RESUMO
Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1's brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.
Assuntos
Síndrome Linfoproliferativa Autoimune , Dioxigenases , Neoplasias Hematológicas , Masculino , Humanos , Síndrome Linfoproliferativa Autoimune/diagnóstico , Síndrome Linfoproliferativa Autoimune/genética , Mutação em Linhagem Germinativa , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Mutação/genética , Fenótipo , Vitamina B 12 , Proteínas de Ligação a DNA/genética , Dioxigenases/genéticaRESUMO
Papillary dermal elastolysis is a rare acquired disease of the elastic tissue that mainly affects elderly women with a clinical presentation of small firm papules in the neck, the supraclavicular areas and the upper back. Histopathologically, it is characteristic to find a complete or almost complete absence of elastic fibers in the papillary dermis with stains such as orcein or Verhoeff-Van Gieson. We present the case of an adult female patient presenting a clinical picture of years of evolution of elastic skin-colored papules on her neck, occasionally pruritic. Two biopsies were performed. In one of them an inflammatory infiltrate affecting the hair follicles was observed, and she was diagnosed with mycosis fungoides. The other biopsy showed a total absence of elastic fibers in the papillary dermis and was diagnosed as elastolysis of the papillary dermis. In early stages of papillary dermal elastolysis, a perivascular and periadnexal lymphocytic inflammatory infiltrate has been described, as is the case described above. It is important for dermatopathologist to know this atypical but possible presentation, as it may require a differential diagnosis with other entities such as follicular mycosis fungoides.
Assuntos
Cútis Laxa , Micose Fungoide , Neoplasias Cutâneas , Adulto , Feminino , Humanos , Idoso , Tecido Elástico/patologia , Micose Fungoide/diagnóstico , Micose Fungoide/patologia , Cútis Laxa/patologia , Derme/patologia , Neoplasias Cutâneas/patologiaRESUMO
Primary effusion lymphoma (PEL), Kaposi's sarcoma (KS), and multicentric Castleman's disease (MCD) is an uncommon group of diseases included in the same spectrum with related characteristics. The coexistence of all of them in the same individual is a rare occurrence. We present the case of a 25-year-old patient diagnosed with human immunodeficiency virus (HIV) and the development of all these related pathologies. Despite the use of intensive treatment according to the latest recommendations, the evolution was unfavorable. This case reflects the need for new therapies and research in this field.
Assuntos
Infecções por HIV , Herpesvirus Humano 8 , Linfoma de Efusão Primária , Sarcoma de Kaposi , Humanos , Adulto , Sarcoma de Kaposi/complicações , Sarcoma de Kaposi/patologia , Linfoma de Efusão Primária/complicações , Linfoma de Efusão Primária/diagnóstico , Infecções por HIV/complicaçõesRESUMO
Human immunodeficiency virus (HIV) infection is known to be associated with the development of Hodgkin's lymphoma (HL). Exclusive extranodal bone marrow involvement is less common. Co-infection by other viruses, such as the Epstein-Barr virus (EBV), increases the incidence of a frequent complication denominated by hemophagocytic lymphohistocytosis (HLH). We present the case of a 50-year-old patient with the above clinical spectrum who develops several serious complications during treatment.
Assuntos
Infecções por Vírus Epstein-Barr , Infecções por HIV , Doença de Hodgkin , Linfo-Histiocitose Hemofagocítica , Humanos , Pessoa de Meia-Idade , Linfo-Histiocitose Hemofagocítica/complicações , Linfo-Histiocitose Hemofagocítica/diagnóstico , Infecções por Vírus Epstein-Barr/complicações , Doença de Hodgkin/complicações , Herpesvirus Humano 4 , Infecções por HIV/complicações , Medula Óssea/patologiaRESUMO
In situ follicular neoplasia (ISFN) is the earliest morphologically identifiable precursor of follicular lymphoma (FL). Although it is genetically less complex than FL and has low risk for progression, ISFN already harbors secondary genetic alterations, in addition to the defining t(14;18)(q32;q21) translocation. FL, in turn, frequently progresses to diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBL). By BCL2 staining of available reactive lymphoid tissue obtained at any time point in patients with aggressive B-cell lymphoma (BCL), we identified ten paired cases of ISFN and DLBCL/HGBL, including six de novo tumors and four tumors transformed from FL as an intermediate step, and investigated their clonal evolution using microdissection and next-generation sequencing. A clonal relationship between ISFN and aggressive BCL was established by immunoglobulin and/or BCL2 rearrangements and/or the demonstration of shared somatic mutations for all ten cases. Targeted sequencing revealed CREBBP, KMT2D, EZH2, TNFRSF14 and BCL2 as the genes most frequently mutated already in ISFN. Based on the distribution of private and shared mutations, two patterns of clonal evolution were evident. In most cases, the aggressive lymphoma, ISFN and, when present, FL revealed divergent evolution from a common progenitor, whereas linear evolution with sequential accumulation of mutations was less frequent. In conclusion, we demonstrate for the first time that t(14;18)+ aggressive BCL can arise from ISFN without clinically evident FL as an intermediate step and that during this progression, branched evolution is common.
