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1.
Leuk Res ; 116: 106827, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35430388

RESUMO

NOTCH1 is one of the most frequently mutated genes in chronic lymphocytic leukemia and has emerged as a marker of poor prognosis. In addition to coding NOTCH1 mutations involving exon 34, non-coding NOTCH1 mutations involving the 3' UTR have been described in a limited number of chronic lymphocytic leukemia (CLL) patients and were associated with adverse outcomes. In this study, 1574 CLL patients were assessed using targeted sequencing with a 29 gene panel and the results were correlated with prognostic characteristics. NOTCH1 mutations were detected in 252 (16%) patients, including both coding (220/252, 14%), non-coding (24/252, 1.5%) and a mixture of coding and non-coding (8/252, 0.5%) NOTCH1 mutations. NOTCH1 mutations were more commonly seen in patients with unmutated IGHV, ZAP70 positivity and CD38 positivity. Mixed NOTCH1 mutations were also more commonly seen in patients with unmutated IGHV and ZAP70. There was no association between mixed NOTCH1 mutations and CD38 expression in this cohort. The most common cytogenetic alteration detected in patients with coding and mixed NOTCH1 mutations was trisomy 12, whereas del13q was the most common cytogenetic alteration detected in patients with non-coding NOTCH1 mutation. The most common gene mutations co-occurring with coding NOTCH1 mutations were: TP53 (23.2%), SF3B1 (16.4%) and SPEN (10%). The most common gene mutations co-occurring with non-coding NOTCH1 mutations were: SF3B1 11(34.4%), ATM 4(12.5%) and TP53 4(12.5%). CLL patients with clonal coding and non-coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (4.3 vs 10.0 years and 0.9 vs 10.0 years respectively, p < 0.05). Similarly, CLL patients with subclonal coding NOTCH1 mutations had a significantly shorter time-to-first treatment than patients with wild type NOTCH1 (5.6 vs 10.0 years, p < 0.05). CLL patients with subclonal non-coding NOTCH1 mutations also had a shorter time-to-first treatment than patients with wild type NOTCH1 mutations, however, the difference was not significant (5.1 vs 10.0 years, p = 0.15). These data confirm that both coding and non-coding NOTCH1 mutations carry adverse prognostic impact and need to be included in sequencing assays performed for the prognostic workup of CLL patients.


Assuntos
Leucemia Linfocítica Crônica de Células B , Biomarcadores , Humanos , Leucemia Linfocítica Crônica de Células B/genética , Mutação , Prognóstico , Receptor Notch1/genética
2.
Ann Diagn Pathol ; 58: 151934, 2022 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-35299081

RESUMO

Intravascular large B-cell lymphoma (IVLBCL) is a rare, clinically aggressive form of large B-cell lymphoma that is preferentially located within blood vessel lumina. Despite its intravascular location, a leukemic phase of disease seems to be uncommon. After encountering a patient with IVLBCL with numerous circulating lymphoma cells, we reviewed the literature and identified 6 patients with IVLBCL who had numerous circulating lymphoma cells (defined by ≥10% lymphoma cells in peripheral blood). The percentage of circulating lymphoma cells in this patient cohort was variable, with a median of 36% (range, 14% - 87%), Bone marrow was involved in all 5 patients assessed. Elevation of liver transaminases preferentially affecting aspartate aminotransferase (AST, 3/3, 100%), hepatosplenomegaly (4/5, 80%), thrombocytopenia (100%), CD5 positivity (100%) and monotypic lambda light chain predominance (3/4, 75%) were common features. Conventional cytogenetic analysis performed in 4 patients revealed a complex karyotype with multiple abnormalities particularly deletions and copy number aberrations involving chromosomes 6q and 18. The clinical courses of these patients were highly variable, but overall there was a high mortality rate of 75% with 18-months of follow-up. Due to the rarity of IVLBCL, along with its variable clinical manifestations and subtle pathologic changes, the diagnosis is often delayed which may contribute to the poor outcome of IVLBCL patients. Recognition that this disease can present rarely with a leukemic phase further expands our knowledge of the clinicopathologic spectrum of IVLBC.

