLPS xenografts. These findings support further investigations of HGF-induced Met signaling inhibition in DDLPS, as a potential strategy to enhance clinical outcomes for this disease.
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Factor de Crecimiento de Hepatocito/metabolismo , Liposarcoma/metabolismo , Proteínas Proto-Oncogénicas c-met/metabolismo , Animales , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Femenino , Técnicas de Silenciamiento del Gen , Humanos , Ratones , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-met/genética , Piridazinas/farmacología , Pirimidinas/farmacologíaRESUMEN
BACKGROUND: Desmoid tumors (DTs) are rare mesenchymal lesions that can recur repeatedly. When it is feasible, DTs are surgically resected; however, this often results in high recurrence rates. Recently, treatment with PF-03084014, a potent γ-secretase inhibitor, has been shown to have antitumor activity in several tumor types by affecting the WNT/ß-catenin pathway. Consequently, Notch pathway inhibition by PF-03084014 might be a promising approach for DT treatment. METHODS: The expression of Notch pathway components was analyzed in DT tissues and cell strains with immunohistochemistry and Western blotting, respectively. A panel of DT cell strains was exposed to PF-03084014 and evaluated for cell proliferation. Antitumor effects were assessed via cell cycle, apoptosis, and migration and invasion analysis. Cells treated with PF-03084014 were characterized with a gene array analysis combined with Ingenuity Pathway Analysis. RESULTS: The results showed that Notch pathway components were expressed at different levels in DTs. Hes1 (Hes Family BHLH Transcription Factor 1) was overexpressed in DT tumors versus dermal scar tissue, and PF-03084014 caused significant decreases in Notch intracellular domain and Hes1 expression in DT cell strains. PF-03084014 decreased DT cell migration and invasion and also caused cell growth inhibition in DT cell strains, most likely through cell cycle arrest. Gene array analysis combined with Ingenuity Pathway Analysis showed that Wnt1-inducible signaling pathway protein 2 possibly regulated Notch and WNT pathways after treatment with PF-03084014 through integrin. CONCLUSION: Our findings suggest that the Notch pathway is an important DT therapeutic target. Furthermore, PF-03084014 has significant antitumor activity against DTs, and it may be an alternative strategy for DT treatment.
Asunto(s)
Fibromatosis Agresiva/tratamiento farmacológico , Receptores Notch/antagonistas & inhibidores , Transducción de Señal/fisiología , Proteínas CCN de Señalización Intercelular/fisiología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Fibromatosis Agresiva/etiología , Fibromatosis Agresiva/patología , Humanos , Invasividad Neoplásica , Receptores Notch/fisiología , Proteínas Represoras/fisiología , Tetrahidronaftalenos/farmacología , Valina/análogos & derivados , Valina/farmacologíaRESUMEN
New York esophageal squamous cell carcinoma 1 (NY-ESO-1, CTAG1B) is a cancer-testis antigen and currently a focus of several targeted immunotherapeutic strategies. We performed a large-scale immunohistochemical expression study of NY-ESO-1 using tissue microarrays of mesenchymal tumors from three institutions in an international collaboration. A total of 1132 intermediate and malignant and 175 benign mesenchymal lesions were enrolled in this study. Immunohistochemical staining was performed on tissue microarrays using a monoclonal antibody for NY-ESO-1. Among mesenchymal tumors, myxoid liposarcomas showed the highest positivity for NY-ESO-1 (88%), followed by synovial sarcomas (49%), myxofibrosarcomas (35%), and conventional chondrosarcomas (28%). Positivity of NY-ESO-1 in the remaining mesenchymal tumors was consistently low, and no immunoreactivity was observed in benign mesenchymal lesions. On the basis of these findings, nearly 90% of myxoid liposarcomas, as well as a significant proportion of synovial sarcomas, myxofibrosarcomas, and conventional chondrosarcomas are good candidates for immunotherapy targeting NY-ESO-1.