Assuntos
Linfoma Folicular , Linfoma Difuso de Grandes Células B , Evolução Molecular , Centro Germinativo , Humanos , Linfoma Folicular/genética , Translocação GenéticaRESUMO
Gastric neuroendocrine tumours (NETs) arise from enterochromaffin-like cells, which are located in oxyntic glands within the stomach. Type I tumours represent 70-80% of gastric NETs and are associated with hypergastrinaemia, chronic atrophic gastritis and achlorhydria. Gastrin is involved in the endocrine regulation of gastric acid production. Most type I gastric NETs are sporadic, have a good prognosis and their genetic basis are unknown. We performed an exome sequencing study in a family with consanguineous parents and 10 children, five of whom were affected by type I gastric NET. Atypical clinical traits included an earlier age of onset (around 30 years), aggressiveness (three had nodal infiltration requiring total gastrectomy and one an adenocarcinoma) and iron-deficiency rather than megaloblastic anaemia. We identified a homozygous missense mutation in the 14th exon of the ATP4A gene (c.2107C>T), which encodes the proton pump responsible for acid secretion by gastric parietal cells. The amino acid p.Arg703Cys is highly conserved across species and originates a change of one of the transmembrane domains that avoids the liberation of protons from cells to stomach. This is consistent with the achlorhydria that was observed in the affected individuals. No germline or somatic mutations in the ATP4A gene were found in sporadic gastric NET patients. Based on the results of this large family, it seems that this atypical form of gastric NET has an earlier age of onset, behaves more aggressively and has atypical clinical traits that differentiated from other studied cases.
Assuntos
Predisposição Genética para Doença , ATPase Trocadora de Hidrogênio-Potássio/genética , Mutação de Sentido Incorreto , Tumores Neuroendócrinos/genética , Neoplasias Gástricas/genética , Adenocarcinoma/genética , Adolescente , Adulto , Idoso , Exoma , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Análise de Sequência de DNA , Adulto JovemRESUMO
Plasmablastic lymphoma is an uncommon aggressive non-Hodgkin B-cell lymphoma type defined as a high-grade large B-cell neoplasm with plasma cell phenotype. Genetic alterations in MYC have been found in a proportion (~60%) of plasmablastic lymphoma cases and lead to MYC-protein overexpression. Here, we performed a genetic and expression profile of 36 plasmablastic lymphoma cases and demonstrate that MYC overexpression is not restricted to MYC-translocated (46%) or MYC-amplified cases (11%). Furthermore, we demonstrate that recurrent somatic mutations in PRDM1 are found in 50% of plasmablastic lymphoma cases (8 of 16 cases evaluated). These mutations target critical functional domains (PR motif, proline rich domain, acidic region, and DNA-binding Zn-finger domain) involved in the regulation of different targets such as MYC. Furthermore, these mutations are found frequently in association with MYC translocations (5 out of 9, 56% of cases with MYC translocations were PRDM1-mutated), but not restricted to those cases, and lead to expression of an impaired PRDM1/Blimp1α protein. Our data suggest that PRDM1 mutations in plasmablastic lymphoma do not impair terminal B-cell differentiation, but contribute to the oncogenicity of MYC, usually disregulated by MYC translocation or MYC amplification. In conclusion, aberrant coexpression of MYC and PRDM1/Blimp1α owing to genetic changes is responsible for the phenotype of plasmablastic lymphoma cases.