3.
Hum Pathol ; 121: 36-45, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34995673

RESUMO

Activating mutations in the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway have been shown in nearly half of the cases of Rosai-Dorfman disease (RDD). Cyclin D1, a key cell cycle regulator, constitutes a major downstream target of the MAPK/ERK pathway. In this study, we aim to further understand the pathogenesis of RDD by assessing the lesional histiocytes for cyclin D1, p-ERK, Ki-67, and BCL-2 by immunohistochemistry. We assessed 35 samples of RDD and a control group of histiocyte-rich reactive lesions. Cyclin D1 was expressed in about 90% of cases of RDD. Cyclin D1 was positive in 25-95% (median, 85%) of lesional histiocytes, was moderately/strongly expressed in 97% of cyclin D1-positive cases, and was significantly higher than in control specimens. p-ERK was positive in 16 of 30 (53%) cases of RDD and was negative in all controls. All p-ERK-positive RDD cases had concurrent cyclin D1 expression, whereas more than a third of cyclin D1-positive cases were negative for p-ERK. Ki-67 was low in RDD (median, 3%). BCL-2 was positive in lesional histiocytes in nine of 10 RDD cases assessed. Overall, these findings point to unexpected, potential roles of these molecules in the pathogenesis of RDD. Overexpression of cyclin D1 in the absence of ERK phosphorylation in a subset of RDD cases opens the possibility of oncogenic mechanisms bypassing ERK and supports the notion that cyclin D1 overexpression in RDD is multifactorial. Moreover, the observed lack of correlation between cyclin D1 with Ki-67 proliferative index suggests that prosurvival actions of cyclin D1 are, at least in part, cell cycle independent. Finally, expression of BCL-2 and the low Ki-67 index suggest that RDD might be driven by antiapoptotic rather than proproliferative oncogenic mechanisms.


Assuntos
Histiocitose Sinusal , Ciclina D1/genética , MAP Quinases Reguladas por Sinal Extracelular , Histiocitose Sinusal/patologia , Humanos , Antígeno Ki-67 , Proteínas Proto-Oncogênicas c-bcl-2
4.
Bone Marrow Transplant ; 57(3): 370-376, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34992253

RESUMO

The role of WT1 protein in hematopoiesis and leukemogenesisis incompletely elucidated. WT1 overexpression is common in acute myeloid leukemia (AML); however, WT1 mutations occur in only about 10% of cases, with increasing incidence in the setting of relapse. In this study, we investigated the clinical and molecular characteristics of WT1 mutations in NPM1-mutated AML, to enhance our understanding of the biology and potential therapeutic implications of WT1 mutations. Our study cohort included 67 patients with NPM1 mutated AML and a median follow-up of 13.7 months. WT1 mutations were identified in 7% (n = 5) of patients at the time of initial diagnosis. WT1 mutant clones were presumed to be present as co-dominant clones in 3/5 and in subclonal populations in 2/5 cases based on variant allelic frequency (VAF) when compared with NPM1 mutation VAF. All WT1 mutations became undetectable at time of MRD-negative (NPM1-wild type) remission. None of these patients experienced relapse at the time of last follow-up (median, 15 months; range, 4.5-20.2 months). A total of 15/67 (22%) patients relapsed; among these patient, four (27%) relapsed with WT1 mutant AML. Three of four patients had undergone allogeneic hematopoietic stem cell transplantation (HSCT). None of these patients had detectable WT1 mutations at the time of initial diagnosis. WT1 mutations were presumed clonal in two cases and subclonal in the other two cases, based on VAF. Our results indicate that WT1 mutations contribute to relapse in NPM1 mutated AML, especially in the setting of HSCT. These findings suggest that emerging WT1 mutations may serve as a conduit for relapse in NPM1-mutated AML, and that sequential molecular profiling to evaluate potential emergent WT1 mutations during surveillance and particularly at relapse likely has prognostic value in patients with NPM1 mutated AML.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Proteínas WT1 , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/terapia , Mutação , Proteínas Nucleares/genética , Prognóstico , Recidiva , Proteínas WT1/genética
7.
Leuk Res ; 111: 106704, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34735934