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Antígenos de Neoplasias/metabolismo , Neoplasias Óseas/metabolismo , Proteínas de la Membrana/metabolismo , Sarcoma/metabolismo , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias Óseas/patología , Humanos , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Análisis de Matrices TisularesRESUMEN
BACKGROUND: Surgery is the primary treatment for all subtypes of retroperitoneal liposarcoma, but neoadjuvant therapy may be warranted in cases of dedifferentiated liposarcoma (DDLS), which has an increased risk of recurrence and metastasis. Therefore, an accurate subtype-specific diagnosis is vital for appropriate consideration of neoadjuvant therapy. Previous studies assessing the subtype-specific accuracy of percutaneous biopsy are limited. We aimed to analyze the accuracy of preoperative percutaneous biopsy in the subtype-specific diagnosis of retroperitoneal liposarcoma and thus the reliability of percutaneous biopsy in guiding decisions about neoadjuvant treatment. METHODS: We retrospectively reviewed the medical records, including the pathologic reports, interventional radiology reports, and operative reports, of patients registered in the retroperitoneal/well-differentiated liposarcoma (WDLS/DDLS) database at The University of Texas MD Anderson Cancer Center between 1993 and 2013. RESULTS: We identified 120 patients who underwent 137 preoperative percutaneous biopsies followed by surgical resections. Pathologic examination following resection indicated that 74 of the patients had WDLS and 63 had DDLS. The overall diagnostic accuracy of percutaneous biopsy for identifying the subtype of liposarcoma was 62.8 % (86/137); the accuracy for identifying WDLS was significantly higher (85.1 %; 63/74) than that for identifying DDLS (36.5 %; 23/63) (p < 0.01). CONCLUSIONS: Percutaneous biopsy has low accuracy in the diagnosis of retroperitoneal DDLS. This can potentially mislead physicians in the decision to implement neoadjuvant treatment. When developing treatment strategies, including clinical trials for patients with retroperitoneal liposarcoma, physicians should carefully consider the low accuracy of percutaneous biopsy in detecting DDLS.
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Diferenciación Celular , Liposarcoma/clasificación , Liposarcoma/diagnóstico , Cuidados Preoperatorios , Neoplasias Retroperitoneales/clasificación , Neoplasias Retroperitoneales/diagnóstico , Biopsia , Estudios de Seguimiento , Humanos , Liposarcoma/cirugía , Estadificación de Neoplasias , Pronóstico , Reproducibilidad de los Resultados , Neoplasias Retroperitoneales/cirugía , Estudios Retrospectivos , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Radiation therapy is used increasingly as a component of multidisciplinary treatment for many solid tumors. One complication of such treatment is the development of radiation-associated sarcoma (RAS). Undifferentiated pleomorphic sarcoma (UPS), previously termed "malignant fibrous histiocytoma" (MFH) is the most common histologic subtype of RAS. This study investigated the clinical outcomes for patients with radiation-associated UPS (RA-UPS/MFH). METHODS: The study identified 1068 patients with UPS/MFH treated at the authors' institution. Patient and tumor factors were collected and compared. Regression analysis was performed to identify independent predictors of survival. A matched-cohort survival and recurrence analysis was performed for radiation-associated and sporadic UPS/MFH. RESULTS: The findings showed that RA-UPS/MFH comprised 5.1 % of the UPS population. The median latency to the development of RA-UPS/MFH was 9.3 years. The 5-year disease-specific survival (DSS) was 52.2 % for patients identified with RA-UPS/MFH (n = 55) compared with 76.4 % for patients with unmatched sporadic UPS/MFH (n = 1,013; p < 0.001). A matched-cohort analysis also demonstrated that the 5-year DSS was significantly worse for RA-UPS/MFH (52.2 vs 73.4 %; p = 0.002). Furthermore, higher local recurrence rates were observed for patients with RA-UPS/MFH than for patients with sporadic lesions (54.5 vs 23.5 %; p < 0.001). Radiation-associated status and incomplete resection were identified as independent predictors of local recurrence. CONCLUSION: This study demonstrated worse clinical outcomes for patients with RA-UPS/MFH than for patients with sporadic UPS/MFH. Local recurrence was significantly higher for patients with RA-UPS/MFH, suggesting a unique tumor biology for this challenging disease.
