RESUMO
BACKGROUND: Abnormal spindle-like microcephaly-associated protein (ASPM) has been implicated in the aggressive behavior of several malignant tumors. However, its potential effects on diffuse large B-cell lymphoma (DLBCL) still remain unknown. METHODS: ASPM levels were determined by immunohistochemically in DLBCL tissues from 54 patients and 15 reactive lymphoid hyperplasia (RLH) tissues as control, and its association with clinical features and overall survival were evaluated. The effects of ASPM on cell growth, cell apoptosis and cell cycle of DLBCL cells were assessed. Bioinformatics, quantitative RT-PCR and western blotting were conducted for mechanic investigation. RESULTS: ASPM expression was upregulated in DLBCL tissues compared with RLH tissues. Its high expression was correlated with inferior clinicopathological characteristics and poor outcomes of DLBCL patients. Multivariate analysis revealed that high ASPM expression emerged as an independent factor for poor prognosis. In DLBCL cell lines, silencing of ASPM suppressed cell growth, induced cell apoptosis and arrested the cell cycle. Mechanically, effects of ASPM knockdown on DLBCL cells were partially dependent on its block of the Wnt/ß-catenin pathway. CONCLUSION: Collectively, our results suggested that ASPM potentially served as a predictive biomarker of DLCBL tumorigenesis and prognosis, representing a potential therapeutic target for DLCBL.
Assuntos
Carcinogênese/metabolismo , Proliferação de Células , Linfoma Difuso de Grandes Células B , Proteínas do Tecido Nervoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Ciclofosfamida/administração & dosagem , Progressão da Doença , Doxorrubicina/administração & dosagem , Descoberta de Drogas , Feminino , Perfilação da Expressão Gênica/métodos , Técnicas de Silenciamento de Genes/métodos , Humanos , Imuno-Histoquímica , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prednisona/administração & dosagem , Prognóstico , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Vincristina/administração & dosagem , Via de Sinalização Wnt/genéticaRESUMO
BACKGROUND: Hippo-Yes-associated protein (YAP) signaling is a key regulator of organ size and tumorigenesis, yet the underlying molecular mechanism is still poorly understood. At present, the significance of the Hippo-YAP pathway in diffuse large B-cell lymphoma (DLBCL) is ill-defined. METHODS: The expression of YAP in DLBCL was determined in public database and clinical specimens. The effects of YAP knockdown, CRISPR/Cas9-mediated YAP deletion, and YAP inhibitor treatment on cell proliferation and the cell cycle were evaluated both in vitro and in vivo. RNA sequencing was conducted to detect dysregulated RNAs in YAP-knockout DLBCL cells. The regulatory effects of insulin-like growth factor-1 receptor (IGF-1R) on Hippo-YAP signaling were explored by targeted inhibition and rescue experiments. RESULTS: High expression of YAP was significantly correlated with disease progression and poor prognosis. Knockdown of YAP expression suppressed cell proliferation and induced cell cycle arrest in DLBCL cells. Verteporfin (VP), a benzoporphyrin derivative, exerted an anti-tumor effect by regulating the expression of YAP and the downstream target genes, CTGF and CYR61. In vitro and in vivo studies revealed that deletion of YAP expression with a CRISPR/Cas9 genome editing system significantly restrained tumor growth. Moreover, downregulation of IGF-1R expression led to a remarkable decrease in YAP expression. In contrast, exposure to IGF-1 promoted YAP expression and reversed the inhibition of YAP expression induced by IGF-1R inhibitors. CONCLUSIONS: Our study highlights the critical role of YAP in the pathogenesis of DLBCL and uncovers the regulatory effect of IGF-1R on Hippo-YAP signaling, suggesting a novel therapeutic strategy for DLBCL.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/fisiologia , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas de Neoplasias/fisiologia , Proteínas Serina-Treonina Quinases/fisiologia , Receptor IGF Tipo 1/fisiologia , Transdução de Sinais/fisiologia , Fatores de Transcrição/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/deficiência , Idoso , Animais , Apoptose/efeitos dos fármacos , Linfócitos B/metabolismo , Sistemas CRISPR-Cas , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Via de Sinalização Hippo , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Linfoma Difuso de Grandes Células B/etiologia , Linfoma Difuso de Grandes Células B/patologia , Masculino , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Podofilotoxina/análogos & derivados , Podofilotoxina/farmacologia , Pseudolinfoma/metabolismo , Interferência de RNA , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/farmacologia , Distribuição Aleatória , Receptor IGF Tipo 1/antagonistas & inibidores , Receptor IGF Tipo 1/biossíntese , Receptor IGF Tipo 1/genética , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/deficiência , Tirfostinas/farmacologia , Tirfostinas/uso terapêutico , Verteporfina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas de Sinalização YAPRESUMO
Cutaneous pseudolymphomas (PSLs) belong to a group of lymphocytic infiltrates that histopathologically and/or clinically simulate lymphomas. Different causative agents (e.g., Borrelia sp., injected substances, tattoo, arthropod bite) have been described, but in many cases no cause can be identified, hence the term idiopathic PSL. Clinicopathological correlation is important to make the diagnosis. Four main groups of cutaneous PSL can be distinguished based on histopathologic and/or clinical presentation: (a) nodular PSL; (b) pseudo-mycosis fungoides (pseudo-MF) and simulators of other CTCLs; (c) other PSL (representing distinct clinical entities); and (d) intravascular PSL. This article gives an overview of the histopathologic and clinical characteristics of cutaneous PSLs and proposes a new classification.