RESUMO

Light-chain restricted hematogones (LCR HGs) detected by flow cytometry analysis can mimic bone marrow involvement by B-cell lymphoma. This phenomenon can present a diagnostic pitfall and negatively impact patient management, as misinterpretation may upgrade disease stage. In this study, we characterized the immunophenotype of LCR HGs with an aim to differentiate them from B-cell lymphoma. We analyzed 24 patients with LCR HGs, 12 (50 %) were kappa light chain restricted and 12 (50 %) were lambda light chain restricted. LCR HGs account for 51 % (range, 1.5%-99%) of B cells, and 0.5 % (range, 0.1%-3.7%) of total cells. In 15 patients in whom multiple specimens were analyzed, 10 (67 %) showed persistent LCR HGs in more than 1 specimen, and the duration of the light chain restriction ranged from 4 months to 2 years. Among 24 patients, 4 (16.6 %) cases were concurrently involved by B-cell lymphoma/myeloma in addition to LCR HGs. With the exception of light chain restriction, LCR HGs showed a similar immunophenotype as normal HGs and had a distinct location on the CD45/Side Scatter (SSC) plot. They were also consistently positive for CD10, CD19, CD38 (bright), CD43, and CD200. CD20 expression showed a spectrum from dim/negative to positive.


Assuntos
Linfócitos B/patologia , Medula Óssea/patologia , Cadeias lambda de Imunoglobulina/imunologia , Linfoma de Células B/diagnóstico , Mieloma Múltiplo/diagnóstico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Imunofenotipagem , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/imunologia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/imunologia , Prognóstico
8.
Mod Pathol ; 33(6): 1104-1121, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31896812

RESUMO

Dermatopathic lymphadenopathy is a distinctive form of paracortical lymph node hyperplasia that usually occurs in the setting of chronic dermatologic disorders. The aim of this study is to update our understanding of the clinicopathologic and immunophenotypic features of dermatopathic lymphadenopathy. The study cohort was 50 lymph node samples from 42 patients diagnosed with dermatopathic lymphadenopathy. The patients included 29 women and 13 men with a median age of 49 years (range, 12-79). Twenty-two (52%) patients had a dermatologic disorder, including mycosis fungoides (n = 6), chronic inflammatory dermatoses (n = 13), melanoma (n = 1), squamous cell carcinoma (n = 1), and Kaposi sarcoma in the context of human immunodeficiency virus infection (n = 1). Twenty (48%) patients did not have dermatologic manifestations. Lymph node biopsy specimens were axillary (n = 22), inguinal (n = 21), cervical (n = 4), and intramammary (n = 3). All lymph nodes showed paracortical areas expanded by lymphocytes; dendritic cells, including interdigitating dendritic cells and Langerhans cells; and macrophages. Melanophages were detected in 48 (98%) lymph nodes. Immunohistochemical analysis provided results that are somewhat different from those previously reported in the literature. In the paracortical areas of lymph node, S100 protein was expressed in virtually all dendritic cells, and CD1a was expressed in a significantly greater percentage of cells than langerin (80 vs. 35%, p < 0.0001). These results suggest that the paracortical regions of dermatopathic lymphadenopathy harbor at least three immunophenotypic subsets of dendritic cells: Langerhans cells (S100+, CD1a+(high), langerin+), interdigitating dendritic cells (S100+, CD1a+(low), langerin-), and a third (S100+, CD1a-, langerin-) minor population of dendritic cells. Furthermore, in more than 60% of dermatopathic lymph nodes, langerin highlighted trabecular and medullary sinuses and cords, showing a linear and reticular staining pattern, which could be a pitfall in the differential diagnosis with Langerhans cell histiocytosis involving lymph nodes.


Assuntos
Linfonodos/patologia , Linfadenopatia/patologia , Dermatopatias/patologia , Adolescente , Adulto , Idoso , Biomarcadores/metabolismo , Criança , Feminino , Humanos , Imuno-Histoquímica , Linfonodos/metabolismo , Linfadenopatia/metabolismo , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Proteínas S100/metabolismo , Dermatopatias/metabolismo , Adulto Jovem
10.
Mod Pathol ; 32(1): 16-26, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30323237