Assuntos
Variação Genética , Linfoma Plasmablástico/genética , Fator 1 de Ligação ao Domínio I Regulador Positivo/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Infecções por HIV/complicações , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Linfoma Plasmablástico/complicações , Linfoma Plasmablástico/patologiaRESUMO
Screening for germline mutations in breast cancer-associated genes BRCA1 and BRCA2 is indicated for patients with breast cancer from high-risk breast cancer families and influences both treatment options and clinical management. However, only 25% of selected patients test positive for BRCA1/2 mutation, indicating that additional diagnostic biomarkers are necessary. We analyzed 124 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients with hereditary (104) and sporadic (20) invasive breast cancer, divided into two series (A and B). Microarray expression profiling of 829 human miRNAs was performed on 76 samples (Series A), and bioinformatics tool Prophet was used to develop and test a microarray classifier. Samples were stratified into a training set (n = 38) for microarray classifier generation and a test set (n = 38) for signature validation. A 35-miRNA microarray classifier was generated for the prediction of BRCA1/2 mutation status with a reported 95% (95% CI = 0.88-1.0) and 92% (95% CI: 0.84-1.0) accuracy in the training and the test set, respectively. Differential expression of 12 miRNAs between BRCA1/2 mutation carriers versus noncarriers was validated by qPCR in an independent tumor series B (n = 48). Logistic regression model based on the expression of six miRNAs (miR-142-3p, miR-505*, miR-1248, miR-181a-2*, miR-25* and miR-340*) discriminated between tumors from BRCA1/2 mutation carriers and noncarriers with 92% (95% CI: 0.84-0.99) accuracy. In conclusion, we identified miRNA expression signatures predictive of BRCA1/2 mutation status in routinely available FFPE breast tumor samples, which may be useful to complement current patient selection criteria for gene testing by identifying individuals with high likelihood of being BRCA1/2 mutation carriers.
Assuntos
Neoplasias da Mama/genética , Genes BRCA1 , Genes BRCA2 , MicroRNAs/análise , Mutação , Feminino , Formaldeído , Humanos , Modelos Logísticos , Inclusão em ParafinaRESUMO
We describe a retrospective series of B-cell lymphoproliferative disorders associated with hepatitis C virus infection. In addition to splenic marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma, all of which showed some specific features, we found two poorly described groups of cases. The first featured disseminated marginal zone lymphoma without splenic marginal zone lymphoma features, defying the current marginal zone lymphoma classification; the other consisted of monoclonal B lymphocytes in the peripheral blood, bone marrow or other tissues, with no clinical or histological evidence of lymphoma, and exhibiting a pattern that requires proper identification in order to avoid the misdiagnosis of the lymphoma. Diagnosis of hepatitis C virus infection-associated lymphoproliferative disorders requires the integration of clinical, pathological and molecular findings to establish an adequate diagnosis and decide the appropriate therapy to be applied.
Assuntos
Hepatite C/complicações , Linfoma de Células B/patologia , Linfoma de Células B/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Transtornos Linfoproliferativos/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Nodal marginal zone lymphoma (NMZL) is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed gene expression, miRNA profile, and copy number data from 15 NMZL cases. For comparison, 16 follicular lymphomas (FLs), 9 extranodal marginal zone lymphomas, and 8 reactive lymph nodes and B-cell subtypes were included. The results were validated by quantitative RT-PCR in an independent series, including 61 paraffin-embedded NMZLs. NMZL signature showed an enriched expression of gene sets identifying interleukins, integrins, CD40, PI3K, NF-κB, and TGF-ß, and included genes expressed by normal marginal zone cells and memory B cells. The most highly overexpressed genes were SYK, TACI, CD74, CD82, and CDC42EP5. Genes linked to G(2)/M and germinal center were down-regulated. Comparison of the gene expression profiles of NMZL and FL showed enriched expression of CHIT1, TGFB1, and TACI in NMZL, and BCL6, LMO2, and CD10 in FL. NMZL displayed increased expression of miR-221, miR-223, and let-7f, whereas FL strongly expressed miR-494. Our study identifies new candidate diagnostic molecules for NMZL and reveals survival pathways activated in NMZL.
