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1.
Lab Invest ; 99(1): 85-92, 2019 01.
Artículo en Inglés | MEDLINE | ID: mdl-30353131

RESUMEN

Distinct populations of effector memory T cells use different homing receptors to traffic to the skin and gut. Whether tissue-selective T cells are needed for early rejection of a neoplasm growing in these tissues remains an open question. We chose to study an allogeneic tumor model because growth of such a fully mismatched tumor would signify a profound immune deficit. We implanted allogeneic tumor cells in the skin or gut of mice deficient in either α(1,3) fucosyltransferases IV and VII, enzymes critical for generating E-selectin ligands on skin-homing T cells, or ß7 integrin, a component of the α4ß7 integrin ligand for the mucosal adressin MAdCAM. During the first 9 days after tumor implantation, FucTVII-/- mice showed a profoundly impaired capacity to reject tumors growing in the skin, but readily rejected tumors implanted in the gut. Rejection of tumors in the skin was even more impaired in mice deficient in both FucTIV and FucTVII. This impairment was corrected by infusion of T cells from normal mice. By contrast, ß7 integrin-/- mice showed profoundly impaired rejection of tumors in the gut, but no defect in the skin tumor rejection. These differences were unrelated to antigen recognition or effector function of T cells, since all strains of mice were capable of generating tumor-specific CTLs in vitro against the tumor cell line used in vivo. These results demonstrate that T-cell homing defects in vivo impair immune surveillance of peripheral epithelial tissues in a specific and selective fashion.


Asunto(s)
Neoplasias/inmunología , Linfocitos T/fisiología , Aloinjertos , Animales , Línea Celular Tumoral , Fucosiltransferasas/metabolismo , Cadenas beta de Integrinas/metabolismo , Ratones Endogámicos BALB C , Ratones Noqueados , Trasplante de Neoplasias
2.
Cancer ; 121(22): 4088-96, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26349011

RESUMEN

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/farmacología
3.
J Pathol ; 227(2): 223-33, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22294416

RESUMEN

Soft-tissue sarcomas are a group of malignant tumours whose clinical management is complicated by morphological heterogeneity, inadequate molecular markers and limited therapeutic options. Receptor tyrosine kinases (RTKs) have been shown to play important roles in cancer, both as therapeutic targets and as prognostic biomarkers. An initial screen of gene expression data for 48 RTKs in 148 sarcomas showed that ROR2 was expressed in a subset of leiomyosarcoma (LMS), gastrointestinal stromal tumour (GIST) and desmoid-type fibromatosis (DTF). This was further confirmed by immunohistochemistry (IHC) on 573 tissue samples from 59 sarcoma tumour types. Here we provide evidence that ROR2 expression plays a role in the invasive abilities of LMS and GIST cells in vitro. We also show that knockdown of ROR2 significantly reduces tumour mass in vivo using a xenotransplantation model of LMS. Lastly, we show that ROR2 expression, as measured by IHC, predicts poor clinical outcome in patients with LMS and GIST, although it was not independent of other clinico-pathological features in a multivariate analysis, and that ROR2 expression is maintained between primary tumours and their metastases. Together, these results show that ROR2 is a useful prognostic indicator in the clinical management of these soft-tissue sarcomas and may represent a novel therapeutic target.


Asunto(s)
Biomarcadores de Tumor/metabolismo , Tumores del Estroma Gastrointestinal/enzimología , Leiomiosarcoma/enzimología , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/metabolismo , Neoplasias Uterinas/enzimología , Animales , Biomarcadores de Tumor/genética , Línea Celular Tumoral , Movimiento Celular , Supervivencia sin Enfermedad , Femenino , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/terapia , Perfilación de la Expresión Génica/métodos , Terapia Genética , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Leiomiosarcoma/genética , Leiomiosarcoma/mortalidad , Leiomiosarcoma/patología , Leiomiosarcoma/terapia , Masculino , Ratones , Ratones Endogámicos NOD , Ratones SCID , Análisis Multivariante , Invasividad Neoplásica , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , Modelos de Riesgos Proporcionales , Interferencia de ARN , ARN Mensajero/metabolismo , Receptores Huérfanos Similares al Receptor Tirosina Quinasa/genética , Factores de Tiempo , Transfección , Carga Tumoral , Neoplasias Uterinas/genética , Neoplasias Uterinas/mortalidad , Neoplasias Uterinas/patología , Neoplasias Uterinas/terapia , Ensayos Antitumor por Modelo de Xenoinjerto
4.
Nat Med ; 12(4): 395-7, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16565724

RESUMEN

We found that one-third of human sebaceous tumors examined had double-nucleotide substitutions in the same LEF1 allele, irrespective of DNA mismatch repair status. The mutations impaired both LEF1 binding to beta-catenin and transcriptional activation, and are the first tumor-associated mutations that inactivate Wnt signaling. Mutant LEF1 not only inhibited expression of beta-catenin target genes but also stimulated expression of sebocyte markers, suggesting that it may determine the differentiated characteristics of sebaceous tumors.


