RESUMEN
The histone methyltransferase EZH2 has an essential role in the development of follicular lymphoma (FL). Recurrent gain-of-function mutations in EZH2 have been described in 25% of FL patients and induce aberrant methylation of histone H3 lysine 27 (H3K27). We evaluated the role of EZH2 genomic gains in FL biology. Using RNA sequencing, Sanger sequencing and SNP-arrays, the mutation status, copy-number and gene-expression profiles of EZH2 were assessed in a cohort of 159 FL patients from the PRIMA trial. Immunohistochemical (IHC) EZH2 expression (n=55) and H3K27 methylation (n=63) profiles were also evaluated. In total, 37% of patients (59/159) harbored an alteration in the EZH2 gene (mutation n=46, gain n=23). Both types of alterations were associated with highly similar transcriptional changes, with increased proliferation programs. An H3K27me3/me2 IHC score fully distinguished mutated from wild-type samples, showing its applicability as surrogate for EZH2 mutation analysis. However, this score did not predict the presence of gains at the EZH2 locus. The presence of an EZH2 genetic alteration was an independent factor associated with a longer progression-free survival (hazard ratio 0.58, 95% confidence interval 0.36-0.93, P=0.025). We propose that the copy-number status of EZH2 should also be considered when evaluating patient stratification and selecting patients for EZH2 inhibitor-targeted therapies.
Asunto(s)
Proteína Potenciadora del Homólogo Zeste 2/genética , N-Metiltransferasa de Histona-Lisina/genética , Linfoma Folicular/genética , Adulto , Anciano , Línea Celular Tumoral , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Histona Metiltransferasas , Humanos , Linfoma Folicular/tratamiento farmacológico , Linfoma Folicular/patología , Masculino , Metilación/efectos de los fármacos , Persona de Mediana Edad , Mutación/genética , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ARNAsunto(s)
Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/efectos adversos , Enfermedades Renales/etiología , Linfoma no Hodgkin/terapia , Trasplante de Células Madre/efectos adversos , Acondicionamiento Pretrasplante/efectos adversos , Adulto , Anciano , Autoinjertos , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: ALK-negative anaplastic large cell lymphoma associated with breast implant (i-ALCL) has been recently recognized as a distinct entity. Among 43 830 lymphomas registered in the French Lymphopath network since 2010, 300 breast lymphomas comprising 25 peripheral T-cell lymphomas (PTCL) were reviewed. Among PTCL, ALK-negative ALCL was the most frequent and all of them were associated with breast implants. PATIENTS AND METHODS: Since 2010, all i-ALCL cases were collected from different institutions through Lymphopath. Immuno-morphologic features, molecular data and clinical outcome of 19 i-ALCLs have been retrospectively analyzed. RESULTS: The median age of the patients was 61 years and the median length between breast implant and i-ALCL was 9 years. Most implants were silicone-filled and textured. Implant removal was performed in 17 out of 19 patients with additional treatment based on mostly CHOP or CHOP-like chemotherapy regimens (n = 10/19) or irradiation (n = 1/19). CHOP alone or ABVD following radiation without implant removal have been given in two patients. The two clinical presentations, i.e. effusion and less frequently tumor mass correlated with distinct histopathologic features: in situ i-ALCL (anaplastic cell proliferation confined to the fibrous capsule) and infiltrative i-ALCL (pleomorphic cells massively infiltrating adjacent tissue with eosinophils and sometimes Reed-Sternberg-like cells mimicking Hodgkin lymphoma). Malignant cells were CD30-positive, showed a variable staining for EMA and were ALK negative. Most cases had a cytotoxic T-cell immunophenotype with variable T-cell antigen loss and pSTAT3 nuclear expression. T-cell receptor genes were clonally rearranged in 13 out of 13 tested cases. After 18 months of median follow-up, the 2-year overall survival for in situ and infiltrative i-ALCL was 100% and 52.5%, respectively. CONCLUSIONS: In situ i-ALCLs have an indolent clinical course and generally remain free of disease after implant removal. However, infiltrative i-ALCLs could have a more aggressive clinical course that might require additional therapy to implant removal.
