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1.
PLoS One ; 14(2): e0212813, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30802265

RESUMO

Follicular lymphoma (FL) is an indolent but largely incurable disease. Some patients suffer histological transformation to a more aggressive subtype with poorer prognosis. This study aimed to improve our understanding of the genetics underlying FL histological transformation, and to identify genetic drivers or promoters of the transformation by elucidating the differences between FL samples from patients who did and did not transform. We conducted targeted massive parallel sequencing of 22 pre-transformed FL/transformed diffuse large B-cell lymphoma pairs and 20 diagnostic samples from non-transformed FL patients. Additionally, 22 matched samples from 11 transformed FL patients (pre-transformed FL and diffuse large B-cell lymphoma) and 9 non-transformed FLs were studied for copy number variation using SNP arrays. We identified recurrently mutated genes that were enriched at transformation, most notably LRP1B, GNA13 and POU2AF1, which have roles in B-cell differentiation, GC architecture and migration. Mutations in POU2AF1 might be associated with lower levels of expression, were more frequent in transformed FLs, and seemed to be specific to transformed- compared with de novo-diffuse large B-cell lymphomas. Pre-transformed FLs carried more mutations per sample and had greater subclonal heterogeneity than non-transformed FLs. Finally, we identified four mutated genes in FL samples that differed between patients who did and did not transform: NOTCH2, DTX1, UBE2A and HIST1H1E. The presence of mutations in these genes was associated with shorter time to transformation when mutated in the FL biopsies. This information might be useful for identifying patients at higher risk of transformation.


Assuntos
Linfócitos B , Transformação Celular Neoplásica , Linfoma Folicular , Linfoma Difuso de Grandes Células B , Mutação , Proteínas de Neoplasias , Adulto , Idoso , Linfócitos B/metabolismo , Linfócitos B/patologia , Biópsia , Diferenciação Celular/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Feminino , Seguimentos , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo
2.
Hematol Oncol ; 37(2): 151-159, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30736096

RESUMO

Hormone therapy has been used for patients with estrogen receptor alpha (ERα)-positive breast cancers. Recently, some studies reported the expression of ERα on neoplastic cells from B-cell lymphomas. However, there has been only one report of ERα expression on the follicular dendritic cells (FDCs) that structurally and functionally support the microenvironment of follicular lymphomas (FLs). The objective of this study was to investigate the frequency of ERα expression on FDCs in nonneoplastic reactive lymphoid tissues and to compare the frequency of ERα expression on FDCs in the axillary lymph nodes between patients with and without antiestrogen therapy and among patients with grades 1-3 of FL. Reverse transcription-polymerase chain reaction was performed to detect ERα mRNA in FL. In nonneoplastic germinal centers (GCs) from patients with tonsillitis or reactive lymphadenitis, ERα was expressed in the light zone. ERα-positive cells strongly correlated with the width of GCs (rs  = 0.81, P < 0.01) and the CD21-positive (rs  = 0.69, P < 0.01) and CD23-positive (rs  = 0.83, P < 0.01) FDC meshwork. The axillary lymph nodes had fewer ERα-positive cells, smaller GCs, and a looser CD21- and CD23-positive FDC meshwork with hormone therapy than without hormone therapy (P < 0.01). Neoplastic follicles of G1-2 FL had more ERα-positive cells and a larger CD23+ FDC meshwork than those of G3 FL (P < 0.01). ERα mRNA was detected in both G1-2 FL and G3 FL by reverse transcription-polymerase chain reaction. In conclusion, these results suggested that antiestrogen hormone therapy may decrease the number of ERα-positive FDCs and that the responses mediated by the estrogen-ERα interaction on FDCs may differ between G1-2 FL and G3 FL.