Assuntos
Pseudolinfoma , Neoplasias Cutâneas , Borrelia/metabolismo , Infecções por Borrelia/classificação , Infecções por Borrelia/metabolismo , Infecções por Borrelia/patologia , Humanos , Pseudolinfoma/classificação , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Neoplasias Cutâneas/classificação , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Tatuagem/efeitos adversosRESUMO
Combination therapy with ipilimumab and nivolumab is an adjuvant treatment approach for metastatic melanoma that boasts increased 3-year survival when compared with a single immunotherapy agent. Combination therapy, however, is associated with increased toxicities, especially cutaneous side-effects. Here we present a patient with metastatic melanoma and a sudden eruption of painful nodules on the face and arms 10 days after the administration of the fourth dose of combination ipilimumab/nivolumab. Biopsies demonstrated lymphoid hyperplasia, not clinically or pathologically consistent with an infectious, malignant or autoimmune etiology; a diagnosis of pseudolymphoma secondary to ipilimumab/nivolumab was made. After a steroid taper, the lesions resolved, and the patient was restarted on nivolumab monotherapy 2 weeks later without recurrence of symptoms or disease.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Melanoma , Segunda Neoplasia Primária , Pseudolinfoma , Neoplasias Cutâneas , Esteroides/administração & dosagem , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Humanos , Ipilimumab/administração & dosagem , Ipilimumab/efeitos adversos , Masculino , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Melanoma/patologia , Segunda Neoplasia Primária/tratamento farmacológico , Segunda Neoplasia Primária/metabolismo , Segunda Neoplasia Primária/patologia , Nivolumabe/administração & dosagem , Nivolumabe/efeitos adversos , Pseudolinfoma/induzido quimicamente , Pseudolinfoma/tratamento farmacológico , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Melanoma Maligno CutâneoRESUMO
To describe the clinicopathological features of nine patients with acute Epstein-Barr virus (EBV)-positive cytotoxic T cell lymphoid hyperplasia (EBV+TLH) in the upper aerodigestive tract, in which initial findings led to a preliminary misdiagnosis of extranodal NK/T cell lymphoma, nasal type (ENKTL). A series of nine cases of EBV+TLH in one Chinese institution over a 9-year interval was retrospectively analyzed. Median age was 16 years (range 5-29 years) with a M:F ratio of 5:4. All patients were previously healthy with an acute onset period of < 1 month. Six patients (66%) presented with masses or polypoid protrusions in the upper aerodigestive tract. Nasopharyngeal symptoms, cervical lymphadenopathy, and fever were found in 89%, 78%, and 56% of patients, respectively. In seven cases, morphology mainly showed small-sized irregular cells and in two cases medium-to-large cells. In all cases, the cells diffusely expressed cytoplasmic CD3 and at least one marker for cytotoxic granules, but were negative for CD56. CD5 expression was detected in eight cases (8/9, 89%). In all cases, double staining for CD3 and EBER indicated that most T cells were infected with EBV. T cell receptor gene rearrangement was performed in five cases and all showed polyclonal results. All patients achieved complete remission within 1 month after diagnosis without any chemoradiotherapy and were followed up 19-124 months without recurrent disease. EBV+TLH in the upper aerodigestive tract is occasionally observed in China. The histopathologic features of EBV+TLH can mimic ENKTL. EBV+TLH should be taken into consideration as a potential diagnosis when the disease duration is short, spontaneous remission is achieved without intervention, and when histology shows infiltration with EBV-infected T lymphocytes.