Asunto(s)
Sustitución de Aminoácidos , Factor de Unión 1 al Potenciador Linfoide/genética , Neoplasias de las Glándulas Sebáceas/genética , Activación Transcripcional , beta Catenina/metabolismo , Adenoma/patología , Alelos , Secuencia de Aminoácidos , Secuencia de Bases , Línea Celular , Secuencia Conservada , ADN/análisis , ADN/genética , Regulación Neoplásica de la Expresión Génica , Genes Reporteros , Marcadores Genéticos , Humanos , Luciferasas/análisis , Luciferasas/metabolismo , Factor de Unión 1 al Potenciador Linfoide/análisis , Factor de Unión 1 al Potenciador Linfoide/metabolismo , Datos de Secuencia Molecular , Neoplasias de las Glándulas Sebáceas/metabolismo , Neoplasias de las Glándulas Sebáceas/patología , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Transducción de Señal , Transcripción Genética , Proteínas Wnt/metabolismo , beta Catenina/análisis , beta Catenina/genética
5.
Proc Natl Acad Sci U S A ; 107(32): 14333-8, 2010 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-20660757

RESUMEN

Although gastrointestinal stromal tumors (GISTs) harboring activating KIT or platelet-derived growth factor receptor A (PDGFRA) mutations respond to treatment with targeted KIT/PDGFRA inhibitors such as imatinib mesylate, these treatments are rarely curative. Most often, a sizeable tumor cell subpopulation survives and remains quiescent for years, eventually resulting in acquired resistance and treatment failure. Here, we report that imatinib induces autophagy as a survival pathway in quiescent GIST cells. Inhibiting autophagy, using RNAi-mediated silencing of autophagy regulators (ATGs) or antimalarial lysosomotrophic agents, promotes the death of GIST cells both in vitro and in vivo. Thus, combining imatinib with autophagy inhibition represents a potentially valuable strategy to promote GIST cytotoxicity and to diminish both cellular quiescence and acquired resistance in GIST patients.


Asunto(s)
Antimaláricos/farmacología , Autofagia/efectos de los fármacos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Benzamidas , Muerte Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Quimioterapia Combinada , Tumores del Estroma Gastrointestinal/patología , Humanos , Mesilato de Imatinib , Piperazinas/farmacología , Pirimidinas/farmacología
6.
J Cutan Pathol ; 39(3): 356-60, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-22335595

RESUMEN

We report two unique cases of dermatofibrosarcoma protuberans (DFSP) that included a pseudocystic component. Molecular analysis of one of the cases showed a characteristic COL1A1-PDGFB rearrangement in both the main tumor and also in the cells lining the pseudocystic portion of the tumor, confirming the diagnosis and indicating that the lining represented a component of the proliferation. It is important to raise awareness of this rare variant within the varied spectrum of DFSP. Shvartsbeyn M, Lazar AJF, Lopez-Terrada D, Meehan SA. Pseudocystic dermatofibrosarcoma protuberans: report of two cases and demonstration of COL1A1-PDGFB rearrangement.


Asunto(s)
Colágeno Tipo I/genética , Quistes , Dermatofibrosarcoma , Reordenamiento Génico , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-sis/genética , Neoplasias Cutáneas , Adulto , Proliferación Celular , Cadena alfa 1 del Colágeno Tipo I , Quistes/genética , Quistes/patología , Dermatofibrosarcoma/genética , Dermatofibrosarcoma/patología , Femenino , Humanos , Masculino , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología
7.
Mol Cell Proteomics ; 9(11): 2405-13, 2010 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-20651304