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Histiocitoma Fibroso Maligno/mortalidad , Histiocitoma Fibroso Maligno/patología , Recurrencia Local de Neoplasia/epidemiología , Neoplasias Inducidas por Radiación/mortalidad , Neoplasias Inducidas por Radiación/patología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Histiocitoma Fibroso Maligno/cirugía , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Neoplasia Residual , Neoplasias Inducidas por Radiación/cirugía , Modelos de Riesgos Proporcionales , Radioterapia/efectos adversos , Tasa de Supervivencia , Adulto JovenRESUMEN
AIMS: Well-differentiated leiomyosarcomas show morphologically recognizable smooth muscle differentiation, whereas poorly differentiated tumours may form a spectrum with a subset of undifferentiated pleomorphic sarcomas. The expression of certain muscle markers has been reported to have prognostic impact. We investigated the correlation between the morphological spectrum and the muscle marker expression profile of leiomyosarcoma, and the impact of these factors on patient outcomes. METHODS AND RESULTS: Tissue microarrays including 202 non-uterine and 181 uterine leiomyosarcomas with a spectrum of tumour morphologies were evaluated for expression of immunohistochemical markers of muscle differentiation. Poorly differentiated tumours frequently lost one or more conventional smooth muscle markers [smooth muscle actin, desmin, h-caldesmon, and smooth muscle myosin (P < 0.0001)], as well as the more recently described markers SLMAP, MYLK, and ACTG2 (P < 0.0001). In primary tumours, both desmin and CFL2 expression predicted improved overall survival in multivariate analyses (P = 0.0111 and P = 0.043, respectively). Patients with muscle marker-enriched tumours (expressing all four conventional markers or any three of ACTG2, CFL2, CASQ2, MYLK, and SLMAP) had improved overall survival (P < 0.05) in univariate analyses. CONCLUSIONS: Morphologically and immunohistochemically, poorly differentiated leiomyosarcomas can masquerade as undifferentiated pleomorphic sarcomas with progressive loss of muscle markers. The expression of muscle markers has prognostic significance in primary leiomyosarcomas independently of tumour morphology.
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Leiomiosarcoma/diagnóstico , Músculo Liso/patología , Neoplasias Retroperitoneales/diagnóstico , Neoplasias Uterinas/diagnóstico , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Cofilina 2/metabolismo , Desmina/metabolismo , Femenino , Humanos , Inmunohistoquímica , Leiomiosarcoma/clasificación , Leiomiosarcoma/mortalidad , Masculino , Músculo Liso/metabolismo , Pronóstico , Neoplasias Retroperitoneales/clasificación , Neoplasias Retroperitoneales/mortalidad , Análisis de Matrices Tisulares/métodos , Neoplasias Uterinas/clasificación , Neoplasias Uterinas/mortalidadRESUMEN
BACKGROUND: AXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined. METHODS: Immunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo. RESULTS: In this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo. CONCLUSIONS: Our results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors.
