RESUMEN
Sarcomas are a heterogeneous group of malignancies with mesenchymal lineage differentiation. The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions as tissue-agnostic oncogenic drivers has led to new personalized therapies for a subset of patients with sarcoma in the form of tropomyosin receptor kinase (TRK) inhibitors. NTRK gene rearrangements and fusion transcripts can be detected with different molecular pathology techniques, while TRK protein expression can be demonstrated with immunohistochemistry. The rarity and diagnostic complexity of NTRK gene fusions raise a number of questions and challenges for clinicians. To address these challenges, the World Sarcoma Network convened two meetings of expert adult oncologists and pathologists and subsequently developed this article to provide practical guidance on the management of patients with sarcoma harboring NTRK gene fusions. We propose a diagnostic strategy that considers disease stage and histologic and molecular subtypes to facilitate routine testing for TRK expression and subsequent testing for NTRK gene fusions.
Asunto(s)
Sarcoma , Tropomiosina , Adulto , Fusión Génica , Humanos , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas , Receptor trkA/genética , Sarcoma/diagnóstico , Sarcoma/tratamiento farmacológico , Sarcoma/genéticaRESUMEN
BACKGROUND: Recurrent/metastatic adenoid cystic carcinoma (ACC) is an incurable disease with no standard treatments. The majority of ACCs express the oncogenic transcription factor MYB (also c-myb), often in the context of a MYB gene rearrangement. This phase II trial of the tyrosine kinase inhibitor (TKI) axitinib (Pfizer) tested the hypothesis that targeting pathways activated by MYB can be therapeutically effective for ACC. PATIENTS AND METHODS: This is a minimax two-stage, phase II trial that enrolled patients with incurable ACC of any primary site. Progressive or symptomatic disease was required. Patients were treated with axitinib 5 mg oral twice daily; dose escalation was allowed. The primary end point was best overall response (BOR). An exploratory analysis correlating biomarkers to drug benefit was conducted, including next-generation sequencing (NGS) in 11 patients. RESULTS: Thirty-three patients were registered and evaluable for response. Fifteen patients had the axitinib dose increased. Tumor shrinkage was achieved in 22 (66.7%); 3 (9.1%) had confirmed partial responses. Twenty-five (75.8%) patients had stable disease, 10 of whom had disease stability for >6 months. The median progression-free survival (PFS) was 5.7 months (range 0.92-21.8 months). Grade 3 axitinib-related toxicities included hypertension, oral pain and fatigue. A trend toward superior PFS was noted with the MYB/NFIB rearrangement, although this was not statistically significant. NGS revealed three tumors with 4q12 amplification, producing increased copies of axitinib-targeted genes PDGFR/KDR/KIT. Two 4q12 amplified patients achieved stable disease for >6 months, including one with significant tumor reduction and the longest PFS on study (21.8 months). CONCLUSIONS: Although the primary end point was not met, axitinib exhibited clinical activity with tumor shrinkage achieved in the majority of patients with progressive disease before trial enrollment. Analysis of MYB biomarkers and genomic profiling suggests the hypothesis that 4q12 amplified ACCs are a disease subset that benefit from TKI therapy.
Asunto(s)
Carcinoma Adenoide Quístico/tratamiento farmacológico , Imidazoles/administración & dosificación , Indazoles/administración & dosificación , Factores de Transcripción NFI/genética , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Proto-Oncogénicas c-myb/genética , Adulto , Anciano , Axitinib , Carcinoma Adenoide Quístico/genética , Carcinoma Adenoide Quístico/patología , Cromosomas Humanos Par 4/genética , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Imidazoles/efectos adversos , Indazoles/efectos adversos , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Inhibidores de Proteínas Quinasas/efectos adversosRESUMEN
BACKGROUND: Radiation-associated breast angiosarcoma (RT-AS) is an uncommon malignancy with an incidence of less than 1 % of all soft tissue sarcomas. The overall prognosis is quite dismal with high rates of recurrences and poor overall survival. There is an obvious paucity of data regarding clinical outcomes of patients with breast RT-AS. METHODS: We identified all patients with RT-AS treated at the Memorial Sloan-Kettering Cancer Center between 1982-2011 and collected their correlative clinical information. RESULTS: We identified 79 women with RT-AS with a median age of 68 (range 36-87). The median interval between radiation and development of RT-AS was 7 years (range 3-19). The median time to local and distant recurrence was 1.29 years (95 % CI 0.72-NA) and 2.48 years (95 % CI 1.29-NA), respectively. The median disease-specific survival was 2.97 years (95 % CI 2.21-NA). Independent predictors of worse disease-specific survival included age î¶68 years (HR 3.11, 95 % CI 1.20-8.08, P=0.020) and deep tumors (HR 3.23, 95 % CI 1.02-10.21, P=0.046.) CONCLUSION: RT-AS has high local/distant recurrence rates, limited duration on standard chemotherapy and poor disease-specific survival.