Assuntos
Células Dendríticas Foliculares/metabolismo , Receptor alfa de Estrogênio/biossíntese , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/metabolismo , Proteínas de Neoplasias/biossíntese , Células Dendríticas Foliculares/patologia , Feminino , Humanos , Linfonodos/metabolismo , Linfonodos/patologia , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Masculino , Gradação de Tumores
4.
Medicine (Baltimore) ; 98(3): e13985, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30653103

RESUMO

RATIONALE: Considering the low incidence of colorectal follicular lymphoma (FL) and its clinical features in endoscopic views, only a few studies have described the pathological diagnosis and treatment of this disease. This study aimed to reveal the overall process of clinical diagnosis and treatment of colorectal FL by conducting a case review. PATIENT CONCERNS: A 27-year-old female presented to our department because of "severe bloody stool" lasting for more than 1 month. Her primary symptom was melena. Colonoscopy revealed widespread flat polyps with various immunophenotypes (CD10+, BCL2+, BCL6+, cyclin D1-, CD5-) in the colorectal area. DIAGNOSIS: In accordance with manifestations on positron emission tomography-computed tomography (PET/CT), the patient was diagnosed with stage IV colorectal FL. INTERVENTIONS: PET/CT reexamination after 2 courses of rituximab, cyclophosphamide, liposomal doxorubicin, vincristine sulfate, and hydroprednisone (R-CHOP) regimen and 3 courses of R-CHOP plus etoposide regimen for chemotherapy indicated a significant reduction in tumor burden. Subsequently, rituximab was administered alone in 2 treatment courses. OUTCOMES: Lesions on PET/CT disappeared after reexamination. No recurrence was observed within the 12-month follow-up period. LESSONS: Colorectal FL is a rare disease with an inert clinical course and is common in the ileocecal area. Endoscopic views show multiple polyps. Interventional treatment is usually provided after observation of clinical symptoms or during disease progression. The disease has a relatively good prognosis.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Linfoma Folicular/patologia , Melena/diagnóstico , Adulto , Assistência ao Convalescente , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Colonoscopia/métodos , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Feminino , Humanos , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/metabolismo , Melena/etiologia , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons/métodos , Doenças Raras , Rituximab/administração & dosagem , Rituximab/uso terapêutico , Resultado do Tratamento
5.
Mol Carcinog ; 58(6): 944-956, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30693983

RESUMO

Follicular lymphoma (FL) is the most common indolent B-cell non-Hodgkin lymphoma (NHL) with genetic alterations of BCL-2, KMT2B, and KMT6. FL is refractory to conventional chemotherapy and is still incurable in most patients. Thus, new drugs and/or novel combination treatment strategies are needed to further improve FL patient outcome. We investigated the efficacy of the histone deacetylase 6 (HDAC6) inhibitor A452 combined with a Bruton's tyrosine kinase (BTK) inhibitor ibrutinib on NHL and the underlying mechanisms compared with the current clinically tested HDAC6 inhibitor ACY-1215. We first showed that FL is the most sensitive to HDAC6 inhibitor. We showed that combining A452 with ibrutinib led to the synergistic inhibition of cell growth and decreased viability of FL cells, as well as increased levels of apoptosis. Similar synergistic interactions occur in chronic lymphocytic leukemia (CLL) and germinal center diffuse large B-cell lymphoma cells (DLBCL). Enhanced cell death is associated with AKT and ERK1/2 inactivation and increased DNA damage (induction of γH2A.X and reduction of pChk1/2). In addition, A452 downregulates c-Myc, an effect significantly enhanced by ibruninib. Although ACY-1215 is less potent than A452, it displays synergism with ibrutinib. Overall, our results suggest that A452 is more effective as an anticancer agent than ACY-1215 in FL. These findings suggest that a combination of HDAC6-selective inhibitor and ibrutinib is a potent therapeutic strategy for NHL including FL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desacetilase 6 de Histona/antagonistas & inibidores , Inibidores de Histona Desacetilases/farmacologia , Linfoma Folicular/metabolismo , Pirazóis/farmacologia , Pirimidinas/farmacologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sinergismo Farmacológico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Ácidos Hidroxâmicos/farmacologia , Linfoma Folicular/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo
6.
Cancer Sci ; 110(1): 443-457, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30417470