RESUMEN

Leiomyosarcoma is one of the most common mesenchymal tumors. Proteomics profiling analysis by reverse-phase protein lysate array surprisingly revealed that expression of the epithelial marker E-cadherin (encoded by CDH1) was significantly elevated in a subset of leiomyosarcomas. In contrast, E-cadherin was rarely expressed in the gastrointestinal stromal tumors, another major mesenchymal tumor type. We further sought to 1) validate this finding, 2) determine whether there is a mesenchymal to epithelial reverting transition (MErT) in leiomyosarcoma, and if so 3) elucidate the regulatory mechanism responsible for this MErT. Our data showed that the epithelial cell markers E-cadherin, epithelial membrane antigen, cytokeratin AE1/AE3, and pan-cytokeratin were often detected immunohistochemically in leiomyosarcoma tumor cells on tissue microarray. Interestingly, the E-cadherin protein expression was correlated with better survival in leiomyosarcoma patients. Whole genome microarray was used for transcriptomics analysis, and the epithelial gene expression signature was also associated with better survival. Bioinformatics analysis of transcriptome data showed an inverse correlation between E-cadherin and E-cadherin repressor Slug (SNAI2) expression in leiomyosarcoma, and this inverse correlation was validated on tissue microarray by immunohistochemical staining of E-cadherin and Slug. Knockdown of Slug expression in SK-LMS-1 leiomyosarcoma cells by siRNA significantly increased E-cadherin; decreased the mesenchymal markers vimentin and N-cadherin (encoded by CDH2); and significantly decreased cell proliferation, invasion, and migration. An increase in Slug expression by pCMV6-XL5-Slug transfection decreased E-cadherin and increased vimentin and N-cadherin. Thus, MErT, which is mediated through regulation of Slug, is a clinically significant phenotype in leiomyosarcoma.


Asunto(s)
Transición Epitelial-Mesenquimal , Genómica/métodos , Leiomiosarcoma , Proteómica/métodos , Factores de Transcripción/metabolismo , Biomarcadores , Cadherinas/genética , Cadherinas/metabolismo , Movimiento Celular , Proliferación Celular , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/metabolismo , Tumores del Estroma Gastrointestinal/patología , Regulación Neoplásica de la Expresión Génica , Humanos , Leiomiosarcoma/genética , Leiomiosarcoma/metabolismo , Leiomiosarcoma/patología , Análisis por Micromatrices , Factores de Transcripción de la Familia Snail , Tasa de Supervivencia , Factores de Transcripción/genética , Vimentina/metabolismo
8.
J Cutan Pathol ; 38(6): 475-82, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21352259

RESUMEN

BACKGROUND: We describe a series of previously unreported, distinctive, polypoid solitary T-cell-rich cutaneous pseudolymphomas. METHODS: The clinicopathologic features were examined in 17 cases. RESULTS: Patient ages ranged from 16 to 71 years (mean = 38.5) with a female predominance (female : male = 14 : 3). All lesions, clinically diagnosed most often as pyogenic granuloma, presented as a solitary, polypoid, erythematous, papule ranging in size from 2.5 to 7.5 mm (mean = 5.8). Most occurred on the head and neck (7) and trunk (6) with other sites including the thigh (1), shoulder (1) and knee (1). A dense dermal infiltrate composed of mildly atypical lymphocytes with variable numbers of admixed plasma cells and histiocytes was prototypical. Commonly, there was an associated epidermal collarette (16/17), Grenz zone (11/17) or admixed eosinophils (8/17). Prominent vessels lined by plump endothelial cells, reminiscent of high endothelial venules of lymph nodes, were universal and some degree of telangiectasia was also common (12/17). CD3-positive T-cells consisted of an admixture of CD4-positive and CD8-positive forms (15/16). Multiple studies suggested polyclonality (seven cases). No recurrences after lesional excision were noted in the 17 patients with a follow-up range from 24 to 120 months (mean = 46.6). CONCLUSION: Although these lesions share histopathologic features of the so-called acral pseudolymphomatous angiokeratoma of children (APACHE), they occur in a completely different clinical setting, present in solitary and polypoid fashion and are T-cell rich. We propose the diagnostic label T-cell-rich angiomatoid polypoid pseudolymphoma for this distinctive but presumably reactive lesion.


Asunto(s)
Seudolinfoma/clasificación , Seudolinfoma/patología , Enfermedades de la Piel/clasificación , Enfermedades de la Piel/patología , Linfocitos T/patología , Adulto , Anciano , Antígenos CD/biosíntesis , Biomarcadores/análisis , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Adulto Joven
9.
Am J Dermatopathol ; 33(4): 354-60, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21478726