Asunto(s)
Neoplasias de la Mama/radioterapia , Hemangiosarcoma/etiología , Hemangiosarcoma/patología , Neoplasias Inducidas por Radiación/etiología , Neoplasias Primarias Secundarias/etiología , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/etiología , Neoplasias de la Mama/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias Inducidas por Radiación/patología , Neoplasias Primarias Secundarias/patología , Pronóstico , Radioterapia Adyuvante/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib. PATIENTS AND METHODS: The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12 pts received 600 mg twice a week (BIW) and 11 patients received 400 mg three times a week (TIW). All had prior imatinib and sunitinib but stopped>14 days before starting BIIB021. RESULTS: The median age was 59 years (33-88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600 mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25-138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5 µmol and the mean AUC was 2.9 µmol h. Cmax>1.5 µmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment. CONCLUSIONS: This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.
Asunto(s)
Adenina/análogos & derivados , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Proteínas HSP90 de Choque Térmico/antagonistas & inhibidores , Piridinas/uso terapéutico , Adenina/efectos adversos , Adenina/farmacocinética , Adenina/farmacología , Adenina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Fluorodesoxiglucosa F18 , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones , Piridinas/efectos adversos , Piridinas/farmacocinética , Piridinas/farmacología , Resultado del TratamientoRESUMEN
BACKGROUND: Data regarding the role of systemic therapy in patients with advanced well-differentiated/dedifferentiated liposarcomas (WDLPS/DDLPS) are limited. METHODS: From 2000 to 2010, 208 patients with advanced WDLPS/DDLPS received chemotherapy in 11 participating institutions. Clinical and pathological data were collected by reviewing medical records. RESULTS: Median age was 63 years (range 32-84). Combination chemotherapy was delivered in 85 cases (41%) and single agent in 123 cases (59%), respectively. One hundred and seventy-one patients (82%) received an anthracycline-containing regimen. Using RECIST, objective response was observed in 21 patients (12%), all treated with anthracyclines. Median progression-free survival (PFS) was 4.6 months [95% confidence interval (CI) 3.3-5.9]. On multivariate analysis, age and performance status (PS) were the sole factors significantly associated with poor PFS. Median overall survival (OS) was 15.2 months (95% CI 11.8 -18.7). On multivariate analysis, grade and PS were the sole factors significantly associated with OS. CONCLUSIONS: Chemotherapy was associated with clinical benefit in 46% of patients with advanced WDLPS/DDLPS. OS remains poor, even though visceral metastatic disease is less frequent than in other sarcomas.
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Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Liposarcoma/tratamiento farmacológico , Neoplasias Retroperitoneales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Supervivencia sin Enfermedad , Femenino , Humanos , Estimación de Kaplan-Meier , Liposarcoma/mortalidad , Liposarcoma/secundario , Masculino , Persona de Mediana Edad , Análisis Multivariante , Clasificación del Tumor , Pronóstico , Modelos de Riesgos Proporcionales , Neoplasias Retroperitoneales/mortalidad , Neoplasias Retroperitoneales/patología , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
The purpose of this study was to develop a method of classifying cancers to specific diagnostic categories based on their gene expression signatures using artificial neural networks (ANNs). We trained the ANNs using the small, round blue-cell tumors (SRBCTs) as a model. These cancers belong to four distinct diagnostic categories and often present diagnostic dilemmas in clinical practice. The ANNs correctly classified all samples and identified the genes most relevant to the classification. Expression of several of these genes has been reported in SRBCTs, but most have not been associated with these cancers. To test the ability of the trained ANN models to recognize SRBCTs, we analyzed additional blinded samples that were not previously used for the training procedure, and correctly classified them in all cases. This study demonstrates the potential applications of these methods for tumor diagnosis and the identification of candidate targets for therapy.