RESUMO

Despite receiving rituximab-combined chemotherapy, follicular lymphoma (FL) patients often suffer tumor recurrence and understand that the cause of relapse in FL would thus significantly ameliorate the tumor therapeutics. In the present study, we show that TRA-1-60-expressing cells are a unique population in FL, converge to the conventional stem cell marker Oct3/4 and ALDH1-positive population, and resist current B-lymphoma agents. TRA-1-60 expression was observed in scattered lymphoma cells in FL tissues only as well as in resting B-lymphocytes inside germinal centers. Retrospective comparison between recurrent and cognate primary tissues showed that the number of TRA-1-60-positive cells from rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP)-treated FL had increased relative to primary tissue, a finding corroborated by assays on different rituximab-treated FL cell lines, FL-18 and DOHH2, wherein TRA-positive cell numbers increased over 10-fold compared to the untreated sample. Concordantly, scanty TRA-1-60-positive FL-18 cells implanted s.c. into mice evinced potent tumor-initiating capacity in vivo, where tumors were 12-fold larger in volume (P = 0.0021 < 0.005) and 13-fold heavier in weight (P = 0.0015 < 0.005) compared to those xenografted from TRA-negative cells. To explain these results, gene expression profiling and qPCR analysis indicated that TRA-1-60-positive cells defined a distinct population from that of TRA-negative cells, with upregulation of multiple drug transporters and therapeutic resistance genes. Hence, TRA-1-60-expressing cells in FL are considered to be vigorously intractable against conventional therapeutic agents, which may explain its refractory recurrence.


Assuntos
Antígenos de Superfície/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Linfoma Folicular/tratamento farmacológico , Proteoglicanas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Linhagem Celular Tumoral , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos SCID , Pessoa de Meia-Idade , Estudos Retrospectivos , Transplante Heterólogo , Carga Tumoral
7.
Hum Pathol ; 85: 112-118, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30448222

RESUMO

Immunohistochemistry is not only the most important tool for pathologists to establish a final diagnosis, but it can also inform decisions regarding optimal treatment methods. However, there is no universal standard notation for expressing immunohistochemical findings. For a diagnosis of malignant lymphoma, it is important to confirm the presence or absence of MYC translocation and communicate these results to a clinical audience. However, the criteria for selecting cases for fluorescence in situ hybridization (FISH) analysis to confirm MYC translocation are ill defined. We therefore devised a notation that we termed proportion of immunoreactivity/expression for immunohistochemistry (PRIME notation) based on the cellular proportion showing different antigen-antibody reactivity in immunohistochemistry (CPAR) and used it to examine the relationship between MYC translocation and the proportion of c-MYC+ lymphoma cells. We reviewed 82 cases diagnosed as diffuse large B-cell lymphoma or diffuse large B-cell lymphoma coexisting with grade 3A to 3B follicular lymphoma. The most common notation was "+/(weak)+/-" (49/82 cases [59.8%]); cases that were CPAR positive, weakly positive, and negative for tumor cells each accounted for about one-third of the total. Unexpectedly, no MYC translocation was observed by FISH in this group. Thus, FISH is not needed even if more than half of cells are c-MYC positive by PRIME notation. This is the first report describing a correspondence between immunohistochemical findings and chromosomal abnormality, reflecting findings at the protein and gene levels, respectively.


Assuntos
Rearranjo Gênico , Linfoma Folicular/metabolismo , Linfoma Difuso de Grandes Células B/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Biomarcadores Tumorais/metabolismo , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma Folicular/genética , Linfoma Folicular/patologia , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética
8.
Hematol Oncol ; 37(1): 3-14, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30187496

RESUMO

The introduction of new therapeutic agents in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), including the new kinase inhibitor idelalisib, has changed the therapeutic landscape of these diseases. However, the use of idelalisib is associated with a peculiar profile of side effects, which require an optimization of the current approach to prophylaxis and supportive treatment. Moving from the recognition that the abovementioned issue represents an unmet need in CLL and FL, a multidisciplinary panel of experts was convened to produce a consensus document aiming to provide practical recommendations for the management of the side effects during idelalisib therapy for CLL and FL. The present publication represents a consensus document from a series of meetings held during 2017. The Panel generated clinical key questions using the criterion of clinical relevance through a Delphi process and explored 4 domains, ie, diarrhea/colitis, transaminitis, pneumonitis, and infectious complications. Using the consensus method, the Panel was able to shape recommendations which may assist hematologist to minimize adverse events and guarantee adherence to treatment in patients with CLL and FL candidate to receive idelalisib.