RESUMEN

Dermatofibrosarcoma protuberans (DFSP) is a superficial sarcoma of intermediate malignancy usually composed of monotonous short spindle cells with storiform architecture. The tumor cells are diffusely reactive for CD34 and characterized by a translocation involving chromosomes 17 and 22 or a supernumerary ring chromosome that results in the fusion of exon 2 of platelet-derived growth factor beta (PDGFß; 22q13) to various exons of collagen type 1 alpha 1 (COL1A1; 17q22). In some tumors, fibrosarcomatous transformation can occur and is characterized by a monotonous spindle cell proliferation arranged in fascicles or a herringbone-type pattern. We report 4 DFSPs with unusual and pleomorphic sarcomatous transformation. They occurred on the back, scalp, shoulder, and forehead of women (ages 31,48, 48, and 27 year). In addition to areas of conventional DFSP that strongly expressed CD34, 2 cases showed pleomorphic areas mimicking undifferentiated pleomorphic sarcoma/malignant fibrous histiocytoma: 1 case had a patternless area and 1 case had combined round/spindled cells with myxoid areas. Reverse transcription--polymerase chain reaction was performed in 1 case, confirming the presence of a COL1A1-PDGFß fusion transcript. The remaining three cases were found to be positive for a PDGFß gene rearrangement by fluorescence in situ hybridization. This series illustrates that sarcomatous transformation in DFSP may occasionally display areas, which can mimic undifferentiated pleomorphic or unclassified sarcoma. Ancillary diagnostic testing may be helpful to confirm the diagnosis, especially in small biopsies.


Asunto(s)
Transformación Celular Neoplásica/patología , Dermatofibrosarcoma/patología , Neoplasias Cutáneas/patología , Adulto , Antígenos CD34/metabolismo , Biomarcadores de Tumor/metabolismo , Transformación Celular Neoplásica/genética , ADN de Neoplasias/análisis , Dermatofibrosarcoma/genética , Dermatofibrosarcoma/metabolismo , Femenino , Humanos , Hibridación Fluorescente in Situ , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/metabolismo , Translocación Genética
10.
Mod Pathol ; 23(10): 1301-6, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20495536

RESUMEN

Well-differentiated liposarcoma/atypical lipomatous tumor can be difficult to differentiate from benign lipomatous tumors, especially on limited biopsy material. Adjunctive tests for MDM2 (murine double minute 2) have proven useful in whole-tissue sections; however, their utility has not been determined within the increasingly popular core needle biopsy. Herein, we compare the ability of MDM2 immunohistochemistry and MDM2 fluorescence in situ hybridization (FISH) to discriminate benign lipomatous tumors from well-differentiated liposarcoma on core needle biopsies. Well-differentiated liposarcoma (n=17) and an assortment of benign lipomatous tumors (n=37), which had concurrent or previous core needle biopsies, and resection specimens were subjected to both MDM2 immunohistochemistry and MDM2 FISH on both whole-tissue sections and corresponding core needle biopsy sections. Percentage tumor cells positive for MDM2 by immunohistochemistry and an MDM2:CEP12 FISH ratio was calculated in each biopsy and resection specimen pair and the results were compared. MDM2 FISH had a higher sensitivity (100%) and specificity (100%) compared with MDM2 immunohistochemistry (65 and 89%) in core needle biopsies, respectively. In addition, MDM2 immunohistochemistry had a false-positive rate of 11%, compared to 0% with FISH. The average MDM2:CEP12 ratio was similar in the biopsy material compared with the whole-tissue sections in both well-differentiated liposarcoma and the benign lipomatous tumor group of neoplasms. Detection of MDM2 amplification by FISH is a more sensitive and specific adjunctive test than MDM2 immunohistochemistry to differentiate well-differentiated liposarcoma from various benign lipomatous tumors, especially on limited tissue samples.


Asunto(s)
Biomarcadores de Tumor/análisis , Biopsia con Aguja , Liposarcoma/diagnóstico , Proteínas Proto-Oncogénicas c-mdm2/biosíntesis , Diagnóstico Diferencial , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Lipoma/diagnóstico , Liposarcoma/metabolismo , Sensibilidad y Especificidad
11.
Histopathology ; 56(1): 133-47, 2010 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-20055911

RESUMEN

Sebaceous neoplasia comprises a spectrum ranging from benign to malignant. Proper histological identification is important for treatment, prognosis and potential association with the Muir-Torre syndrome (MTS). Our increased understanding of the significance and pathogenesis of these tumours has led to improved risk stratification, screening recommendations, and treatment of patients with an initial presentation of a sebaceous tumour. This review focuses on the diagnostic and histological features of sebaceous lesions, the MTS, and recent insights into the molecular pathogenesis of sebaceous tumours.