Asunto(s)
Perfilación de la Expresión Génica , Neoplasias/clasificación , Neoplasias/diagnóstico , Redes Neurales de la Computación , Análisis de Secuencia por Matrices de Oligonucleótidos , Linfoma de Burkitt/clasificación , Linfoma de Burkitt/diagnóstico , Linfoma de Burkitt/genética , Interpretación Estadística de Datos , Humanos , Modelos Biológicos , Neoplasias/genética , Neuroblastoma/clasificación , Neuroblastoma/diagnóstico , Neuroblastoma/genética , Rabdomiosarcoma/clasificación , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/genética , Sarcoma de Ewing/clasificación , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Células Tumorales CultivadasRESUMEN
Epithelioid hemangioendothelioma (EHE) is an ultra-rare, translocated, vascular sarcoma. EHE clinical behavior is variable, ranging from that of a low-grade malignancy to that of a high-grade sarcoma and it is marked by a high propensity for systemic involvement. No active systemic agents are currently approved specifically for EHE, which is typically refractory to the antitumor drugs used in sarcomas. The degree of uncertainty in selecting the most appropriate therapy for EHE patients and the lack of guidelines on the clinical management of the disease make the adoption of new treatments inconsistent across the world, resulting in suboptimal outcomes for many EHE patients. To address the shortcoming, a global consensus meeting was organized in December 2020 under the umbrella of the European Society for Medical Oncology (ESMO) involving >80 experts from several disciplines from Europe, North America and Asia, together with a patient representative from the EHE Group, a global, disease-specific patient advocacy group, and Sarcoma Patient EuroNet (SPAEN). The meeting was aimed at defining, by consensus, evidence-based best practices for the optimal approach to primary and metastatic EHE. The consensus achieved during that meeting is the subject of the present publication.
Asunto(s)
Hemangioendotelioma Epitelioide , Sarcoma , Adulto , Niño , Consenso , Hemangioendotelioma Epitelioide/diagnóstico , Hemangioendotelioma Epitelioide/tratamiento farmacológico , Humanos , Oncología Médica , Defensa del Paciente , Sarcoma/diagnóstico , Sarcoma/tratamiento farmacológicoRESUMEN
Desmoid tumors and fibrosarcomas (FS) are part of a wide spectrum of disordered fibroblastic growth that display striking clinical and phenotypic differences. This study was designed to characterize molecular abnormalities that are associated with these differences and to determine their clinical relevance. A cohort of 24 desmoid tumors and 25 low-grade (LG) and 14 high-grade (HG) FS that were clinically and pathologically well characterized was analyzed for alterations in expression of Ki-67, Bcl-2, retinoblastoma gene product (pRB), and p53 by immunohistochemistry. LG-FS and HG-FS showed abnormal expression of Ki-67 (32 versus 86%), Bcl-2 (48 versus 57%), and pRB (56 versus 93%). In contrast, desmoid tumors showed a normal phenotype with these markers. p53 overexpression was identified in 20% of LG-FS and in 29% of HG-FS cases but only in 4% of desmoid tumors. There was an increasing trend in the proportion of abnormal expression of Ki-67, Bcl-2, pRB, and p53 with the increase of tumor aggressiveness from desmoid tumors to LG-FS to HG-FS. The molecular differences between tumor entities were highly statistically significant (P < 0.01). Significant associations between abnormal expression of pRB and recurrence-free survival of LG-FS patients (P = 0.05) and between Ki-67 overexpression and recurrence-free survival for tumors of >5 cm were observed (P = 0.02). The demonstrated differences of molecular alterations in HG-FS, LG-FS, and desmoids appear to be related to biological aggressiveness of such tumors, and they might be useful to differentiate between histologically similar cases of desmoid tumors and LG-FS. pRB and Ki-67 status may be useful to predict recurrence in certain subsets of patients.
Asunto(s)
Fibromatosis Agresiva/genética , Fibrosarcoma/genética , Neoplasias de los Tejidos Blandos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Apoptosis/fisiología , Biomarcadores de Tumor/biosíntesis , Biomarcadores de Tumor/genética , Ciclo Celular/fisiología , División Celular/fisiología , Niño , Supervivencia sin Enfermedad , Fibromatosis Agresiva/metabolismo , Fibromatosis Agresiva/patología , Fibrosarcoma/metabolismo , Fibrosarcoma/patología , Expresión Génica , Genotipo , Humanos , Antígeno Ki-67/biosíntesis , Antígeno Ki-67/genética , Persona de Mediana Edad , Fenotipo , Proteína de Retinoblastoma/biosíntesis , Proteína de Retinoblastoma/genética , Neoplasias de los Tejidos Blandos/metabolismo , Neoplasias de los Tejidos Blandos/patología , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genéticaRESUMEN