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Liposarcoma/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Diferenciación Celular/fisiología , Línea Celular Tumoral , Movimiento Celular/fisiología , Proliferación Celular/fisiología , Ensayo de Inmunoadsorción Enzimática , Humanos , Inmunohistoquímica , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Liposarcoma/patología , Invasividad Neoplásica/fisiopatología , Tirosina Quinasa del Receptor AxlRESUMEN
Epithelioid sarcoma is a rare, aggressive keratin-positive sarcoma that co-expresses CD34 in 50% of cases and may mimic an angiosarcoma. Recently, we have observed one case of epithelioid sarcoma that labeled for ERG, an ETS family regulatory transcription factor, which is considered to be a reliable marker for vascular differentiation. We investigated the prevalence of nuclear expression of ERG and FLI1, a homologous transcription factor, in these tumors. A formalin-fixed paraffin-embedded tissue microarray of 37 epithelioid sarcomas was examined. Immunohistochemistry was performed using anti-ERG monoclonal antibody to the N-terminus, anti-ERG monoclonal antibody to the C-terminus and anti-FLI1 monoclonal antibody. Comparison was made with CD34, CD31, and D2-40 labeling. The extent of immunoreactivity was graded according to the percentage of positive tumor cell nuclei (0: no staining; 1+: <5%; 2+: 5-25%; 3+: 26-50%; 4+: 51-75%; and 5+: 76-100%), and the intensity of staining was graded as weak, moderate, or strong. Nuclear staining for the N-terminus of ERG was seen in 19 out of 28 cases: 10 with diffuse(4 to 5+) strong/moderate labeling; 1 with 2+ moderate labeling and 8 with weak labeling (1 to 4+, 2 each). Focal staining for the C-terminus of ERG was seen in only 1 out of 29 cases (2+ moderate). FLI1 labeling was seen in nearly all (28 out of 30) cases: 16 with diffuse (5+) predominantly moderate labeling, and 8 cases with diffuse(5+) weak labeling. The remainder had variable moderate (1 to 3+) or weak (1 to 4+) FLI1 staining. CD34 was positive in 22 out of 30 cases and D2-40 was found to be positive in 22 out of 31 cases. All cases were negative for CD31 (0 out of 30). Epithelioid sarcoma can label with antibodies to the N-terminus of ERG, FLI1, and D2-40, which may cause diagnostic confusion for a vascular tumor. A panel of other antibodies including SMARCB1 and CD31 should be used in evaluating these tumors. ERG antibody selection is also critical, as those directed against the C-terminus are less likely to label epithelioid sarcoma.
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Biomarcadores de Tumor/análisis , Proteína Proto-Oncogénica c-fli-1/análisis , Sarcoma/química , Transactivadores/análisis , Anticuerpos Monoclonales , Anticuerpos Monoclonales de Origen Murino , Especificidad de Anticuerpos , Antígenos CD34/análisis , Núcleo Celular/química , Núcleo Celular/patología , Reacciones Cruzadas , Humanos , Inmunohistoquímica , Molécula-1 de Adhesión Celular Endotelial de Plaqueta/análisis , Valor Predictivo de las Pruebas , Proteína Proto-Oncogénica c-fli-1/inmunología , Reproducibilidad de los Resultados , Sarcoma/patología , Análisis de Matrices Tisulares , Transactivadores/inmunología , Regulador Transcripcional ERGRESUMEN
Spindle cell hemangioma (SCH) is a rare, benign vascular tumor of the dermis and subcutis. The lesions can be multifocal and are overrepresented in Maffucci syndrome, in which patients also have multiple enchondromas. Somatic mosaic R132C IDH1 hotspot mutations were recently identified in Maffucci syndrome. We evaluated the presence of mutations in solitary and multiple SCHs in patients without multiple enchondromas and tested a range of other vascular lesions that enter into the differential diagnosis. The R132C IDH1 mutation was identified by hydrolysis probes assay and confirmed by Sanger sequencing in 18 of 28 (64%) SCHs; of the 10 negative cases, 2 harbored a mutation in IDH2 (R172T and R172M) by Sanger sequencing. None of 154 other vascular malformations and tumors harbored an IDH1 R132C mutation, and R132H IDH1 mutations were absent in all 182 cases. All 16 SCHs examined by immunohistochemistry were negative for expression of HIF-1α. In conclusion, 20 of 28 (71%) SCHs harbored mutations in exon 4 of IDH1 or IDH2. Given that mutations were absent in 154 other vascular lesions, the mutation seems to be highly specific for SCH. The mutation does not induce expression of HIF-1α in SCH, and therefore the exact mechanism by which mutations in IDH1 or IDH2 lead to vascular tumorigenesis remains to be established.