Asunto(s)
Implantes de Mama/efectos adversos , Linfoma Anaplásico de Células Grandes/patología , Linfoma de Células T Periférico/patología , Siliconas/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años , Quinasa de Linfoma Anaplásico , Femenino , Enfermedad de Hodgkin/patología , Humanos , Inmunofenotipificación , Antígeno Ki-1/metabolismo , Linfoma Anaplásico de Células Grandes/inducido químicamente , Linfoma Anaplásico de Células Grandes/mortalidad , Linfoma de Células T Periférico/inducido químicamente , Linfoma de Células T Periférico/mortalidad , Persona de Mediana Edad , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Estudios Retrospectivos , Factor de Transcripción STAT3/metabolismo , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Epitheliomesenchymal biphasic neoplasms are extremely rare in the duodenum, and most of these are carcinosarcomas. Miettinen et al. (Am J Surg Pathol 33:1370-7, 2009) recently reported three cases of a novel distinctive epitheliomesenchymal biphasic tumor of the stomach in young adults. In view of the resemblance to other childhood blastomas, they proposed to refer to this entity as a gastroblastoma. Since none of the components were sufficiently atypical, the gastroblastoma seemed more comparable to this kind of tumor than carcinosarcomas or other aggressive and malignant biphasic tumors. This report describes a duodenal location of a similar epitheliomesenchymal biphasic tumor in a 22-year-old woman. To our knowledge, this is the first reported case occurring primarily in the duodenum and might be the first case of "duodenoblastoma."
Asunto(s)
Neoplasias Duodenales/clasificación , Neoplasias Duodenales/patología , Epitelio/patología , Mesodermo/patología , Procedimientos Quirúrgicos del Sistema Digestivo/métodos , Neoplasias Duodenales/cirugía , Duodeno/diagnóstico por imagen , Duodeno/patología , Duodeno/cirugía , Femenino , Humanos , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Adulto JovenAsunto(s)
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Mutación/genética , Proteínas Nucleares/genética , Proteínas Represoras/genética , Adulto , Anciano , Anciano de 80 o más Años , Hibridación Genómica Comparativa , Femenino , Humanos , Cariotipificación , Masculino , Persona de Mediana Edad , Nucleofosmina , Análisis de Secuencia por Matrices de Oligonucleótidos , Polimorfismo Genético , Pronóstico , Adulto Joven , Tirosina Quinasa 3 Similar a fms/genética , Proteínas ras/genéticaRESUMEN
The ubiquitous herpesvirus Epstein-Barr virus (EBV) is linked to the development of several malignancies, including nasopharyngeal carcinoma (UCNT) and Hodgkin lymphoma (HL). Despite the well-known oncogenic properties of the EBV latent membrane protein 1 (LMP-1), the different oncogenic pathways involved in the pathogenesis of each disease remain unclear. This study reported, for the first time, the case of a patient with sequential development of UCNT and HL. Polymerase chain reaction was used to determine the LMP-1 gene sequence and demonstrate that the two tumours contained different clonal viral genomes, suggesting a central and specific role of EBV infection.
Asunto(s)
Infecciones por Virus de Epstein-Barr/genética , Herpesvirus Humano 4/genética , Enfermedad de Hodgkin/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Primarias Secundarias/genética , Proteínas de la Matriz Viral/genética , Adulto , Enfermedad de Hodgkin/virología , Humanos , Masculino , Neoplasias Nasofaríngeas/virología , Neoplasias Primarias Secundarias/virología , Técnicas de Amplificación de Ácido Nucleico , Reacción en Cadena de la PolimerasaRESUMEN
Multicystic peritoneal mesothelioma is a rare lesion occurring mainly in women in a reproductive age. Its pathogenesis is unclear. We report three cases of multicystic peritoneal mesothelioma in patients that were 28, 38 and 47 years of age (one male, two females). A history of abdominal surgery was reported in two cases. Explorative laparotomy was presumptive of a pseudomyxoma peritoni in two cases, and hyperthermic intraperitoneal chemotherapy was performed. Histological examination demonstrated multicystic lesions with mesothelial cells lining confirmed by immunohistochemical analysis. Unusual findings such as hyperplasia, hobnail features, cytoplasmic vacuolisation and papillary pattern were occasionally noted. The clinical presentation, pathogenesis and pathologic features including differential diagnosis of multicystic peritoneal mesothelioma are discussed.