Alveolar soft part sarcoma (ASPS) is an unusual tumor with highly characteristic histopathology and ultrastructure, controversial histogenesis, and enigmatic clinical behavior. Recent cytogenetic studies have identified a recurrent der(17) due to a non-reciprocal t(X;17)(p11.2;q25) in this sarcoma. To define the interval containing the Xp11.2 break, we first performed FISH on ASPS cases using YAC probes for OATL1 (Xp11.23) and OATL2 (Xp11.21), and cosmid probes from the intervening genomic region. This localized the breakpoint to a 160 kb interval. The prime candidate within this previously fully sequenced region was TFE3, a transcription factor gene known to be fused to translocation partners on 1 and X in some papillary renal cell carcinomas. Southern blotting using a TFE3 genomic probe identified non-germline bands in several ASPS cases, consistent with rearrangement and possible fusion of TFE3 with a gene on 17q25. Amplification of the 5' portion of cDNAs containing the 3' portion of TFE3 in two different ASPS cases identified a novel sequence, designated ASPL, fused in-frame to TFE3 exon 4 (type 1 fusion) or exon 3 (type 2 fusion). Reverse transcriptase PCR using a forward primer from ASPL and a TFE3 exon 4 reverse primer detected an ASPL-TFE3 fusion transcript in all ASPS cases (12/12: 9 type 1, 3 type 2), establishing the utility of this assay in the diagnosis of ASPS. Using appropriate primers, the reciprocal fusion transcript, TFE3-ASPL, was detected in only one of 12 cases, consistent with the non-reciprocal nature of the translocation in most cases, and supporting ASPL-TFE3 as its oncogenically significant fusion product. ASPL maps to chromosome 17, is ubiquitously expressed, and matches numerous ESTs (Unigene cluster Hs.84128) but no named genes. The ASPL cDNA open reading frame encodes a predicted protein of 476 amino acids that contains within its carboxy-terminal portion of a UBX-like domain that shows significant similarity to predicted proteins of unknown function in several model organisms. The ASPL-TFE3 fusion replaces the N-terminal portion of TFE3 by the fused ASPL sequences, while retaining the TFE3 DNA-binding domain, implicating transcriptional deregulation in the pathogenesis of this tumor, consistent with the biology of several other translocation-associated sarcomas. Oncogene (2001) 20, 48 - 57.
Asunto(s)
Cromosomas Humanos Par 17/genética , Proteínas de Unión al ADN/genética , Proteínas de Neoplasias/genética , Proteínas de Fusión Oncogénica/genética , Sarcoma de Parte Blanda Alveolar/genética , Factores de Transcripción/genética , Translocación Genética , Cromosoma X/genética , Adolescente , Adulto , Secuencia de Aminoácidos , Axila , Secuencia de Bases , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Southern Blotting , Niño , Rotura Cromosómica , Mapeo Cromosómico , ADN Complementario/aislamiento & purificación , Extremidades , Femenino , Perfilación de la Expresión Génica , Humanos , Hibridación Fluorescente in Situ , Péptidos y Proteínas de Señalización Intracelular , Cariotipificación , Masculino , Datos de Secuencia Molecular , Proteínas de Neoplasias/biosíntesis , Proteínas de Neoplasias/aislamiento & purificación , Proteínas de Fusión Oncogénica/biosíntesis , Proteínas de Fusión Oncogénica/aislamiento & purificación , Especificidad de Órganos/genética , ARN Mensajero/aislamiento & purificación , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de Proteína , Células Tumorales CultivadasRESUMEN
PURPOSE: Synovial sarcoma is a high-grade tumor that is associated with poor prognosis. Previous studies analyzing prognostic factors are limited because of inclusion of heterogeneous cohorts of patients with nonextremity and recurrent tumors. The objective of this study was to determine independent prognostic factors of primary synovial sarcoma localized to the extremity. PATIENTS AND METHODS: Between July 1, 1982, and June 30, 1996, 112 patients underwent surgical resection for cure at our institution and then were followed-up prospectively. Clinical and pathologic factors examined for prognostic value included age, sex, tumor site and location, depth, size, microscopic status of surgical margins, invasion of bone or neurovascular structures, and monophasic or biphasic histology. The end points analyzed were the time to first local recurrence that was not preceded by a distant recurrence, time to any distant recurrence, and time to disease-related mortality. These end points were modeled using the method of Kaplan and Meier and analyzed by the log-rank test and Cox regression. RESULTS: The median duration of follow-up among survivors in this cohort of 112 patients was 72 months. The 5-year local-recurrence, distant-recurrence, and mortality rates were 12%, 39%, and 25%, respectively. Tumor size > or = 5 cm (P =.001; relative risk [RR] = 2. 7; 95% confidence interval [CI], 1.5 to 5.2) and the presence of bone or neurovascular invasion (P =.04; RR = 2.3; 95% CI, 1.0 to 5. 3) were independent adverse predictors of distant recurrence. Tumor size > or= 5 cm (P =.003; RR = 2.3; 95% CI, 1.4 to 6.3) and the presence of bone or neurovascular invasion (P =.03; RR = 2.7; 95% CI, 1.0 to 6.5) were also independent adverse predictors of mortality. CONCLUSION: The natural history of primary synovial sarcoma of the extremity is related to tumor size and invasion of bone and neurovascular structures.