Asunto(s)
Adenocarcinoma Sebáceo/patología , Adenoma/patología , Síndrome de Muir-Torre/patología , Neoplasias de las Glándulas Sebáceas/patología , Adenocarcinoma Sebáceo/complicaciones , Adenoma/complicaciones , Humanos , Síndrome de Muir-Torre/complicaciones , Neoplasias de las Glándulas Sebáceas/complicaciones
12.
J Cutan Pathol ; 37(2): 231-6, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19614729

RESUMEN

Sebaceous carcinoma has a predominant periocular origin but can also be extraocular. These two groups have distinct clinical courses. Insight into the molecular determinants of tumorigenesis and metastasis is limited. There is no effective treatment for metastatic sebaceous carcinoma. Epidermal growth factor receptor (EGFR) is implicated in tumorigenesis and can be a therapeutic target in certain settings. We evaluated EGFR levels by immunohistochemistry (IHC), comparing its expression between periocular and extraocular tumors and assessed EGFR mutation status. IHC was performed in 36 cases: 19 periocular and 17 extraocular (10 associated with Muir-Torre syndrome-MTS). EGFR IHC was scored for percentage of positive cells (< 5%, 5-25%, 26-50%, > 50%) and intensity (+1 = low , +2 = moderate , +3 = high ). Extraocular carcinomas showed markedly increased levels of EGFR when compared to periocular carcinoma cases, both in terms of distribution (88% were > 25% of tumor cells vs. 16%) and intensity (77% were 2+ or 3+ vs. 21%) (p < 0.001). Among extraocular cases, there was significantly lower EGFR expression in MTS-related cases (p < 0.05). No EGFR mutations were identified. Our results underscore the divergent mechanisms underlying the tumorigenesis of periocular and extraocular sebaceous carcinoma and suggest an association between aggressive behavior and increased EGFR expression in extraocular sebaceous carcinoma.


Asunto(s)
Adenocarcinoma Sebáceo/metabolismo , Receptores ErbB/metabolismo , Neoplasias de las Glándulas Sebáceas/metabolismo , Adenocarcinoma Sebáceo/complicaciones , Adenocarcinoma Sebáceo/genética , Adulto , Anciano , Anciano de 80 o más Años , Distribución de Chi-Cuadrado , Receptores ErbB/genética , Femenino , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Síndrome de Muir-Torre/complicaciones , Síndrome de Muir-Torre/genética , Síndrome de Muir-Torre/metabolismo , Mutación , Reacción en Cadena de la Polimerasa , Neoplasias de las Glándulas Sebáceas/complicaciones , Neoplasias de las Glándulas Sebáceas/genética
13.
Am J Dermatopathol ; 32(2): 149-53, 2010 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-19940748

RESUMEN

Indeterminate fibrohistiocytic lesions of the skin share histological and immunohistochemical features of both benign fibrous histiocytoma/dermatofibroma and dermatofibrosarcoma protuberans (DFSP). Unlike dermatofibroma, DFSP harbors recurrent genetic aberrations resulting in the fusion of COL1A1 on chromosome 17 and PDGFB on chromosome 22. Because indeterminate fibrohistiocytic lesions share some features with DFSP, they were evaluated for the possible presence of COL1A1-PDGFB chimeric transcripts. Twelve formalin-fixed paraffin-embedded cases were examined for COL1A1-PDGFB chimeric transcripts using a previously validated sensitive multiplex reverse transcriptase-polymerase chain reaction assay. The median patient age was 52.5 years (33-70 years) with 9 females and 3 males. The most common site was the extremities (n = 8) followed by the trunk (n = 2) and the head and neck region (n = 2). All demonstrated the expected reactivity for both CD34 and factor XIIIa, and the majority focally infiltrated into subcutaneous fat. Of the 6 patients with follow-up, 2 had residual tumor excised, but no patient developed a recurrence. None of the tumors harbored COL1A1-PDGFB fusion transcripts identified by reverse transcriptase-polymerase chain reaction. Although indeterminate fibrohistiocytic lesions share some features with DFSP, the lack of COL1A1-PDGFB chimeric transcripts suggests that they are distinct entities.


Asunto(s)
Quimera/genética , Colágeno Tipo I/genética , Dermatofibrosarcoma/genética , Histiocitoma Fibroso Benigno/genética , Proteínas Proto-Oncogénicas c-sis/genética , Neoplasias Cutáneas/genética , Adulto , Anciano , Biopsia , Quimera/metabolismo , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Dermatofibrosarcoma/diagnóstico , Dermatofibrosarcoma/metabolismo , Diagnóstico Diferencial , Femenino , Regulación Neoplásica de la Expresión Génica , Histiocitos/metabolismo , Histiocitos/patología , Histiocitoma Fibroso Benigno/diagnóstico , Histiocitoma Fibroso Benigno/metabolismo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Prevalencia , Proteínas Proto-Oncogénicas c-sis/metabolismo , Estudios Retrospectivos , Piel/metabolismo , Piel/patología , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología
14.
Curr Opin Oncol ; 21(4): 352-9, 2009 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-19436199