Asunto(s)
Mesotelioma Quístico/patología , Neoplasias Peritoneales/patología , Dolor Abdominal/etiología , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apendicectomía , Terapia Combinada , Quiste Dermoide , Diagnóstico Diferencial , Endometriosis/complicaciones , Femenino , Humanos , Hipertermia Inducida , Perforación Intestinal/etiología , Laparotomía , Masculino , Mesotelioma Quístico/complicaciones , Mesotelioma Quístico/diagnóstico , Mesotelioma Quístico/tratamiento farmacológico , Mesotelioma Quístico/cirugía , Persona de Mediana Edad , Neoplasias Primarias Múltiples , Neoplasias Ováricas , Neoplasias Peritoneales/complicaciones , Neoplasias Peritoneales/diagnóstico , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/cirugía , Peritonitis/etiología , Seudomixoma Peritoneal/diagnóstico , Inducción de RemisiónRESUMEN
Common fragile sites (CFSs) are regions of chromosomal break that may play a role in oncogenesis. The most frequent alteration occurs at FRA3B, within the FHIT gene, at chromosomal region 3p14. We studied a series of breast carcinomas for break of a CFS at 6q26, FRA6E, and its associated gene PARK2, using fluorescence in situ hybridization on tissue microarrays (TMA). We found break of PARK2 in 6% of cases. We studied the PARK2-encoded protein Parkin by using immunohistochemistry on the same TMA. Loss of Parkin was found in 13% of samples but was not correlated with PARK2 break. PARK2 break but not Parkin expression was correlated with prognosis. Alteration of PARK2/FRA6E may cause haplo-insufficiency of one or several telomeric potential tumor suppressor genes (TSG). The AF-6/MLLT4 gene, telomeric of PARK2, encodes the Afadin scaffold protein, which is essential for epithelial integrity. Loss of Afadin was found in 14.5% of cases, and 36% of these cases showed PARK2 break. Loss of Afadin had prognostic impact, suggesting that AF-6 may be a TSG. Loss of Afadin was correlated with loss of FHIT expression, suggesting fragility of FRA6E and FRA3B in a certain proportion of breast tumors.
Asunto(s)
Ácido Anhídrido Hidrolasas/genética , Neoplasias de la Mama/genética , Rotura Cromosómica , Cinesinas/genética , Miosinas/genética , Proteínas de Neoplasias/genética , Ubiquitina-Proteína Ligasas/genética , Ácido Anhídrido Hidrolasas/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Western Blotting , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/diagnóstico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Sitios Frágiles del Cromosoma , Cromosomas Humanos Par 6/genética , Femenino , Técnica del Anticuerpo Fluorescente , Genes Supresores de Tumor , Humanos , Técnicas para Inmunoenzimas , Hibridación Fluorescente in Situ , Cinesinas/metabolismo , MicroARNs , Persona de Mediana Edad , Miosinas/metabolismo , Invasividad Neoplásica/patología , Proteínas de Neoplasias/metabolismo , Pronóstico , Interferencia de ARN , Tasa de Supervivencia , Análisis de Matrices Tisulares , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The potential benefit of rituximab as adjuvant to high-dose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2-3) CD20+ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- s.d.) were 65 +/- 16 and 63 +/- 15%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86 +/- 14 and 82 +/- 15%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Linfoma de Células B/terapia , Linfoma de Células B Grandes Difuso/terapia , Trasplante de Células Madre de Sangre Periférica/métodos , Adulto , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales de Origen Murino , Antígenos CD20/sangre , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Cisplatino/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Epirrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prednisona/administración & dosificación , Pronóstico , Rituximab , Análisis de Supervivencia , Trasplante Autólogo , Vincristina/administración & dosificaciónAsunto(s)
Cromosomas Humanos Par 12 , Cromosomas Humanos Par 5 , Coenzima A Ligasas/genética , Fusión de Oncogenes/genética , Policitemia Vera/genética , Proteínas Proto-Oncogénicas c-ets/genética , Proteínas Represoras/genética , Adulto , Anciano , Empalme Alternativo , Progresión de la Enfermedad , Resultado Fatal , Femenino , Humanos , Janus Quinasa 2 , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Mutación , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Translocación Genética , Proteína ETS de Variante de Translocación 6RESUMEN
A better molecular characterization of breast cell lines (BCL) may help discover new markers to apply to tumour samples. We performed gene and protein expression profiling of 31 BCL using whole-genome DNA microarrays and immunohistochemistry (IHC) on 'cell microarrays' (CMA), respectively. Global hierarchical clustering discriminated two groups of BCL: group I corresponded to luminal cell lines, group II to basal and mesenchymal cell lines. Correlations with centroids calculated from a published 'intrinsic 500-gene set' assigned 15 cell lines as luminal, eight as basal and four as mesenchymal. A set of 1.233 genes was differentially expressed between basal and luminal samples. Mesenchymal and basal subtypes were rather similar and discriminated by only 227 genes. The expression of 10 proteins (CAV1, CD44, EGFR, MET, ETS1, GATA3, luminal cytokeratin CK19, basal cytokeratin CK5/6, CD10, and ERM protein moesin) encoded by luminal vs basal discriminator genes confirmed the subtype classification and the validity of the identified markers. Our BCL basal/luminal signature correctly re-classified the published series of tumour samples that originally served to identify the molecular subtypes, suggesting that the identified markers should be useful for tumour classification and might represent promising targets for disease management.