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Extremidades/patología , Sarcoma Sinovial/patología , Neoplasias de los Tejidos Blandos/patología , Adolescente , Adulto , Anciano , Estudios de Cohortes , Extremidades/cirugía , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Factores de Riesgo , Sarcoma Sinovial/mortalidad , Sarcoma Sinovial/cirugía , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/cirugía , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: More than 90% of Ewing's sarcomas (ES) contain a fusion of the EWS and FLI1 genes, due to the t(11;22)(q24;q12) translocation. At the molecular level, the EWS-FLI1 rearrangements show great diversity. Specifically, many different combinations of exons from EWS and FLI1 encode in-frame fusion transcripts and result in differences in the length and composition of the chimeric protein, which functions as an oncogenic aberrant transcription factor. In the most common fusion type (type 1), EWS exon 7 is linked in frame with exon 6 of FLI1. As the fundamental pathogenetic lesion in ES, the molecular heterogeneity of these fusion transcripts may have functional and clinical significance. PATIENTS AND METHODS: We performed a clinical and pathologic analysis of 112 patients with ES in which EWS-FLI1 fusion transcripts were identified by reverse-transcriptase polymerase chain reaction (RT-PCR). Adequate treatment and follow-up data were available in 99 patients treated with curative intent. Median follow-up in these 99 patients was 26 months (range, 1 to 140 months). Univariate and multivariate survival analyses were performed that included other prognostic factors, such as age, tumor location, size, and stage. RESULTS: Among the 99 patients suitable for survival analysis, the tumors in 64 patients contained the type 1 fusion and in 35 patients contained less common fusion types. Stage at presentation was localized in 74 patients and metastatic in 25. Metastases (relative risk [RR] = 2.6; P = .008), and type 1 EWS-FLI1 fusion (RR = 0.37; P = .014) were, respectively, independent negative and positive prognostic factors for overall survival by multivariate analysis. Among 74 patients with localized tumors, the type 1 EWS-FLI1 fusion was also a significant positive predictor of overall survival (RR = 0.32; P = .034) by multivariate analysis. CONCLUSION: EWS-FLI1 fusion type appears to be prognostically relevant in ES, independent of tumor site, stage, and size. Further studies are needed to clarify the biologic basis of this phenomenon.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Óseas/tratamiento farmacológico , Proteínas de Fusión Oncogénica/genética , Sarcoma de Ewing/tratamiento farmacológico , Adolescente , Adulto , Neoplasias Óseas/genética , Neoplasias Óseas/mortalidad , Exones , Femenino , Humanos , Masculino , Análisis Multivariante , Proteínas de Fusión Oncogénica/clasificación , Reacción en Cadena de la Polimerasa , Pronóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/mortalidad , Análisis de SupervivenciaRESUMEN
Multifocal presentation, defined as the presence of tumor at two or more anatomically separate sites, before the manifestation of disease in sites where sarcomas usually metastasize (e.g., lungs) occurs in about 1% of extremity soft tissue sarcomas (STSs). Debate still persists whether multifocal STSs represent an unusual pattern of metastasis or multiple separate primary tumors. Among STSs with multifocal presentation, myxoid liposarcoma is the predominant histological type. This subtype of liposarcoma contains the specific t(12;16) chromosomal translocation, which results in rearrangement of the TLS and CHOP genes that is clone specific at the DNA level. We, therefore, sought to address the question of clonality by molecular analysis in six patients who presented with either synchronous or metachronous multifocal myxoid liposarcoma. In all six cases, adequate frozen tumor was available for DNA extraction from at least two distinct anatomical sites. Southern blot analysis using CHOP, TLS, and EWS cDNA probes was performed on genomic DNA. Five cases contained a TLS-CHOP rearrangement, and one case had the variant EWS-CHOP fusion (seen in <5% of cases). The size of the rearranged CHOP fragment differed among the six patients, as expected, but was identical in all anatomically separate tumor samples from each patient. Likewise, the sizes of the rearranged bands observed with either the TLS or EWS probes supported the monoclonality of all cases. Our results confirm the monoclonal origin of multifocal myxoid liposarcoma, establishing the metastatic nature of distant soft tissue lesions in these cases. It remains unclear whether this unusual pattern of metastasis represents an intrinsic property of this subset of myxoid liposarcoma or merely a rare chance occurrence. The clinical outcomes observed in this small series suggest that the prognosis of multifocal myxoid liposarcoma is poor, regardless of its often bland or "low-grade" histological appearance.