Assuntos
Neoplasias de Cabeça e Pescoço/diagnóstico , Pseudolinfoma/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , China , Erros de Diagnóstico , Infecções por Vírus Epstein-Barr/imunologia , Feminino , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 4/patogenicidade , Humanos , Hiperplasia/patologia , Imunofenotipagem/métodos , Células Matadoras Naturais/patologia , Doenças Linfáticas/patologia , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pseudolinfoma/metabolismo , Pseudolinfoma/virologia , Estudos Retrospectivos , Linfócitos T/metabolismo , Linfócitos T Citotóxicos/virologiaRESUMO
PURPOSE: To explore whether lncRNA (Long non-coding RNA) H19 could promote the development of Hodgkin's lymphoma (HL) by regulating cell proliferation via AKT pathway. METHODS: H19 expressions in 60 HL tissues, 40 RH (reactive hyperplasia of lymph nodes) tissues, L428, A20 and Ly1 cell lines were evaluated by quantitative real-time polymerase chain reaction (qRT-PCR). H19 siRNA and pcDNA-H19 were constructed. Cell viability after altering H19 expression was detected by EdU and cell counting kit-8 (CCK-8) assay. The mRNA level of AKT in HL tissues and RH tissues was detected by qRT-PCR. The relationship between AKT and H19 was further detected by Western blot. RESULTS: H19 was overexpressed in HL tissues and cell lines compared with those of controls. HL patients with huge lump and in Ann Arbor stage III-IV presented higher expression of H19. Besides, H19 expression was negatively correlated to overall survival (OS) of HL patients. In vitro experiments suggested that H19 downregulation decreased proliferation and viability of HL cells. AKT expression was upregulated in HL tissues compared with RH tissues, and was positively regulated by H19. Western blot results also indicated that H19 overexpression upregulated protein expression of AKT in HL cells. CONCLUSIONS: Overexpressed lncRNA H19 promotes HL development by stimulating proliferation of HL cells via AKT pathway.
Assuntos
Biomarcadores Tumorais/metabolismo , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Doença de Hodgkin/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Pseudolinfoma/patologia , RNA Longo não Codificante/genética , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Feminino , Seguimentos , Doença de Hodgkin/genética , Doença de Hodgkin/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteínas Proto-Oncogênicas c-akt/genética , Pseudolinfoma/genética , Pseudolinfoma/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais CultivadasRESUMO
The enormous number of archived formalin-fixed paraffin-embedded (FFPE) tissues available are a valuable resource of material for research. However, the use of such tissues poses many challenges, among which is the difficulty of isolating different cell populations within the tissue. In this study, we used tissue from two types of non-Hodgkin lymphoma as a model to demonstrate a method we have established and optimized to separate FFPE samples into distinct tumor and nonmalignant populations. Using FFPE reactive tonsil sections, various approaches for antigen retrieval and labeling, and the effectiveness of flow cytometric sorting were tested. We found that, among the 11 cell surface or intracellular antigen markers investigated, CD3É, CD79A, LAT, PD-1, and PAX5 could be successfully labeled after antigen retrieval in Tris-EDTA buffer (pH 8.0) at 65 °C for 60 min, and 1.8-2.7 µg DNA per million cells could be extracted after sorting with DNA quality similar to that of tissue without staining or sorting. To test whether we could perform next-generation sequencing using a custom capture platform on sorted cells, we used three lymphoma cases with FFPE tissues which had been stored for 1 to 4 years. We demonstrated that the DNA from sorted cells was adequate for exon capture sequencing. By comparing the sequencing results between neoplastic and normal populations, somatic mutations could be clearly identified in the tumor population with variant frequencies as low as 11.7%.The corresponding normal fraction clearly helps in the analysis of somatic mutations and the exclusion of artifacts. This study provides an approach using flow cytometric sorting to separate different cellular populations in paraffin-embedded tissues and to unambiguously distinguish somatic mutations from germline variants or artifacts. This approach is also useful in enriching the tumor component in samples with heterogeneous components and low tumor content.
Assuntos
Linfócitos B/metabolismo , DNA de Neoplasias/isolamento & purificação , Linfonodos/patologia , Linfoma Folicular/genética , Linfoma de Células T/genética , Mutação , Linfócitos T/metabolismo , Linfócitos B/patologia , Bancos de Espécimes Biológicos , Biomarcadores/metabolismo , Análise Mutacional de DNA , DNA de Neoplasias/química , Éxons , Citometria de Fluxo , Sequenciamento de Nucleotídeos em Larga Escala , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Hiperplasia , Linfonodos/metabolismo , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma de Células T/metabolismo , Linfoma de Células T/patologia , Tonsila Palatina/metabolismo , Tonsila Palatina/patologia , Pseudolinfoma/genética , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Análise de Célula Única , Linfócitos T/patologiaRESUMO
BACKGROUND: Klotho, is a transmembrane protein, performs as a circulating hormone and upstream modulator of the insulin-like growth factor-1 receptor (IGF-1R), fibroblast growth factor (FGF), and Wnt signaling pathways. These pathways are involved in the development and progression of B cell lymphoma. We aimed to explore the expression pattern and functional mechanism of Klotho in diffuse large B cell lymphoma (DLBCL). METHODS: Immunohistochemistry (IHC) and western blotting were performed to detect the expression level of Klotho in DLBCL patients and cell lines. Tumor suppressive effect of Klotho was determined by both in vitro and in vivo studies. Signaling pathway activity was assessed by western blotting. RESULTS: Remarkable lower expression levels of Klotho were observed in DLBCL patients and cell lines. Enforced expression of Klotho could significantly induce cell apoptosis and inhibit tumor growth in DLBCL. Upregulation of Klotho resulted in declined activation of IGF-1R signaling, accompanied with decreased phosphorylation of its downstream targets, including AKT and ERK1/2. Moreover, xenograft model treated with either Klotho overexpression vector or recombinant human Klotho administration presented restrained tumor growth and lower Ki67 staining. CONCLUSIONS: Our findings establish that Klotho performs as a tumor suppressor and modulator of IGF-1R signaling in DLBCL. Targeting Klotho may provide novel strategies for future therapeutic intervention.