RESUMO

Rosai-Dorfman disease is a rare histiocytic disorder shown to have gene mutations that activate the MAPK/ERK pathway in at least one-third of cases. Most patients with Rosai-Dorfman disease present with bulky lymphadenopathy or extranodal disease, but rarely Rosai-Dorfman disease is detected concomitantly with lymphoma in the same biopsy specimen. The underlying molecular mechanisms of focal Rosai-Dorfman disease occurring in the setting of lymphoma have not been investigated. We report 12 cases of Rosai-Dorfman disease and lymphoma involving the same anatomic site. There were five men and seven women (age, 23 to 77 years) who underwent lymph node (n = 11) or skin (n = 1) biopsy; the lymphomas included nodular lymphocyte predominant Hodgkin lymphoma (n = 6), classical Hodgkin lymphoma (n = 4), small lymphocytic lymphoma (n = 1) and extranodal marginal zone lymphoma (n = 1). The foci of Rosai-Dorfman disease in all cases had S100 protein-positive histiocytes undergoing emperipolesis. No patients had Rosai-Dorfman disease at other anatomic sites at initial diagnosis and at last follow-up (median, 40 months). We performed immunohistochemical analysis to assess activity of the MAPK/ERK pathway in the Rosai-Dorfman disease foci. We also micro-dissected disease foci and analyzed 146 genes using next-generation sequencing in four cases with adequate DNA; the panel included genes previously reported to be mutated in Rosai-Dorfman disease. All cases were negative for gene mutations. Nevertheless, all cases were positive for cyclin D1 and most cases showed p-ERK expression indicating that the MAPK/ERK pathway is active in the histiocytes of focal Rosai-Dorfman disease. We conclude that focal Rosai-Dorfman disease coexisting with lymphoma is a clinically benign and localized histiocytic proliferation. These data also indicate that the MAPK/ERK pathway is active in focal Rosai-Dorfman disease although we did not identify activating mutations. These findings suggest that the pathogenesis of focal Rosai-Dorfman disease is different from that of usual cases of Rosai-Dorfman disease.


Assuntos
Histiocitose Sinusal/complicações , Linfoma/complicações , Sistema de Sinalização das MAP Quinases/fisiologia , Adulto , Idoso , Feminino , Histiocitose Sinusal/enzimologia , Humanos , Linfoma/enzimologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Hum Pathol ; 82: 215-231, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30086334

RESUMO

The presence of expanded proliferation centers (PCs) in lymph nodes involved by chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma has been associated with adverse clinical outcomes, but the frequency and significance of PCs in bone marrow (BM) remain unclear. The study group included 36 patients with BM involvement by CLL in which PCs were present. We compared this group with 110 randomly selected BM samples involved by CLL without morphologically discernable PCs. Patients with PCs in BM were younger (median age, 53 years [range,18-71 years] versus 58 years [range, 31-82 years]; P = .007), more frequently experienced B symptoms (27.8% versus 8.2%, P = .0076), more often had Rai stage IV disease (30.6% versus 17.3%, P = .02) and higher serum lactate dehydrogenase (P = .0037) and ß2-microglobulin (P = .0001) levels, and lower hemoglobin (P = .026) and platelet counts (P = .0422). TP53 alterations were more common in patients with PCs in BM (45.4% versus 18.7%; P = .0049), as was a complex karyotype (26.4% versus 9%; P = .019). There were no significant differences in the frequency of ZAP70 or CD38 positivity or IGHV mutation status. The median time to first treatment was shorter in patients with PCs in BM (7 months versus 19 months, P = .047), and the frequency of Richter syndrome was higher (14% versus 4%, P = .041). Patients with PCs in BM had significantly shorter overall survival compared with the control group (median, 249.3 months versus undefined; P = .0241). These data suggest that identification of PCs in BM samples involved by CLL is associated with adverse prognostic features.


Assuntos
Cariótipo Anormal , Biomarcadores Tumorais/genética , Células da Medula Óssea/patologia , Proliferação de Células , Leucemia Linfocítica Crônica de Células B/genética , Leucemia Linfocítica Crônica de Células B/patologia , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Humanos , Leucemia Linfocítica Crônica de Células B/mortalidade , Leucemia Linfocítica Crônica de Células B/terapia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto Jovem
12.
BMJ Case Rep ; 20172017 Aug 11.
Artigo em Inglês | MEDLINE | ID: mdl-28801332

RESUMO

In children with newly diagnosed acute myeloid leukaemia (AML), myeloid sarcomas (MS) of the central nervous system (CNS) are rare. Since MS involving the CNS are potentially curable, timely recognition is paramount. Establishing a diagnosis may be problematic as they can easily mimic primary CNS neoplasms. We report the case of a 5-year-old boy with AML with t(8;21)(q22;q22) rearrangement who presented with a massive intracranial MS and rapid clinical deterioration suggestive of a meningioma or a primitive neuroectodermal tumour. The peripheral smear showed blasts with Auer rods. Urgent chemotherapy was started for AML with presumptive CNS MS. The mass resolved with chemotherapy, and treatment was consolidated with radiotherapy. Although exceedingly rare, this case highlights the potential for MS to present similarly to a primary CNS tumour. MS should be part of the differential diagnosis as part of a CNS mass, particularly if the complete blood count is abnormal.