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Basocelular/metabolismo , Perfilación de la Expresión Génica , Biomarcadores de Tumor/genética , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/clasificación , Carcinoma Basocelular/genética , Carcinoma Basocelular/patología , Células Epiteliales , Femenino , Genes erbB-2/fisiología , Humanos , Técnicas para Inmunoenzimas , Mesodermo/metabolismo , Análisis de Secuencia por Matrices de OligonucleótidosRESUMEN
The classification of peripheral T-cell lymphomas (PTCL) is still a matter of debate. To establish a molecular classification of PTCL, we analysed 59 primary nodal T-cell lymphomas using cDNA microarrays, including 56 PTCL and three T-lymphoblastic lymphoma (T-LBL). The expression profiles could discriminate angioimmunoblastic lymphoma, anaplastic large-cell lymphoma and T-LBL. In contrast, cases belonging to the broad category of 'PTCL, unspecified' (PTCL-U) did not share a single molecular profile. Using a multiclass predictor, we could separate PTCL-U into three molecular subgroups called U1, U2 and U3. The U1 gene expression signature included genes known to be associated with poor outcome in other tumors, such as CCND2. The U2 subgroup was associated with overexpression of genes involved in T-cell activation and apoptosis, including NFKB1 and BCL-2. The U3 subgroup was mainly defined by overexpression of genes involved in the IFN/JAK/STAT pathway. It comprised a majority of histiocyte-rich PTCL samples. Gene Ontology annotations revealed different functional profile for each subgroup. These results suggest the existence of distinct subtypes of PTCL-U with specific molecular profiles, and thus provide a basis to improve their classification and to develop new therapeutic targets.
Asunto(s)
Perfilación de la Expresión Génica , Ganglios Linfáticos/patología , Linfoma de Células T/genética , Linfoma de Células T/patología , Humanos , Linfoma de Células T/clasificación , Linfoma de Células T/diagnóstico , Reacción en Cadena de la Polimerasa , PronósticoAsunto(s)
Proteínas de Ciclo Celular/genética , Leucemia Eritroblástica Aguda/genética , Trastornos Mieloproliferativos/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Tirosina Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Translocación Genética , Adulto , Autoantígenos , Niño , Cromosomas Humanos Par 8/genética , Cromosomas Humanos Par 9/genética , Femenino , Humanos , Janus Quinasa 2 , Masculino , Persona de Mediana EdadRESUMEN
A 26-year-old woman complained of trijeminal nevralgy and ocular symptoms revealing a paracavernal tumor which had progressed for three months. Histopathological analysis after partial resection led to the diagnosis of Castleman's disease. Six months later, the patient was considered cured after focal adjuvant radiotherapy. Castleman's disease is a lymphoproliferative disorder. Solitary intracranial involvement is unusual. Unlike multifocal disease, localized Castleman's disease has an excellent prognosis.
Asunto(s)
Enfermedad de Castleman/patología , Lóbulo Temporal/patología , Adulto , Antígenos CD/inmunología , Enfermedad de Castleman/inmunología , Enfermedad de Castleman/cirugía , Diplopía/etiología , Exoftalmia/etiología , Femenino , Humanos , Imagen por Resonancia Magnética , Neuralgia del Trigémino/etiologíaRESUMEN
PURPOSE: Because it is unclear whether T-cell/histiocyte-rich large B-cell lymphomas (H/TCRBCL) should be considered as a true clinicopathologic entity, we conducted a matched-control analysis comparing patients with H/TCRBCL and patients with diffuse large-B cell lymphoma (B-DLCL). PATIENTS AND METHODS: More than 4,500 patients were enrolled onto non-Hodgkin's lymphoma trials conducted by the Groupe d'Etude des Lymphomes de l'Adulte. After histologic review, 50 patients were subclassified as H/TCRBCL. They were matched to 150 patients with B-DLCL for each of the factors of the International Prognostic Index (IPI). RESULTS: Clinical characteristics of H/TCRBCL patients showed a male predominance and a median age of 47 years. Performance status was normal in 89% of patients, whereas lactate dehydrogenase level was increased in 60% of patients. The disease was disseminated in 81% of patients, and 48% had two or more involved extranodal sites. The IPI score was >or= 2 in 53% of patients. The complete response rate to chemotherapy was 63%, and 5-year overall survival (OS) and event-free survival (EFS) rates (mean +/- SD) were 58% +/- 18% and 53% +/- 16%, respectively. The matched-control analysis showed a trend toward a better response to chemotherapy for patients with B-DLCL (P =.06), whereas no difference was observed in OS (P =.9) and EFS (P =.8). CONCLUSION: H/TCRBCL is an aggressive disease that often presents with adverse prognostic factors. However, when treatment is adapted to the disease risk, outcome is equivalent to that observed in patients with B-DLCL. Thus H/TCRBCL should be considered a pathologic variant that belongs to the B-DLCL category.