Assuntos
Glucuronidase/fisiologia , Linfoma Difuso de Grandes Células B/genética , Proteínas de Neoplasias/fisiologia , Receptor IGF Tipo 1/antagonistas & inibidores , Proteínas Supressoras de Tumor/fisiologia , Animais , Apoptose , Divisão Celular , Linhagem Celular Tumoral , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Glucuronidase/genética , Humanos , Fator de Crescimento Insulin-Like I/farmacologia , Proteínas Klotho , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Camundongos , Camundongos SCID , Proteínas de Neoplasias/antagonistas & inibidores , Pseudolinfoma/genética , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Organismos Livres de Patógenos EspecíficosRESUMO
DLBCL is the most common lymphoma subtype occurring in older populations as well as in younger HIV infected patients. The current treatment options for DLBCL are effective for most patients yet the relapse rate is high. While many biomarkers for DLBCL exist, they are not in clinical use due to low sensitivity and specificity. In addition, these biomarkers have not been studied in the HIV context. Therefore, the identification of new biomarkers for HIV negative and HIV positive DLBCL, may lead to a better understanding of the disease pathology and better therapeutic design. Protein biomarkers for DLBCL were determined using MALDI imaging mass spectrometry (IMS) and characterised using LC-MS. The expression of one of the biomarkers, heat shock protein (Hsp) 70, was confirmed on a separate cohort of samples using immunohistochemistry. The biomarkers identified in the study consisted of four protein clusters including glycolytic enzymes, ribosomal proteins, histones and collagen. These proteins could differentiate between control and tumour tissue, and the DLBCL immunohistochemical subtypes in both cohorts. The majority (41/52) of samples in the confirmation cohort were negative for Hsp70 expression. The HIV positive DLBCL cases had a higher percentage of cases expressing Hsp70 than their HIV negative counterparts. The non-GC subtype also frequently overexpressed Hsp70, confirming MALDI IMS data. The expression of Hsp70 did not correlate with survival in both the HIV negative and HIV positive cohort. This study identified potential biomarkers for HIV negative and HIV positive DLBCL from FFPE tissue sections. These may be used as diagnostic and prognostic markers complementary to current clinical management programmes for DLBCL.
Assuntos
Biomarcadores , Infecções por HIV/complicações , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/metabolismo , Proteoma , Proteômica , Diagnóstico Diferencial , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/mortalidade , Peptídeos/metabolismo , Prognóstico , Proteômica/métodos , Pseudolinfoma/complicações , Pseudolinfoma/diagnóstico , Pseudolinfoma/metabolismo , Transdução de SinaisRESUMO
BACKGROUND: The most common type of ocular lymphoma is non-Hodgkin lymphoma (NHL), categorized into two groups: indolent (slow growing) and aggressive (rapid growing). Differentiating benign reactive lymphoid hyperplasia (RLH) from malignant ocular adnexal lymphoma (OAL) is challenging. Histopathology, immunohistochemistry (IHC) and ow cytometry have been used as diagnostic tools in such cases. MATERIALS AND METHODS: In this retrospective case series, from 2002 to 2013 at Farabi Eye Center, 110 patients with ocular lymphoproliferative disease were enrolled. Prevalence, anatomical locations, mean age at diagnosis and the nal diagnosis of the disease with IHC were assessed. Comparison between previous pathologic diagnoses and results of IHC was made. Immunoglobulin light chains and B-cell and T-cell markers and other immuno-phenotyping markers including CD20, CD3, CD5, CD23, CD10, CYCLIND1 and BCL2 were evaluated to determine the most accurate diagnosis. The lymphomas were categorized based on revised European-American lymphoma (REAL) classi cation. RESULTS: Mean age±SD (years) of the patients was 55.6 ±19.3 and 61% were male. Patients with follicular lymphoma, large B-cell lymphoma or chronic lymphocytic leukemia/small cell lymphoma (CLL/SLL) tended to be older. Nine patients with previous diagnoses of low grade B-cell lymphoma were re-evaluated by IHC and the new diagnoses were as follows: extranodal marginal zone lymphoma(EMZL) (n=1), SLL(n=1), mantle cell lymphoma (MCL) (n=3), reactive lymphoid hyperplasia RLH (n=2). Two cases were excluded due to poor blocks. Flow cytometry reports in these seven patients revealed SLL with positive CD5 and CD23, MCL with positive CD5 and CyclinD1 and negative CD23, EMZL with negative CD5,CD23 and CD10. One RLH patient was negative for Kappa/Lambda and positive for CD3 and CD20 and the other was positive for all of the light chains, CD3 and CD20. Orbit (49.1%), conjunctiva (16.1%) and lacrimal glands (16.1%) were the most common sites of involvement. CONCLUSIONS: Accurate pathological classi cation of lesions is crucial to determine proper therapeutic approaches. This can be achieved through precise histologic and IHC analyses by expert pathologists.