RESUMEN

PURPOSE OF REVIEW: Desmoid tumors are associated with a variable and unpredictable clinical course. Surgery is the therapeutic mainstay, but there has been much discussion of late regarding its proper application. Little is known regarding the molecular determinates of desmoid tumor behavior. Some recent work has focused on the role of beta-catenin in desmoid tumor biology. RECENT FINDINGS: Given the variable clinical course of desmoid tumors, the interpretation of factors classically associated with recurrence such as microscopic status of margins appears more nuanced that previously thought. The application of multidisciplinary assessment with multimodality treatment, including surgery, radiation and systemic therapies may underlie these changes and now form the basis of care for this tumor. The precise CTNNB1 mutation present appears to be strongly predictive of recurrence after initial resection in one large, retrospective, multivariate analysis. SUMMARY: Establishing the population benefiting most from various treatment modalities and combinations is critical for progress in this disease. Assessment and treatment of individual patients in a multidisciplinary setting is critical to achieve the most favorable outcome. Additional study of the molecular determinates of desmoid behavior is needed to guide therapeutic selection.


Asunto(s)
Fibromatosis Agresiva/terapia , Terapia Combinada , Fibromatosis Agresiva/genética , Fibromatosis Agresiva/metabolismo , Fibromatosis Agresiva/patología , Humanos , Mesenquimoma/genética , Mesenquimoma/metabolismo , Mesenquimoma/patología , Mesenquimoma/terapia , Proteínas Wnt/metabolismo , beta Catenina/genética , beta Catenina/metabolismo
15.
Am J Pathol ; 173(5): 1518-27, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18832571

RESUMEN

Desmoid fibromatosis is a rare, nonmetastatic neoplasm marked by local invasiveness and relentless recurrence. Molecular determinants of desmoid recurrence remain obscure. beta-Catenin deregulation has been commonly identified in sporadic desmoids although the incidence of CTNNB1 (the gene encoding beta-catenin) mutations is uncertain. Consequently, we evaluated the prevalence of CTNNB1 mutations in a large cohort of sporadic desmoids and examined whether mutation type was relevant to desmoid outcome. Desmoid specimens (195 tumors from 160 patients, 1985 to 2005) and control dermal scars were assembled into a clinical data-linked tissue microarray. CTNNB1 genotyping was performed on a 138-sporadic desmoid subset. Immunohistochemical scoring was performed per standard criteria and data were analyzed using Kaplan-Meier and other indicated methods. CTNNB1 mutations were observed in 117 of 138 (85%) of desmoids. Three discrete mutations in two codons of CTNNB1 exon 3 were identified: 41A (59%), 45F (33%), and 45P (8%, excluded from further analysis because of rarity). Five-year recurrence-free survival was significantly poorer in 45F-mutated desmoids (23%, P < 0.0001) versus either 41A (57%) or nonmutated tumors (65%). Nuclear beta-catenin expression was observed in 98% of specimens and intensity was inversely correlated with incidence of desmoid recurrence (P < 0.01). In conclusion, CTNNB1 mutations are highly common in desmoid tumors. Furthermore, patients harboring CTNNB1 (45F) mutations are at particular risk for recurrence and therefore may especially benefit from adjuvant therapeutic approaches.


Asunto(s)
Fibromatosis Agresiva/genética , Mutación/genética , beta Catenina/genética , Adulto , Secuencia de Bases , Núcleo Celular/metabolismo , Núcleo Celular/patología , Estudios de Cohortes , Análisis Mutacional de ADN , Exones/genética , Femenino , Fibromatosis Agresiva/cirugía , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Modelos de Riesgos Proporcionales , Recurrencia , Análisis de Regresión , Análisis de Matrices Tisulares
16.
Ann Surg Oncol ; 16(4): 910-9, 2009 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18953611

RESUMEN

Gastrointestinal stromal tumor (GIST) is the most common sarcoma arising in the gastrointestinal (GI) tract. Imatinib mesylate (imatinib) is efficacious in treating advanced and metastatic GIST. Patients undergoing resection of GIST realize a highly variable median disease-free survival (DFS). In the absence of prospective data, we conducted a randomized, phase II study to assess the safety and efficacy of preoperative and postoperative imatinib for the treatment of GIST. Nineteen GIST patients undergoing surgical resection were randomized to receive 3, 5, or 7 days of preoperative imatinib (600 mg daily). Patients received postoperative imatinib for 2 years. Perioperative adverse events were compared with those in an imatinib-naïve historical control. The efficacy of imatinib was assessed by (18)fluorodeoxyglucose positron emission tomography ((18)FDG-PET), dynamic computed tomography (dCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and DFS. Imatinib did not affect surgical morbidity as compared with an imatinib-naïve cohort (p >/= 0.1). Most patients responded to preoperative imatinib by (18)FDG-PET and dCT (69% and 71%, respectively). Tumor cell apoptosis increased by an average of 12% (range 0-33%) and correlated with the duration of preoperative imatinib (p = 0.04). Median DFS of patients treated with surgery and imatinib was 46 months (range 10-46 months). Tumor size was a predictor of recurrence after postoperative imatinib (p = 0.02). Imatinib appears to be safe and may be considered for patients undergoing surgical resection of their GIST. Radiographic response and tumor cell apoptosis occur within the first week of imatinib therapy.