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Proteínas Potenciadoras de Unión a CCAAT/genética , Reordenamiento Génico , Liposarcoma/genética , Neoplasias Primarias Múltiples/genética , Ribonucleoproteínas/genética , Factores de Transcripción/genética , Adulto , Anciano , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 16 , Células Clonales , Daño del ADN , ADN de Neoplasias/aislamiento & purificación , Femenino , Ribonucleoproteínas Nucleares Heterogéneas , Humanos , Liposarcoma/química , Liposarcoma/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Múltiples/química , Neoplasias Primarias Múltiples/patología , Proteína EWS de Unión a ARN , Proteína FUS de Unión a ARN , Proteínas de Unión al ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factor de Transcripción CHOP , Transcripción Genética , Translocación GenéticaRESUMEN
PURPOSE: A specific TLS-CHOP fusion gene resulting from the t(12;16) is present in at least 95% of myxoid liposarcomas (MLS). Three common forms of the TLS-CHOP fusion have been described, differing by the presence or absence of TLS exons 6-8 in the fusion product. Type 5-2 (also known as type II) consists of TLS exons 1-5 fused to CHOP exon 2; type 7-2 (also known as type I) also includes TLS exons 6 and 7 in the fusion, whereas type 8-2 (also known as type III) fuses TLS exons 1-8 to CHOP exon 2. We sought to determine the impact of TLS-CHOP fusion transcript structure on clinical outcome in a group of well-characterized MLS cases. We also analyzed P53 status, because this parameter has been found to have a significant prognostic impact in other sarcomas with chromosomal translocations. METHODS: We analyzed TLS-CHOP fusion transcripts by reverse-transcription PCR using RNA extracted from frozen tissue in 82 MLS confirmed previously to harbor a CHOP rearrangement either by Southern blotting or by cytogenetic detection of the t(12;16). Parameters analyzed included age, location, size, percentage of round cell (RC) component, areas of increased cellularity, necrosis, and surgical margins. In 71 (87%) cases, adequate tumor tissue was available for immunohistochemical analysis of P53 status, using DO7 antibody. The Kaplan-Meier method, log-rank, and Cox regression tests were used for survival analyses. RESULTS: Most MLS were >10 cm (73%), arising in the thigh (70%), and localized at presentation (89%). RC component was <5% in 47 (57%) cases and > or =5% in 35 (43%). The TLS-CHOP fusion transcript was type 5-2 in 55 (67%), type 7-2 in 16 cases (20%), and type 8-2 in 8 (10%). One tumor had a unique variant fusion, between exon 6 TLS and exon 2 CHOP. Two other cases (2%) showed an EWS-CHOP fusion transcript. Overexpression of P53 (defined as > or =10% nuclear staining) was detected in 12 (17%) cases. High histological grade (defined as > or =5% RC; P < 0.01), presence of necrosis (> or =5% of tumor mass; P < 0.05), and overexpression of P53 (P < 0.001) correlated with reduced metastatic disease-free survival in localized tumors. The presence of negative surgical margins (P < 0.01) and extremity location (P = 0.02) were found to be significant in predicting local recurrence in the entire group as well as localized cases by univariate and multivariate analysis. Although there was no significant correlation between TLS-CHOP transcript type and histological grade or disease-specific survival, an association was found between the P53 status and type 5-2 fusion (P < 0.01). CONCLUSION: In contrast to some other translocation-associated sarcomas, the molecular variability of TLS-CHOP fusion transcript structure does not appear to have a significant impact on clinical outcome in MLS. Instead, high histological grade (> or =5% RC), presence of necrosis, and P53 overexpression are predictors of unfavorable outcome in localized MLS.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/genética , Genes p53 , Liposarcoma Mixoide/genética , Proteínas de Fusión Oncogénica/genética , Proteína FUS de Unión a ARN , Transcripción Genética , Adulto , Anciano , Cromosomas Humanos Par 12 , Cromosomas Humanos Par 16 , Cartilla de ADN , Exones , Femenino , Humanos , Liposarcoma Mixoide/mortalidad , Liposarcoma Mixoide/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tasa de Supervivencia , Factores de Tiempo , Factor de Transcripción CHOP , Translocación Genética , Resultado del TratamientoRESUMEN
Myxoid liposarcoma (LS), the most common subtype of LS, is known to be characterized by the specific t(12;16) resulting in a TLS-CHOP fusion in almost all cases. We wished to address the following questions: (i) Is this genetic hallmark also present in other types of LS with predominant myxoid change? (ii) What is the proportion of cases with the variant EWS-CHOP fusion? (iii) What is the optimal approach for Southern blot detection of TLS breakpoints? We identified 59 LS characterized histologically by >90% myxoid component, in which frozen tissue tumor was available for DNA extraction. These 59 LS with myxoid features were divided into 2 groups: 42 LS with classic myxoid/round cell appearance (myxoid LS) and 17 well-differentiated LS (WDLS) with a predominant (>90%) myxoid component. Within the myxoid LS group, 29 tumors were low grade and 13 high grade (>20% round cell component). Among the 17 predominantly myxoid WDLS, there were 15 low grade and 2 focally high grade tumors. In addition, we selected as control group, 20 LS of other histological types with minimal or no myxoid change (17 WDLS and 3 pleomorphic LS) and 13 myxofibrosarcomas. Southern blot analysis was performed in all cases using a CHOP cDNA probe, and in all CHOP rearranged cases using a TLS cDNA probe. Probe/enzyme combinations for Southern blot analysis were CHOP exon 3-4 cDNA probe with BamHI or SacI, TLS exon 3-6 cDNA probe with BclI. All 42 cases of myxoid LS showed a CHOP rearrangement and 38 of them also had a TLS rearrangement. Among the 4 myxoid LS without Southern blot evidence of TLS rearrangement, 1 showed an EWS-CHOP fusion by Southern blotting and reverse transcriptase-polymerase chain reaction and in another case, reverse transcriptase-polymerase chain reaction detected a TLS-CHOP fusion transcript. None of the predominantly myxoid WDLS and none of the tumors included in the control group showed rearranegements with CHOP probe. In addition, 12 predominantly myxoid WDLS, 10 other LS, and 5 myxofibrosarcoma from the control group were also tested for TLS rearrangement; all were negative. The TLS-CHOP fusion is highly sensitive and specific for the entity of classic myxoid/round cell LS. Other types of LS, even with a predominant myxoid component, lack the TLS-CHOP rearrangement, confirming that they represent a genetically distinct group of LS. The prevalence of the EWS-CHOP variant fusion was approximately 2% in this series. The optimal enzyme for TLS genomic breakpoint detection is BclI.