Assuntos
Neoplasias Oculares/patologia , Linfoma/patologia , Transtornos Linfoproliferativos/patologia , Linfócitos B/metabolismo , Linfócitos B/patologia , Biomarcadores Tumorais/metabolismo , Olho/patologia , Neoplasias Oculares/metabolismo , Feminino , Humanos , Cadeias Leves de Imunoglobulina/metabolismo , Irã (Geográfico) , Linfoma/metabolismo , Transtornos Linfoproliferativos/metabolismo , Masculino , Pessoa de Meia-Idade , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Estudos Retrospectivos , Linfócitos T/metabolismo , Linfócitos T/patologia , Centros de Atenção TerciáriaAssuntos
Linfoma de Zona Marginal Tipo Células B/patologia , Neoplasias Cutâneas/patologia , Humanos , Imuno-Histoquímica , Linfoma de Zona Marginal Tipo Células B/metabolismo , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Neoplasias Cutâneas/metabolismo , Linfócitos T/metabolismo , Linfócitos T/patologiaRESUMO
OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma among adults and is characterized by heterogeneous clinical, immunophenotypic, and genetic features. Different mechanisms deregulating cell cycle and apoptosis play a role in the pathogenesis of DLBCL. Growth arrest DNA damage-inducible 45 (GADD45γ) is an important gene family involved in these mechanisms. The aims of this study are to determine the frequency of GADD45γ methylation, to evaluate the correlation between GADD45γ methylation and protein expression, and to investigate the relation between methylation status and clinicopathologic parameters in DLBCL tissues and reactive lymphoid node tissues from patients with reactive lymphoid hyperplasia. MATERIALS AND METHODS: Thirty-six tissue samples of DLBCL and 40 nonmalignant reactive lymphoid node tissues were analyzed in this study. Methylation-sensitive high-resolution melting analysis was used for the determination of GADD45γ methylation status. The GADD45γ protein expression was determined by immunohistochemistry. RESULTS: GADD45γ methylation was frequent (50.0%) in DLBCL. It was also significantly higher in advanced-stage tumors compared with early-stage (p=0.041). In contrast, unmethylated GADD45γ was associated with nodal involvement as the primary anatomical site (p=0.040). CONCLUSION: The results of this study show that, in contrast to solid tumors, the frequency of GADD45γ methylation is higher and this epigenetic alteration of GADD45γ may be associated with progression in DLBCL. In addition, nodal involvement is more likely to be present in patients with unmethylated GADD45γ.
Assuntos
Metilação de DNA , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Linfoma Difuso de Grandes Células B/patologia , Proteínas de Neoplasias/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Lactente , Peptídeos e Proteínas de Sinalização Intracelular/biossíntese , Peptídeos e Proteínas de Sinalização Intracelular/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Desnaturação de Ácido Nucleico , Especificidade de Órgãos , Regiões Promotoras Genéticas/genética , Pseudolinfoma/metabolismo , Adulto JovemRESUMO
BACKGROUND: Pseudolymphomatous folliculitis is a lymphoid proliferation that clinically and histopathologically mimics primary cutaneous extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). In this study, we assessed the diagnostic value of three immunohistochemical markers, programmed death-1 (PD-1), CD1a and S100. METHODS: We evaluated 25 cases of cutaneous lymphoid proliferations with established diagnoses, including 9 patients with pseudolymphomatous folliculitis, 11 with MALT lymphoma, and 5 with cutaneous lymphoid hyperplasia (CLH). The clinical, histopathologic and immunohistochemical characteristics were reviewed and three major characteristics assessed: (a) proportion of T cells expressing PD-1, (b) pattern of expression of CD1a by dendritic cells and (c) pattern of expression of S100 by dendritic cells. RESULTS: We found pseudolymphomatous folliculitis to have a significant increase in PD-1+ T cells compared with MALT lymphoma (p < 0.0001). The pattern of CD1a staining is also informative: MALT lymphoma is significantly more likely to demonstrate a peripheral concentration of CD1a+ dendritic cells around lymphoid nodules than pseudolymphomatous folliculitis (p < 0.0003) or CLH (p < 0.05). Pseudolymphomatous folliculitis demonstrates an interstitial distribution of CD1a+ cells more often than MALT lymphoma (p < 0.04). S100 staining was not a helpful discriminator. CONCLUSIONS: Histopathologic factors including PD-1 and CD1a staining patterns may allow for more certainty in distinguishing lymphoid hyperplasia, including pseudolymphomatous folliculitis, from MALT lymphoma.