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Sustitución de Aminoácidos/genética , Carcinoma/genética , Hemangioma/genética , Isocitrato Deshidrogenasa/genética , Mutación/genética , Malformaciones Vasculares/genética , Adolescente , Carcinoma/enzimología , Carcinoma/patología , Niño , Demografía , Femenino , Hemangioma/enzimología , Hemangioma/patología , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Malformaciones Vasculares/enzimología , Malformaciones Vasculares/patología , Adulto JovenRESUMEN
BACKGROUND: Well-differentiated (WD)/dedifferentiated (DD) liposarcoma is the most common soft tissue sarcoma of the retroperitoneum. The frequency of distant metastasis is low and the major burden of disease is locoregional. We sought to define the patterns of locoregional disease to help guide surgical decision making. METHODS: Data were collected from 247 patients with de novo or recurrent tumors treated at our institution from 1993 to early 2012. The number and location of tumors at both initial presentation and subsequent locoregional recurrence were determined by combined analysis of operative dictations and radiologic imaging. RESULTS: Thirty-four percent of patients had multifocal locoregional disease (two or more tumors) at initial presentation to our institution, including 9 % who had tumors at synchronous remote retroperitoneal sites. The impact of multifocal disease on overall survival was dependent on histologic subtype (WD vs. DD) and disease presentation (de novo vs. recurrence) at the time of resection. Among patients with initial unifocal disease, 57 % progressed to multifocal locoregional disease with subsequent recurrence, including 11 % with new tumors outside of the original resection field. No clinicopathologic or treatment-related variable, including the type or extent of resection, was predictive of either multifocal or 'outside field' progression. CONCLUSIONS: Multifocal disease is common in patients with WD/DD retroperitoneal liposarcoma, and tumors can also develop at remote, locoregional sites. Surgical resection remains the primary method of locoregional control in this disease; however, the aggressiveness of resection should be individualized, with consideration of both tumor and patient-related factors.
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Diferenciación Celular , Liposarcoma/patología , Recurrencia Local de Neoplasia/patología , Neoplasias Retroperitoneales/patología , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Liposarcoma/cirugía , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/cirugía , Estadificación de Neoplasias , Pronóstico , Neoplasias Retroperitoneales/cirugía , Adulto JovenRESUMEN
BACKGROUND: Management of gastrointestinal stromal tumors (GISTs) has been transformed with tyrosine kinase inhibitors (TKIs). While data on optimal duration of adjuvant imatinib remains elusive, guidelines for administration of neoadjuvant TKIs remain unknown. METHODS: Under an institutional review board-approved protocol, patients at our institution with a diagnosis of GIST treated with neoadjuvant TKIs and surgical resection were identified. Clinical and pathologic characteristics were obtained from medical records. RESULTS: Ninety-three patients underwent surgical resection after neoadjuvant TKI therapy; 41 had primary and 52 had recurrent/metastatic GIST. Median follow-up was 2.4 years. Median duration of neoadjuvant therapy was 315 (range 3-1,611) days for primary and 537 (range 4-3,257) days for recurrent/metastatic GIST (p = 0.001). Two-year, recurrence-free survival (RFS) was 85 and 44 % for primary and recurrent/metastatic disease, respectively, whereas 2-year overall survival (OS) was 97 % for primary and 73 % for recurrent/metastatic GIST. For primary GIST, duration of neoadjuvant therapy >365 days (p = 0.02) was associated with higher risk of recurrence on univariate analysis, whereas none of the clinicopathologic factors impacted OS. For recurrent/metastatic disease, disease progression was associated with a shorter OS (p = 0.001), but no factors were found to impact RFS. Lastly, when examining all patients, KIT mutations (p = 0.03) and multivisceral resection (p = 0.011) predicted shorter RFS. CONCLUSIONS: Neoadjuvant TKIs can be effectively used for the treatment of primary and recurrent/metastatic GIST. While duration of neoadjuvant therapy, KIT mutation status, and the need for multivisceral resection can help to predict higher risk for recurrence, progression on neoadjuvant TKIs can aid in selection of patients with recurrent/metastatic disease for surgical resection.