Asunto(s)
Proteínas Potenciadoras de Unión a CCAAT/genética , Carcinoma de Células Pequeñas/diagnóstico , Carcinoma de Células Pequeñas/genética , Liposarcoma Mixoide/diagnóstico , Liposarcoma Mixoide/genética , Proteínas de Fusión Oncogénica/genética , Southern Blotting , Carcinoma de Células Pequeñas/clasificación , Rotura Cromosómica/genética , Mapeo Cromosómico , Fibroma/genética , Ribonucleoproteínas Nucleares Heterogéneas , Histocitoquímica , Humanos , Liposarcoma Mixoide/clasificación , Proteína EWS de Unión a ARN , Proteína FUS de Unión a ARN , Ribonucleoproteínas/genética , Factor de Transcripción CHOP , Translocación Genética/genéticaRESUMEN
Adamantinoma of long bones is a rare neoplasm predominantly involving the tibia. Cytogenetic studies of adamantinoma are few. Cytogenetic or molecular cytogenetic analysis of four adamantinomas, and a review of eleven cases in the literature reveals extra copies of chromosomes 7, 8, 12, 19, and 21 as recurrent in this neoplasm. Adamantinoma may be confused with a variety of primary and metastatic epithelial and mesenchymal neoplasms. Observation of these aneuploidies may be useful in establishing the diagnosis of adamantinoma.
Asunto(s)
Ameloblastoma/genética , Aneuploidia , Cromosomas Humanos , Displasia Fibrosa Ósea/genética , Tibia/patología , Adolescente , Adulto , Ameloblastoma/patología , Femenino , Displasia Fibrosa Ósea/patología , Peroné/patología , Humanos , Cariotipificación , Masculino , RecurrenciaRESUMEN
Leiomyosarcoma of bone is a rare tumor in an unusual location. Previous analysis of this entity mostly involved small numbers of cases with limited follow-up. Thirty-three patients with leiomyosarcoma of bone between 1977 and 1996 were studied, and the histologic appearance and grade were correlated with subsequent treatment and clinical behavior. To be included in this study the tumor had to be intraosseous, with other primary sites of origin clinically excluded. Also, most of the sarcomatous tissue (> or =70%) had to be of intramedullary location with only limited extraosseous extension. The patient's age at diagnosis ranged from 13 to 77 years (average 44.4). The gender distribution was equal. The long bones were preferentially affected (64%), with the lower extremity, around the knee joint, predominantly involved. Five patients (15%) developed postradiation leiomyosarcomas. The histologic analysis showed that the osseous leiomyosarcomas are most commonly of the classic type, followed by the epithelioid, myxoid, and pleomorphic variants. Immunoreactivity for smooth muscle markers (smooth muscle actin, common muscle actin, desmin) was positive in all tumors, and ultrastructural confirmation was obtained in 21% of cases. All sarcomas were histologically graded, which accurately reflected the subsequent prognosis. Seventy-five percent of the lesions were high-grade and the rest low-grade. The histologic grade of the tumors correlated with both the recurrence as well as the metastatic rates and together with the clinicopathologic stage of disease represented the cornerstone on which prudent therapy should be based.