Asunto(s)
Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Benzamidas , Terapia Combinada , Femenino , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Tumores del Estroma Gastrointestinal/cirugía , Humanos , Mesilato de Imatinib , Masculino , Persona de Mediana Edad , Radiografía , Inducción de Remisión
17.
Am J Dermatopathol ; 31(3): 297-300, 2009 May.
Artículo en Inglés | MEDLINE | ID: mdl-19384074

RESUMEN

Gastrointestinal stromal tumors (GISTs) rarely metastasize to the skin. We describe 5 patients with GIST with subcutaneous and cutaneous metastases. The mean age at metastasis was 54 years (range 30-68 years) with a male predominance (4:1). Primary tumors occurred in the stomach (n = 3), small bowel (n = 1), and abdomen, not otherwise specified (n = 1). The average time from primary tumor resection to the resection of skin metastases was 59 months (range 11-155 months). The metastases occurred in the scalp (n = 2), cheek (n = 1), and abdomen (n = 2) with 3 patients presenting with solitary nodules and 2 patients with multiple nodules. The average size was 2 cm (range 0.6-4 cm). Histologically, 2 cases were spindled and 3 cases demonstrated mixed epithelioid and spindle cell morphology. All were confirmed to have CD117 reactivity. KIT genotyping was performed in 4 of 5 cases. Two cases harbored a mutation in exon 11, and the remaining 2 cases were wild type in exons 9, 11, 13, and 17. All 5 patients had multiple concurrent or subsequent abdominal and/or hepatic metastases. In 4 patients with an average follow-up of 32 months (range 6-75 months), after the resection of the metastases, 2 were alive with disease and 2 died of disease. Cutaneous metastases seem to be a late complication of GIST, but their presence does not necessarily herald a rapid demise of the patient.


Asunto(s)
Tumores del Estroma Gastrointestinal/patología , Proteínas Proto-Oncogénicas c-kit , Neoplasias Cutáneas/secundario , Neoplasias de los Tejidos Blandos/secundario , Tejido Subcutáneo/patología , Adulto , Anciano , Análisis Mutacional de ADN , Exones , Femenino , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/inmunología , Tumores del Estroma Gastrointestinal/mortalidad , Tumores del Estroma Gastrointestinal/cirugía , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Mutación , Proteínas Proto-Oncogénicas c-kit/análisis , Proteínas Proto-Oncogénicas c-kit/genética , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/cirugía , Neoplasias de los Tejidos Blandos/genética , Neoplasias de los Tejidos Blandos/inmunología , Neoplasias de los Tejidos Blandos/mortalidad , Neoplasias de los Tejidos Blandos/cirugía , Tejido Subcutáneo/inmunología , Tejido Subcutáneo/cirugía , Factores de Tiempo , Resultado del Tratamiento
18.
Int J Cancer ; 122(3): 711-8, 2008 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-17943734

RESUMEN

Germ-line mutations in the KIT receptor tyrosine kinase gene have been described in families with a propensity to develop gastrointestinal stromal tumor (GIST). There is limited information from large kindreds regarding median age at diagnosis, detailed histopathology, clinical effects of imatinib therapy and chromosomal abnormalities of the KIT gene. We identified a large kindred with GIST. Each family member was interviewed and appropriate medical records and radiographic imaging were obtained. Archival tumor tissue was obtained to confirm diagnosis, extract genomic DNA and perform fluorescent in situ hybridization cytogenetics of the KIT gene. Fifteen of 79 individuals with GIST were identified in this kindred. There were 8 males, the mean age at diagnosis was 53.9 (range 45-71) years. Histopathology revealed microscopic proliferation and nodularity in the myenteric plexus, spindled morphology, diffuse Kit but variable CD34 staining and low mitotic rates in the setting of metastatic disease. A deletion of codon 579 in exon 11 of the KIT gene was identified in tumor and normal tissue of this family. Mutation and cytogenetic analysis revealed homozygous loss of the wild-type KIT sequence in tumor from one individual. Four of 4 individuals treated with imatinib are alive and without progression while 9 of 11 individuals not treated with imatinib are deceased. This study describes a kindred with a propensity to develop GIST in an autosomal dominant pattern. Germ-line deletion of KIT codon 579 in GIST is associated with clinical benefit from imatinib, limited utility of mitoses to predict malignant potential, and a novel homozygous deletion of this codon in one individual.