Assuntos
Biomarcadores Tumorais/genética , Perfilação da Expressão Gênica , Linfoma de Zona Marginal Tipo Células B/genética , Linfoma Folicular/genética , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Feminino , Humanos , Técnicas Imunoenzimáticas , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Telomere shortening is a common event involved in malignant transformation. Critically short telomeres may trigger chromosomal aberrations and produce genomic instability leading to cancer development. Therefore, telomere shortening is a frequent molecular alteration in early stages of many epithelial tumors and in breast cancer correlates with stage and prognosis. A better understanding of the involvement of short telomeres in tumors may have a significant impact on patient management and the design of more specific treatments. To understand the role of telomere length (TL) in breast cancer etiology we measured the length of individual telomere signals in single cells by using quantitative telomere in situ hybridization in paraffin-embedded tissue from hereditary and sporadic breast cancers. A total of 104 tumor tissue samples from 75 familial breast tumors (BRCA1, n = 14; BRCA2, n = 13; non-BRCA1/2, n = 48) and 29 sporadic tumors were analyzed. Assessment of telomere signal intensity allowed estimation of the mean TL and related variables, such as percentage of critically short telomeres and percentage of cells with short telomeres. These data were correlated with the immunohistochemical expression of molecular breast cancer markers. Hereditary BRCA1, BRCA2, and non-BRCA1/2 tumors were characterized by shorter TL comparing to sporadic tumors. Considering all tumors, tumor grade was a strong risk factor determining the proportion of short telomeres or short telomere cells. Moreover, some histopathological features appeared to be differentially associated to hereditary or sporadic subgroups. Short telomeres correlated with ER-negative tumors in sporadic cases but not in familial cases, whereas a high level of apoptosis was associated with shorter telomeres in hereditary BRCA1 and BRCA2 tumors. In addition, TL helped to define a subset of non-BRCA1/2 tumors with short telomeres associated with increased expression of antiapoptotic proteins. These findings highlight the potential interest of TL measurements as markers of aggressiveness in breast cancer.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Encurtamento do Telômero , Adulto , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Mutação , Gradação de TumoresRESUMO
BACKGROUND: Follicular lymphoma is an indolent non-Hodgkin lymphoma that is most commonly diagnosed in elderly individuals. The majority of patients with follicular lymphoma present with advanced disease. Despite the recent advances in treatment, there remains a substantial unmet need for effective treatments for patients with relapsed/refractory follicular lymphoma. The PI3Kδ inhibitor idelalisib was approved by the European Medicines Agency in 2014 as a monotherapy for the treatment of adult patients with follicular lymphoma that is refractory to two prior lines of treatment. Real-world evidence from patients with follicular lymphoma treated with idelalisib indicates its utility in these patients. CASE PRESENTATION: This case report describes an 82-year-old, retired, white, female patient with refractory follicular lymphoma who achieved a partial response with idelalisib treatment. Despite experiencing two incidences of a psoriasis-like rash during idelalisib treatment that required effective management with topical steroids, the patient was able to restart treatment successfully and maintain a continued partial response. CONCLUSIONS: The clinical relevance of the effective management of adverse events in this case demonstrates the opportunity to enable patients to remain on therapy, thereby maintaining long-term response and improving overall outcomes.
Assuntos
Antineoplásicos/uso terapêutico , Exantema/induzido quimicamente , Linfoma Folicular/tratamento farmacológico , Psoríase/induzido quimicamente , Purinas/uso terapêutico , Quinazolinonas/uso terapêutico , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Relação Dose-Resposta a Droga , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Purinas/efeitos adversos , Quinazolinonas/efeitos adversosRESUMO
BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common human neoplasia, of poor prognosis and survival, which frequently displays Akt overactivation. Previously, we reported that mice expressing high levels of constitutively Akt activity (myrAkt) in oral epithelia develop lesions and tumors in the oral cavity. MATERIALS AND METHODS: Functional genomics of primary keratinocytes from different transgenic mouse lines and immunostaining of mouse and human samples were performed in order to identify and validate putative biomarkers of oral cancer progression. RESULTS: The expression of KLF4 was found to be increased only in tumor prone samples from mice bearing overactivation of Akt. Such increased expression was confirmed in oral dysplasias and tumors arising in those mice. Tissue microarray analysis of human samples confirmed the association between active Akt and increased KLF4 expression. CONCLUSION: These data support the notion that KLF4 is potentially a reliable marker of HNSCC, and that myrAkt transgenic mice are valuable tools for preclinical research of HNSCC.