Asunto(s)
Neoplasias Óseas/patología , Leiomiosarcoma/patología , Actinas/análisis , Actinas/ultraestructura , Adolescente , Adulto , Anciano , Neoplasias Óseas/química , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/mortalidad , Neoplasias Óseas/ultraestructura , Femenino , Estudios de Seguimiento , Humanos , Inmunohistoquímica , Rodilla/diagnóstico por imagen , Rodilla/patología , Leiomiosarcoma/química , Leiomiosarcoma/diagnóstico por imagen , Leiomiosarcoma/mortalidad , Leiomiosarcoma/ultraestructura , Masculino , Microscopía Electrónica , Persona de Mediana Edad , Tasa de Supervivencia , Tomografía Computarizada por Rayos XRESUMEN
Sclerosing epithelioid fibrosarcoma (SEF) is an uncommon tumor of deep soft tissues, originally described in 1995 by Meis-Kindblom et al. In the current study, the authors identified 16 cases of SEF in the pathology files of their institutions and studied their pathologic features and disease course. The group consisted of six male and 10 female patients (age range, 14-55 years; mean age, 40 years), and the tumors were located in a limb or limb girdle (n = 7), base of the penis (n = 1), back or chest wall (n = 3), and head and neck (n = 5). Tumor size ranged from 3.7 to 22 cm (mean, 8.9 cm). Histologically, the SEFs were composed predominantly of small to moderate-size round to ovoid, relatively uniform cells, often with clear cytoplasm, embedded in a hyalinized fibrous stroma. The only consistent immunohistochemical finding was a strong, diffuse reactivity of tumor cells for vimentin. Ultrastructural analysis performed in eight cases confirmed their fibroblastic nature. Bone invasion and tumor necrosis, features not reported before, were found in six cases each. Treatment consisted of intralesional excision (n = 2), attempted wide local excision (n = 11), and amputation (n = 3), with either adjuvant radiation therapy (n = 9) or chemotherapy (n = 3). Follow-up of at least 1 year in 14 cases revealed persistent disease or local recurrence in seven patients (50%), and distant metastasis in 12 patients (86%). Eight patients (57%) died of disease 16 to 86 months after diagnosis. Five patients were alive with disease as of last follow-up. SEF shares some pathologic features with two other fibrosing fibrosarcomas, low-grade fibromyxoid sarcoma and hyalinizing spindle cell tumor with giant rosettes, but in the authors' experience behaves clinically as a fully malignant sarcoma.
Asunto(s)
Fibrosarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Adolescente , Adulto , Femenino , Humanos , Masculino , Microscopía Electrónica , Persona de Mediana EdadRESUMEN
Ewing's sarcoma (ES) and primitive neuroectodermal tumor (PNET) are characterized by the presence of the specific t(11;22)(q24;q12) or variants thereof, producing diagnostic EWS fusion transcripts. Cytokeratin has been reported sporadically to be expressed in some cases of ES/PNET. However, its prevalence has not been assessed systematically in a series of cases with confirmatory molecular or cytogenetic evidence of a diagnostic translocation. We present in detail three index patients in whom strong cytokeratin immunoreactivity was a confounding factor in the diagnosis. To establish further the prevalence of cytokeratin immunoreactivity in a series of well-characterized ES/PNET, we then performed immunohistochemical studies with antibodies CAM5.2 and AE1/AE3 on 50 cases of ES/PNET diagnosed at Memorial Sloan-Kettering Cancer Center in which molecular evidence of a specific ES/PNET-associated translocation were available. Immunoreactivity to cytokeratin was present in 10 cases (20%), in five diffusely and five focally. There was no significant association between cytokeratin expression and the following parameters: patient age, sex, skeletal and extraskeletal primary site, and the type of EWS fusion transcript. Cytokeratin expression, a manifestation of epithelial differentiation, is present in as many as 20% of ES/PNET in either a diffuse or focal pattern.
Asunto(s)
Queratinas/inmunología , Neoplasias Primarias Múltiples/inmunología , Tumores Neuroectodérmicos Primitivos/inmunología , Sarcoma de Ewing/inmunología , Adulto , Anciano , Niño , Femenino , Humanos , Inmunohistoquímica , Queratinas/biosíntesis , Masculino , Neoplasias Primarias Múltiples/patología , Tumores Neuroectodérmicos Primitivos/patología , Sarcoma de Ewing/patologíaRESUMEN
"Hyalinizing spindle cell tumor with giant rosettes" is a tumor recently described by Lane et al. and thought by them possibly to represent a form of low-grade fibromyxoid sarcoma. Proof of a metastatic potential was lacking. We report an example of this tumor on the arm of a 28-year-old woman. The ultrastructural study of the tumor confirmed the fibroblastic nature of the lesion, which subsequently metastasized to the lung. Histologically, the giant rosettes simulated palisaded granulomas. Our findings warrant classifying the tumor as a sarcoma, and we suggest the designation low-grade fibrosarcoma with palisaded granulomalike bodies (giant rosettes).