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Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/patología , Humanos , Metástasis Linfática , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Pronóstico , Tasa de SupervivenciaRESUMEN
PURPOSE: Our objective was to determine how positron emission tomography (PET)/CT had been used in the clinical treatment of malignant peripheral nerve sheath tumor (MPNST) patients at The University of Texas MD Anderson Cancer Center. METHODS: We reviewed a database of MPNST patients referred to MD Anderson Cancer Center during 1995-2011. We enrolled 47 patients who underwent PET/CT imaging. Disease stage was based on conventional imaging and PET/CT findings using National Comprehensive Cancer Network (NCCN) guidelines. Treatment strategies based on PET/CT and conventional imaging were determined by chart review. The maximum and mean standardized uptake values (SUVmax, SUVmean), metabolic tumor volume (MTV), total lesion glycolysis (TLG), change in SUVmax, change in MTV, and change in TLG were calculated from the PET/CT studies before and after treatment. Response prediction was based on imaging studies performed before and after therapy and categorized as positive or negative for residual tumor. Clinical outcome was determined from chart review. RESULTS: PET/CT was performed for staging in 16 patients, for restaging in 29 patients, and for surveillance in 2 patients. Of the patients, 88 % were correctly staged with PET/CT, whereas 75 % were correctly staged with conventional imaging. The sensitivity to detect local recurrence and distant metastasis at restaging was 100 and 100 % for PET/CT compared to 86 and 83 % for conventional imaging, respectively. PET/CT findings resulted in treatment changes in 31 % (5/16) and 14 % (4/29) of patients at staging and restaging, respectively. Recurrence, MTV, and TLG were prognostic factors for survival, whereas SUVmax and SUVmean were not predictive. For 21 patients who had imaging studies performed both before and after treatment, PET/CT was better at predicting outcome (overall survival, progression-free survival) than conventional imaging. A decreasing SUVmax ≥ 30 % and decrease in TLG and MTV were significant predictors for overall and progression-free survival. CONCLUSION: PET/CT is valuable in MPNST management because of its high accuracy in staging and high sensitivity and accuracy in restaging as well as improvements in treatment planning. MTV from baseline staging studies is predictive of survival. Additionally, change in SUVmax, TLG, and MTV accurately predicted outcomes after treatment.
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Fluorodesoxiglucosa F18 , Imagen Multimodal , Neurilemoma/diagnóstico , Neurilemoma/terapia , Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Adolescente , Adulto , Anciano , Niño , Femenino , Glucólisis , Humanos , Masculino , Persona de Mediana Edad , Neurilemoma/metabolismo , Neurilemoma/patología , Estudios Retrospectivos , Sensibilidad y Especificidad , Resultado del Tratamiento , Carga Tumoral , Adulto JovenRESUMEN
BACKGROUND: Liposarcoma (LS) is the second-most common type of soft-tissue sarcoma. Despite advances in knowledge and treatment of this disease, there remains a need for more effective LS therapy. Steroid hormone receptors regulate metabolism in adipocytes. Estrogen receptor alpha (ER), progesterone receptor (PR), and androgen receptor (AR) have been implicated in the pathophysiology of other cancer types. We sought to comprehensively determine temporal expression patterns of these receptors in LS. METHODS: We analyzed 561 histologically subtyped LS specimens from 354 patients for expression of ER, PR, and AR by immunohistochemistry (IHC) using diagnostic-grade reagents and protocols. The fractions of positively stained tumor cells were scored within each specimen. IHC scores were compared across LS subtypes using the Kruskal-Wallis test, and subtypes were compared using Dunn's post-hoc test. Ages of patients with receptor-positive vs. -negative LS were compared by t-test. Genders and races were compared for hormone receptor positivity using Fisher's exact test and Chi-square analysis, respectively. Recurrence-free survival was compared between receptor-positive and negative patients by log-rank test. p< 0.05 was considered significant. RESULTS: ER and AR were frequently expressed in LS, while few tumors expressed PR. Most of the ER + and AR + samples were of the well-differentiated LS subtype. A smaller fraction of de-differentiated LS expressed ER or AR, but expression was common within well-differentiated regions of tumors histologically classified as de-differentiated LS. In LS specimens from patients who underwent multiple surgeries over time, receptor expression frequently changed over time, which may be attributable in part to intratumor heterogeneity, varying degrees of de-differentiation, and biopsy bias. ER and AR were frequently co-expressed. Receptor status was not significantly associated with gender or race, but AR and PR expression were associated with earlier age at diagnosis. Receptor expression was not associated with altered recurrence-free survival. CONCLUSIONS: ER and AR are commonly expressed in LS, particularly in well-differentiated tumors. These data warrant further functional study to determine receptor function in LS, and the potential efficacy of anti-hormone therapies for the treatment of patients with LS.