Asunto(s)
Antineoplásicos/uso terapéutico , Tumores del Estroma Gastrointestinal/tratamiento farmacológico , Tumores del Estroma Gastrointestinal/patología , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas c-kit/metabolismo , Pirimidinas/uso terapéutico , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Adulto , Anciano , Benzamidas , Femenino , Tumores del Estroma Gastrointestinal/metabolismo , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Proto-Oncogénicas c-kit/genética , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética
19.
Clin Exp Metastasis ; 25(3): 191-9, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18264782

RESUMEN

Lymphatic mapping and sentinel lymph node biopsy-also termed sentinel lymphadenectomy (SL)-has become a standard of care for patients with primary invasive cutaneous melanoma. This technique has been shown to provide accurate information about the disease status of the regional lymph node basins at risk for metastasis, provide prognostic information, and provide durable regional lymph node control. The potential survival benefit afforded to patients undergoing SL is controversial. Central to this controversy is whether metastasis to regional lymph nodes occurs independent of or prior to widespread hematogenous dissemination. A related area of uncertainty is whether tumor cells residing within regional lymph nodes have increased metastatic potential. We have used a murine model of primary invasive cutaneous melanoma based on injection of B16-BL6 melanoma cells into the pinna to address two questions: (1) does SL plus wide excision of the primary tumor result in a survival advantage over wide excision alone; and (2) do melanoma cells growing within lymph nodes produce a higher incidence of hematogenous metastases than do cells growing at the primary tumor site? We found that SL significantly improved the survival of mice with small primary tumors. We found no difference in the incidence of lung metastases produced by B16-BL6 melanoma cells growing exclusively within regional lymph nodes and cells growing within the pinna.


Asunto(s)
Neoplasias Pulmonares/mortalidad , Escisión del Ganglio Linfático , Melanoma Experimental/mortalidad , Biopsia del Ganglio Linfático Centinela , Neoplasias Cutáneas/mortalidad , Animales , Supervivencia sin Enfermedad , Neoplasias Pulmonares/secundario , Metástasis Linfática , Melanoma Experimental/secundario , Ratones , Ratones Endogámicos C57BL , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Resultado del Tratamiento , Células Tumorales Cultivadas
20.
Mod Pathol ; 21(11): 1303-10, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18587326

RESUMEN

Extraskeletal myxoid chondrosarcoma is a rare soft tissue tumor characterized by a nodular growth pattern with eosinophilic cells usually in a reticular pattern and abundant myxoid stroma. In contrast to other myxoid sarcomas, the majority of extraskeletal myxoid chondrosarcomas harbor a balanced translocation, t(9;22)(q22;q12), that fuses EWSR1 with NR4A3 (also known as CHN). Other less common translocations involving NR4A3 have also been described. We examined the diagnostic utility of fluorescence in situ hybridization for extraskeletal myxoid chondrosarcoma using the LSI EWSR1 break-apart probe (Abbott Molecular/Vysis, Des Plaines, IL, USA). Sixteen cases of extraskeletal myxoid chondrosarcoma with formalin-fixed paraffin-embedded tissue available were retrieved (1991-2007). The mean age at time of presentation was 57 years (range, 30-78). The male to female ratio was 7:1. All cases where either consistent with or highly suggestive of the diagnosis, with most of the primary tumors occurring in the thigh, inguinal or gluteal region. Fifteen of 16 cases were analyzable, of which 14 (93%) were positive for the rearrangement of the EWSR1 locus. In this study, the vast majority of extraskeletal myxoid chondrosarcomas are associated with a rearrangement at the EWSR1 locus (22q12). Fluorescence in situ hybridization is useful to support the diagnosis of extraskeletal myxoid chondrosarcomas and may help to differentiate it from mimics such as other myxoid sarcomas, particularly in limited biopsies.


Asunto(s)
Proteínas de Unión a Calmodulina/genética , Condrosarcoma/diagnóstico , Proteínas de Unión al ARN/genética , Neoplasias de los Tejidos Blandos/diagnóstico , Adulto , Anciano , Condrosarcoma/genética , Condrosarcoma/secundario , Cromosomas Humanos Par 22 , Cromosomas Humanos Par 9 , ADN de Neoplasias/genética , Diagnóstico Diferencial , Extremidades , Femenino , Reordenamiento Génico , Humanos , Hibridación Fluorescente in Situ , Masculino , Persona de Mediana Edad , Proteína EWS de Unión a ARN , Sarcoma/diagnóstico , Neoplasias de los Tejidos Blandos/genética , Translocación Genética
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