Assuntos
Antígenos CD1/biossíntese , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Células B/metabolismo , Receptor de Morte Celular Programada 1/biossíntese , Pseudolinfoma/metabolismo , Proteínas S100/biossíntese , Dermatopatias/metabolismo , Neoplasias Cutâneas/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/biossíntese , Diagnóstico Diferencial , Feminino , Humanos , Imuno-Histoquímica , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/patologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Pseudolinfoma/diagnóstico , Pseudolinfoma/patologia , Dermatopatias/diagnóstico , Dermatopatias/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
The aim of this paper is to present the case of a child with reactive lymphoid hyperplasia of the conjunctiva, whose lesion regressed completely after oral glucocorticosteroid treatment. The final diagnosis was established on the basis of a histopathological examination combined with an immunohistochemical staining test and the exclusion of other conditions that could generate similar lesions. Because of the lack of general contraindications, methylprednisolone treatment was administered and local improvement was obtained. Reactive lymphoid hyperplasia of the conjunctiva is rarely found in children. It is important to emphasize the fact that lymphoproliferative lesions in the conjunctiva may, on the one hand, represent a lymphoma; on the other hand, they may be caused by a benign lesion-reactive lymphoid hyperplasia of the conjunctiva. Many treatment methods have been reported in the literature on the subject, but there are no clear guidelines concerning therapy in children.
Assuntos
Doenças da Túnica Conjuntiva/tratamento farmacológico , Glucocorticoides/uso terapêutico , Metilprednisolona/uso terapêutico , Pseudolinfoma/tratamento farmacológico , Adolescente , Biomarcadores/metabolismo , Doenças da Túnica Conjuntiva/diagnóstico , Doenças da Túnica Conjuntiva/metabolismo , Humanos , Técnicas Imunoenzimáticas , Masculino , Pseudolinfoma/diagnóstico , Pseudolinfoma/metabolismo , Linfócitos T/patologiaRESUMO
Acral pseudolymphomatous angiokeratoma of children (APACHE) is a disease comprised by a dense dermal infiltrate of B-lymphocytes and T-lymphocytes in which prominent blood vessels with plump endothelium are found. In the past, the lesion was interpreted as a variant of angiokeratoma, a vascular malformation, or a nevus. Currently, most authors consider it to be a type of pseudolymphoma with prominent blood vessels. The latter express CD34 and D2-40, while they lack the expression of Glut-1. The expression of Wilms tumor-1 (WT-1) by APACHE has not yet been studied. In this report, we present a case of APACHE on the right foot of a 4-year-old boy and demonstrate immunoexpression of WT-1 by the blood vessels of the lesion. We also performed serial sections and demonstrated that the WT-1+ vessels with prominent endothelium were D2-40-.
Assuntos
Angioceratoma/irrigação sanguínea , Angioceratoma/metabolismo , Pseudolinfoma/metabolismo , Neoplasias Cutâneas/irrigação sanguínea , Neoplasias Cutâneas/metabolismo , Proteínas WT1/sangue , Angioceratoma/patologia , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/patologia , Pré-Escolar , Pé/irrigação sanguínea , Pé/patologia , Humanos , Imuno-Histoquímica , Masculino , Pseudolinfoma/patologia , Neoplasias Cutâneas/patologiaRESUMO
Large lymphoid proliferations are usually regarded as synonymous with lymphomas. However, lymphoma-like lesions. (LLLs) of the cervix are amongst the exception. We report a 46-year-old woman who complained of irregular menses and was found to have superficial erosion in cervix, which on biopsy showed clusters of large atypical appearing lymphoid cells admixed with smaller reactive lymphoid cells. On immunohistochemistry, these large cells were strongly positive for CD20 and CD30 and the background cells were reactive to CD3. Based on the superficial nature of infiltrate and absence of a mass-forming lesion, a diagnosis of LLL of cervix was made. Despite a benign diagnosis, a hysterectomy was done on patient's insistence and only a focus of lymphoid cells similar to biopsy was seen on the operated specimen. Patient is free of disease on follow-up.