RESUMEN
BACKGROUND: The role of preoperative breast MRI to evaluate the extent of disease in breast cancer patients is considered controversial. We aimed at assessing the effect of breast MRI on the management of newly diagnosed breast cancer. MATERIALS: A retrospective review of 202 consecutively seen patients who were newly diagnosed with breast cancer and who underwent preoperative breast MRIs at Assuta Ashdod between June 1, 2017, and June 1, 2020. Data included discovering suspicious lesions by conventional imaging, MRI findings, and surgical pathology results. This was analyzed to determine whether the MRI changed the management and whether it had a justified or unjustified effect on the treatment. RESULTS: The mean age was 54.51 (standard deviation, 11.34 years). Breast MRI revealed additional findings in 56 % of patients and modified therapeutic management in 32 % of the cases evaluated, having a justified effect in 87.6 %. Patients with changed management had a statistically significantly higher mastectomy rate (36 %) than those who did not (14 %). No statistically significant association was found between independent variables such as breast density, tumor location on the breast, type of tumor, patient's demographic information, etc. And whether MRI findings changed the initial treatment plan. CONCLUSIONS: MRI played an essential role in the preoperative staging of breast cancer in our study, modifying therapeutic planning in approximately one-third of the cases and having a justified effect on most of them. We, therefore, support preoperative breast MRI in newly diagnosed breast cancer patients.
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Neoplasias de la Mama , Imagen por Resonancia Magnética , Cuidados Preoperatorios , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/cirugía , Femenino , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Persona de Mediana Edad , Mastectomía , Pronóstico , Estudios de Seguimiento , Adulto , AncianoRESUMEN
Mitochondrial DNA (mtDNA) has increased susceptibility to damage due to its close proximity to the site of reactive oxygen species production, lack of introns and protective histones, and less efficient DNA repair mechanisms than nuclear DNA. The relationship between mtDNA copy number in peripheral blood leukocytes (PBLs) and the risk of soft tissue sarcoma (STS) has not been investigated. In this study, we determined the relative mtDNA copy number in PBLs of 325 patients (cases) with histologically confirmed STS and 330 healthy controls that were frequency matched to cases according to age, sex and ethnicity. Cases had a significantly lower mtDNA copy number than controls (0.93 ± 0.49 for cases versus 1.23 ± 0.59 for controls; P < 0.001). In analyses stratified by sex, ethnicity and smoking status, mtDNA copy number was lower in the cases than in controls in any stratum. Using the median mtDNA copy number in controls as a cutoff, individuals with lower mtDNA copy number were associated with a significantly increased risk of STS compared with those with higher mtDNA copy number (adjusted odds ratio, 2.71; 95% confidence interval, 1.94-3.82). There was a significant dose-response relationship between reduced mtDNA copy number and increased risk of STS in tertile and quartile analyses. The present study provides the first epidemiologic evidence that reduced mtDNA copy number in PBLs is significantly associated with an increased risk of STS, thereby suggesting an important role of mtDNA in STS development.