Assuntos
Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Mucosa Bucal/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Western Blotting , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Fator 4 Semelhante a Kruppel , Fatores de Transcrição Kruppel-Like/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Mucosa Bucal/patologia , Proteínas Proto-Oncogênicas c-akt/genética , RNA Mensageiro/metabolismo , Análise Serial de Tecidos , Regulação para CimaAssuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Brentuximab Vedotin , Desoxicitidina , Gencitabina , Micose Fungoide , Neoplasias Cutâneas , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Brentuximab Vedotin/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Injeções Intralesionais , Micose Fungoide/tratamento farmacológico , Micose Fungoide/patologia , Estadiamento de Neoplasias , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Resultado do TratamentoRESUMO
PURPOSE: Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase overexpressed in a variety of human malignancies, against which targeted therapies have shown efficacy in lung and brain tumors. Clinical responses to EGFR inhibitors have been found to be highly dependent on the presence of activating mutations, whereas gene amplification, downstream activation of Akt, and abnormalities in PTEN are also reported predictive factors. We sought to evaluate these variables in pediatric renal tumors. EXPERIMENTAL DESIGN: We screened a series of 307 pediatric renal tumors for EGFR expression by immunohistochemistry and gene amplification by chromogenic in situ hybridization. In identifying a striking predilection for certain tumor types, we further analyzed the clear cell sarcomas of the kidney (CCSK) for mutations in EGFR and PTEN. RESULTS: Although only 23 of 177 (13.0%) nonanaplastic Wilms' tumors were EGFR positive, 4 of 11 (36.4%) anaplastic tumors showed receptor overexpression. In addition, 5 of 9 (55.6%) mesoblastic nephromas and 12 of 12 (100%) CCSKs were strongly immunoreactive for EGFR. In studying the CCSKs in more detail, we identified gene amplification in 1 of 12 (8.3%) cases and a somatic T790M EGFR mutation in a further case. These two samples additionally harbored mutations in PTEN. Downstream pathway activation, as assayed by phosphorylated Akt expression, was observed in 8 of 12 (66.7%) cases. CONCLUSIONS: Together, these data show dysregulation of the EGFR pathway at multiple levels in CCSKs. Identification of factors predictive of poor response to targeted therapy, including the drug resistance T790M mutation, may provide a rationale for upfront trials with irreversible inhibitors of EGFR in children with these tumors.
Assuntos
Receptores ErbB/metabolismo , Neoplasias Renais/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Sarcoma de Células Claras/metabolismo , Transdução de Sinais , Pré-Escolar , Amplificação de Genes , Humanos , Técnicas Imunoenzimáticas , Hibridização In Situ , Lactente , Neoplasias Renais/patologia , Mutação , Nefroma Mesoblástico/metabolismo , Nefroma Mesoblástico/patologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Tumor Rabdoide/metabolismo , Tumor Rabdoide/patologia , Sarcoma de Células Claras/patologia , Análise Serial de Tecidos , Tumor de Wilms/metabolismo , Tumor de Wilms/patologiaRESUMO
The vaccinia-related kinase (VRK) proteins are a new family with three members in the human kinome. The VRK1 protein phosphorylates several transcription factors and has been postulated to be involved in regulation of cell proliferation. In normal squamous epithelium, VRK1 is expressed in the proliferation area. Because VRK1 can stabilize p53, the expression of the VRK1 protein was analyzed in the context of the p53 pathway and the proliferation phenotype in a series of 73 head and neck squamous cell carcinomas. VRK1 protein level positively correlated with p53 response proteins, particularly hdm2 and p21. The VRK1 protein also correlated positively with several proteins associated with proliferation, such as cyclin-dependent kinase 2 (CDK2), CDK6, cdc2, cyclins B1 and A, topoisomerase II, survivin, and Ki67. The level of VRK1 protein behaves like a proliferation marker in this series of head and neck squamous cell carcinomas. To identify a possible regulatory role for VRK1 and because it regulates gene transcription, the promoters of two genes were studied, CDK2 and SURVIVIN, whose proteins correlated positively with VRK1. VRK1 increases the activity of both the CDK2 and SURVIVIN gene promoters. The expression of VRK1 was analyzed in the context of regulators of the G1-S transition. VRK1 protein levels increase in response to E2F1 and are reduced by retinoblastoma and p16. These data suggest that VRK1 might play a role in cell cycle regulation and is likely to represent the beginning of a new control mechanism of cell cycle, particularly late in the G1-S phase.