Assuntos
Colo do Útero/patologia , Pseudolinfoma/diagnóstico , Neoplasias do Colo do Útero/diagnóstico , Biomarcadores Tumorais/metabolismo , Colo do Útero/cirurgia , Diagnóstico Diferencial , Feminino , Humanos , Histerectomia , Técnicas Imunoenzimáticas , Pessoa de Meia-Idade , Prognóstico , Pseudolinfoma/metabolismo , Pseudolinfoma/cirurgia , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/cirurgiaRESUMO
OBJECTIVE: we aimed to investigate the mutation and expression of BRAF gene in mature T/NK cell lymphoma tissues and cell lines, explore the correlation between gene alterations and clinicopathological features and clinical outcomes of mature T/NK cell lymphoma. METHODS: Firstly, we detected common mutant sites of BRAF (locus 1 799 mutation in exon 15 and loci 463, 465 and 468 mutation in exon 11) in lymphoma Jurkat, Hut-78 and YTS cell lines, normal peripheral blood lymphocytes, different types of mature T/NK cell lymphoma and reactive hyperplasia lymph nodes by direct sequencing. Then we measured the expression of BRAF in Jurkat, Hut-78, YTS cells and normal peripheral blood lymphocytes by real time-PCR and Western-blot detection. We also used immunohistochemistry (IHC) to detect the expression of BRAF in mature T/NK cell lymphoma tissues and reactive hyperplasia lymph nodes, and to analyze the correlation between the expression of BRAF and clinocopathological features and clinical outcomes. RESULTS: We did not find common BRAF mutation in mature T/NK cell lymphoma tissues and cell lines, and the relatively expression of BRAF gene mRNA in normal peripheral blood lymphocytes, YTS, Hut-78 and Jurkat cells were 1.000, 5.207±0.013, 8.412±0.615 and 36.720±1.797, respectively, and protein expressions were 0.051±0.003, 0.102±0.013, 0.113±0.017 and 0.304±0.010, respectively, and the expression of BRAF in peripheral T cell lymphoma Jurkat cells was significantly higher than that of Hut-78, YTS cells and normal lymphocytes (P<0.05). Only 6 of 58 peripheral T cell lymphomas (10.3%) had positive BRAF expression, and were the subgroups of peripheral T cell lymphoma-unspecified type. The statistical data did not show any correlation between positive expression of BRAF and gender, age, clinical stage, location, lactate dehydrogenase in the 21 cases of peripheral T cell lymphoma-unspecified type (P<0.05), but the positive rate of BRAF in the effective treatment group (8.3%) was significantly lower than that of the invalid group (55.6%, P<0.05). CONCLUSION: The expression of BRAF gene may become a marker of malignant biological characteristics and clinical therapeutic target of peripheral T cell lymphoma.
Assuntos
Células Matadoras Naturais , Linfoma de Células T Periférico/genética , Proteínas Proto-Oncogênicas B-raf/genética , Éxons , Humanos , Imuno-Histoquímica , Linfoma de Células T Periférico/metabolismo , Linfoma de Células T Periférico/patologia , Proteínas Proto-Oncogênicas B-raf/metabolismo , Pseudolinfoma/genética , Pseudolinfoma/metabolismo , RNA Mensageiro/metabolismoRESUMO
CONTEXT: Primary cutaneous CD4⺠small/medium T-cell lymphoma is a provisional and controversial entity with a broad differential diagnosis. Despite being an uncommon lymphoma, it is a frequent diagnostic consideration in cutaneous biopsies with a dense lymphoid infiltrate because it shows overlapping features with reactive lymphoid hyperplasia (pseudolymphoma) and a variety of other primary cutaneous and systemic lymphomas. However, proper classification of this process is important for determining patient prognosis and treatment options. OBJECTIVE: To review the clinical, morphologic, immunophenotypic, and genetic features of primary cutaneous CD4⺠small/medium T-cell lymphoma and contrast those features with entities in the differential diagnosis. DATA SOURCES: Applicable literature will be reviewed with emphasis on current controversies and distinguishing characteristics. CONCLUSIONS: Although many consider primary cutaneous CD4⺠small/medium T-cell lymphoma to be indistinguishable from reactive lymphoid hyperplasia/pseudolymphoma, it can be differentiated from other primary cutaneous and systemic lymphomas. Patients with solitary lesions of primary cutaneous CD4⺠small/medium T-cell lymphoma generally have an excellent prognosis. Nevertheless, a subset of patients who have been reported to meet criteria for this lymphoma have followed a more-aggressive course; however, those patients show some differing clinical, morphologic, and immunophenotypic features.