Assuntos
Neoplasias do Sistema Nervoso Central/diagnóstico , Citarabina/uso terapêutico , Daunorrubicina/uso terapêutico , Etoposídeo/uso terapêutico , Leucemia Mieloide Aguda/diagnóstico , Sarcoma Mieloide/diagnóstico , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/fisiopatologia , Pré-Escolar , Humanos , Hibridização in Situ Fluorescente , Leucemia Mieloide Aguda/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Sarcoma Mieloide/tratamento farmacológico , Sarcoma Mieloide/fisiopatologia , Resultado do Tratamento , Tirosina Quinase 3 Semelhante a fms
13.
Mod Pathol ; 30(10): 1367-1377, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28664935

RESUMO

Rosai-Dorfman disease is a histiocytic disorder with a poorly defined pathogenesis. Recent molecular studies have revealed recurrent mutations involving genes in the MAPK/ERK pathway in Langerhans cell histiocytosis and Erdheim-Chester disease. However, cases of Rosai-Dorfman disease have rarely been assessed. We performed next-generation sequencing to assess 134 genes on 21 cases of Rosai-Dorfman disease, including 13 women and 8 men with a median age of 43 years (range, 3-82). In all, 13 had extranodal, 5 had nodal, and 3 had coexistent nodal and extranodal disease. The head and neck region was the most common area involved (n=7). Mutation analysis detected point mutations in 7 (33%) cases, including KRAS (n=4) and MAP2K1 (n=3). No mutations were identified in ARAF, BRAF, PIK3CA, or any other genes assessed. Immunohistochemistry demonstrated p-ERK overexpression in 3 cases, all harboring MAP2K1 mutations. Patients carrying mutated genes were younger (median age, 10 vs 53 years, P=0.0347) with more pediatric patients (4/7 vs 1/14, P=0.0251). The presence of mutations correlated with location being more common in the head and neck region; 6/7 (86%) mutated vs 1/14 (7%) unmutated cases (P=0.0009). All 5 (100%) mutated cases with available staging information had a multifocal presentation, whereas only 3/11 (27%) unmutated patients had multifocal disease (P=0.0256). Treatment information was available in 10 patients, including radical resection (n=4), resection and radiation (n=3), and cladribine-based chemotherapy (n=3). With a median follow-up of 84 months (range, 7-352), 7 remained in clinical remission and 3 had persistent disease. No correlation between mutation status and clinical outcome was noted. In summary, we detected mutually exclusive KRAS and MAP2K1 mutations in one-third of cases of Rosai-Dorfman disease suggesting this subgroup are clonal and involve activation of MAPK/ERK pathway. Our data contribute to the understanding of the biology of Rosai-Dorfman disease and point to potential diagnostic and therapeutic targets.


Assuntos
Histiocitose Sinusal/genética , MAP Quinase Quinase 1/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Adulto Jovem
15.
Urology ; 91: e1-2, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26876464

RESUMO

We present an unusual case of basal cell carcinoma (BCC) arising from a non-sun-exposed area. The patient was 69-year-old male with an enlarging giant fungating mass protruding from his scrotum for which he did not seek medical treatment until recently. The mass did not involve the scrotum or epididymis and was confirmed on ultrasound. The patient underwent wide surgical excision and was diagnosed with BCC of the scrotum. Scrotal BCC appears to be more aggressive and more likely to metastasize compared with lesions arising from other areas of the body.


Assuntos
Carcinoma Basocelular/patologia , Neoplasias dos Genitais Masculinos/patologia , Escroto/patologia , Idoso , Humanos , Masculino
17.
Urol Case Rep ; 2(4): 126-8, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26839788

RESUMO

Paratesticular rhabdomyosarcoma (RMS) occurs more frequently in children and is rare in adults. Embryonal RMS is the most common subtype of paratesticular RMS. Spindle cell is a rare variant of embryonal RMS and is associated with a favorable prognosis in children. Data in adults is lacking. We present a case of paratesticular RMS in a 24-year-old man.

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