Assuntos
Carcinoma de Células Escamosas/patologia , Quinase 2 Dependente de Ciclina/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/patologia , Proteínas Associadas aos Microtúbulos/genética , Proteínas de Neoplasias/genética , Proteínas/metabolismo , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Fator de Transcrição E2F1/metabolismo , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/genética , Humanos , Imuno-Histoquímica , Proteínas Inibidoras de Apoptose , Peptídeos e Proteínas de Sinalização Intracelular , Fenótipo , Regiões Promotoras Genéticas , Proteínas Serina-Treonina Quinases , Proteínas/análise , Transdução de Sinais , Survivina , Proteína Supressora de Tumor p53/metabolismoRESUMO
BACKGROUND: The uveitis masquerade syndromes (UMS) are a group of ocular diseases that may mimic chronic intraocular inflammation. Many malignant entities such as non-Hodgkin's lymphomas may masquerade as uveitis. We report a case of an HIV-positive patient with masquerade syndrome presenting unilateral uveitis. CASE REPORT: 45-year-old Caucasian man with a diagnosis of diffuse large B-cell lymphoma (DLBCL). The patient was diagnosed by a biopsy of an abdominal mass which showed fragments of gastric mucosa with diffuse growth of neoplastic cells. At diagnosis, the patient suffered from unilateral blurring of vision and a sudden decrease of left-eye visual acuity. A slit-lamp examination of the left eye revealed a diagnosis of anterior uveitis. The patient exhibited no signs of posterior uveitis. An anterior-chamber paracentesis was performed and analyzed by multiparameter flow cytometry (MFC), showing cells CD45, CD19, CD20, CD22, and CD38 positives, and moderate expression of CD10 with kappa light chain restriction, showing a monoclonal B-cell population. The patient received CHOP-R with intrathecal methotrexate followed by consolidation high dose methotrexate obtaining a complete response which is ongoing. CONCLUSION: Differential diagnosis between chronic uveitis and ocular lymphoma may be challenging. We advocate anterior-chamber paracentesis in cases of refractory uveitis in patients with hematologic malignancies. © 2016 International Clinical Cytometry Society.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doxorrubicina/análogos & derivados , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Metotrexato/uso terapêutico , Uveíte/diagnóstico , Antígenos CD/genética , Antígenos CD/imunologia , Humor Aquoso/efeitos dos fármacos , Humor Aquoso/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/patologia , Biomarcadores/metabolismo , Ciclofosfamida/uso terapêutico , Diagnóstico Diferencial , Doxorrubicina/uso terapêutico , Citometria de Fluxo/métodos , Expressão Gênica , Humanos , Inflamação , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Paracentese , Prednisona/uso terapêutico , Resultado do Tratamento , Úvea/efeitos dos fármacos , Úvea/imunologia , Úvea/patologia , Uveíte/tratamento farmacológico , Uveíte/imunologia , Uveíte/patologia , Vincristina/uso terapêuticoRESUMO
NK/T-cell lymphomas are a group of clonal proliferations of NK- or, rarely, T-cell types and have peculiar clinicopathologic features. Most common site of involvement is the upper aerodigestive tract (nasal cavity, nasopharynx, paranasal sinuses, and palate). Association of autoimmune paraneoplastic disorders with NK/T-cell lymphomas is not well studied. Our patient was diagnosed with NK/T-cell lymphoma stage IV with skin involvement and treated frontline with CHOEP regimen. While he was under treatment, two immune complications presented: anterior uveitis of autoimmune origin refractory to steroids and myositis in lower limbs muscles. Autologous transplantation was rejected due to confirmed early relapse after first-line treatment, and the patient received second-line treatment according to the SMILE scheme, reaching complete response after four cycles. The patient underwent allogeneic transplantation and at the time of manuscript preparation is alive despite multiple complications. The disease should be suspected in patients with rhinitis or recurrent sinusitis, and early biopsy is recommended for all patients to avoid a delay in diagnosis. Our patient also presented symptoms of disease progression after first-line treatment, representing a paraneoplastic process, a very rare phenomenon in T-type lymphomas. This case is novel for the appearance of an inflammatory myositis, a histologically verified paraneoplastic phenomenon that responded to treatment for lymphoma.