Assuntos
Linfoma Cutâneo de Células T/diagnóstico , Neoplasias Cutâneas/diagnóstico , Pele/patologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biópsia , Antígenos CD4/metabolismo , Diagnóstico Diferencial , Regulação Neoplásica da Expressão Gênica , Humanos , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/metabolismo , Linfadenopatia Imunoblástica/patologia , Linfoma de Zona Marginal Tipo Células B/diagnóstico , Linfoma de Zona Marginal Tipo Células B/metabolismo , Linfoma de Zona Marginal Tipo Células B/patologia , Linfoma Cutâneo de Células T/metabolismo , Linfoma Cutâneo de Células T/patologia , Linfoma Cutâneo de Células T/terapia , Micose Fungoide/diagnóstico , Micose Fungoide/metabolismo , Micose Fungoide/patologia , Prognóstico , Pseudolinfoma/diagnóstico , Pseudolinfoma/metabolismo , Pseudolinfoma/patologia , Pele/metabolismo , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapiaRESUMO
Reactive immunoblastic proliferations can histologically mimic classical Hodgkin lymphoma (CHL), and show diffuse CD30 expression in large cells. The lack of expression of CD15 in a subset of CHL further complicates their separation from immunoblastic proliferations. Loss of expression of B-cell transcription factors is frequently exploited in making a diagnosis of CHL; however, the staining patterns of B-cell transcription factors in immunoblastic proliferations have not been extensively studied. Thirty-three cases of reactive immunoblastic proliferations were evaluated using a panel of immunohistochemistry for CD30, CD15, CD20, CD3, κ, λ, CD45RB, MUM1, PAX5, OCT2, and BOB.1, as well as Epstein-Barr virus (EBV)/EBV-encoded ribonucleic acid in situ hybridization. A newly developed dual-color chromogenic in situ hybridization technology for detection of κ/λ mRNAs was also used. The majority of immunoblasts expressed CD30 in 14 of 33 (42%) cases; none expressed CD15. Loss or weak expression of at least 1 transcription factor in B immunoblasts, most commonly PAX5, was noted in 24 of 29 (83%) cases. A polytypic light chain expression pattern was detected by immunohistochemistry in 14 of 22 (63.6%) cases and by dual-color chromogenic in situ hybridization in 9 of 10 (90%) cases studied. EBV-encoded ribonucleic acid was detected in 8 of 33 (24.2%) cases, 5 of which were clinically unrelated to infectious mononucleosis. We conclude that B-cell transcription factors can show loss or weak expression in a significant proportion of reactive immunoblastic proliferations, and, therefore, staining for B-cell transcription factors together with CD30 should be interpreted with caution before a diagnosis of CHL is made.
Assuntos
Linfócitos B/patologia , Diagnóstico Diferencial , Doença de Hodgkin/diagnóstico , Pseudolinfoma/diagnóstico , Fatores de Transcrição/biossíntese , Adolescente , Adulto , Idoso , Linfócitos B/metabolismo , Biomarcadores Tumorais/análise , Criança , Feminino , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Pseudolinfoma/metabolismo , Fatores de Transcrição/análise , Adulto JovemRESUMO
OBJECTIVE: To investigate the mode of presentation, cytologic features of the plasmacytoid dendritic cells (pDC), and the expression of CD123 and its significance in Kikuchi's disease. METHODS: CD123 expression was evaluated by EliVision immunohistochemical staining in formalin-fixed and paraffin-embedded tissues from 30 cases of Kikuchi's disease, 5 cases of T cell lymphoma, 10 cases of reactive lymphoid hyperplasia and 10 cases of chronic tonsillitis. RESULTS: Clusters of CD123 positive PDC were observed in Kikuchi's disease (28 of 30 cases, 93.3%) and the staining intensity was more prominent in the PDC at the periphery of the lesion and around the high endothelial venule-like vessels. CD123 showed three staining patterns: membranous (10 cases, 33.3%), cytoplasmic (10 cases, 33.3%), and membranous and cytoplasmic (8 cases, 26.7%). In the control group, CD123 showed cytoplasmic staining in reactive hyperplasia and chronic tonsillitis. Regarding the staining intensity, 12 of 28 cases (42.9%) were 3+ for CD123, 8 of 28 cases (28.6%) were 2+, and 8 of 28 cases (28.6%) were 1+. In contrast, PDC clusters with 1+ staining intensity were observed in 1 of 10 cases of reactive lymphoid hyperplasia; 2 of 10 chronic tonsillitis diseases; and much less in T cell lymphoma. CONCLUSIONS: Large cluster of PDC is detected in both proliferative and necrotizing types of Kikuchi's disease, making this a useful adjunctive diagnostic marker.