Assuntos
Antineoplásicos/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma Folicular/tratamento farmacológico , Purinas/efeitos adversos , Quinazolinonas/efeitos adversos , Aldeído Oxidase/metabolismo , Algoritmos , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Colite/diagnóstico , Colite/etiologia , Citocromo P-450 CYP3A/metabolismo , Diarreia/diagnóstico , Diarreia/etiologia , Gerenciamento Clínico , Interações de Medicamentos , Humanos , Leucemia Linfocítica Crônica de Células B/diagnóstico , Leucemia Linfocítica Crônica de Células B/metabolismo , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Purinas/farmacocinética , Purinas/uso terapêutico , Quinazolinonas/farmacocinética , Quinazolinonas/uso terapêutico
9.
Br J Haematol ; 184(3): 373-383, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565652

RESUMO

Long non-coding RNAs (lncRNAs) comprise a family of non-coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA-sequencing at high depth sequencing in primary FL samples ranging from grade 1-3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif-lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif-lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4-694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4-694A7.2 silencing in the WSU-FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4-694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki-67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico-biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Pontos de Checagem da Fase S do Ciclo Celular , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , RNA Longo não Codificante/genética , RNA Neoplásico/genética
10.
Hematology Am Soc Hematol Educ Program ; 2018(1): 189-193, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30504309

RESUMO

Follicular lymphoma (FL) is an incurable but treatable disease with vast treatment options. Despite the abundance of efficacious treatment modalities, there is no universally agreed upon standard approach to treatment, particularly in the relapsed/refractory setting. There is an increasing need for more robust and clinically available tools to risk-stratify patients and identify those likely to experience early relapse, which is currently recognized as the unmet need in FL. Additionally, the use of gene-expression profiling and next-generation sequencing techniques in recent years has led to a wealth of knowledge regarding the molecular drivers of lymphomagenesis. However, much of this knowledge is not currently available in the clinic to inform treatment decisions. Future studies are needed to generate clinically relevant predictive models adept at incorporating patient-specific and molecular features to inform management strategies along the entire disease continuum as treatment decisions should not be made in a vacuum with a one-size-fits-all approach. Sequencing of therapy in the management of relapsed FL should involve personalized decision-making for care plans that balance patient characteristics, preferences, and comorbidities with treatment-related factors such as efficacy, toxicity profile, and mechanisms of action to achieve a durable, quality remission.


Assuntos
Transformação Celular Neoplásica , Sequenciamento de Nucleotídeos em Larga Escala , Linfoma Folicular , Modelos Biológicos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Transformação Celular Neoplásica/patologia , Humanos , Linfoma Folicular/genética , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Recidiva
11.
Lancet Haematol ; 5(11): e543-e553, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30389036

RESUMO

BACKGROUND: Studies in patients with rheumatoid arthritis and advanced follicular lymphoma have shown that CT-P10, a rituximab biosimilar, has equivalent or non-inferior efficacy and pharmacokinetics to rituximab. We aimed to assess the therapeutic equivalence of single-agent CT-P10 and rituximab in patients with newly diagnosed low-tumour burden follicular lymphoma. METHODS: In this ongoing, randomised, double-blind, parallel-group, active-controlled, phase 3 trial, adult patients (≥18 years) with stage II-IV low-tumour-burden follicular lymphoma were randomly assigned (1:1) using an interactive web or voice response system stratified by region, stage, and age to CT-P10 or US-sourced rituximab. Patients received CT-P10 or rituximab (375 mg/m2 intravenous) on day 1 of four 7-day cycles (induction period). Patients who had disease control after the induction period continued to a maintenance period of CT-P10 or rituximab administered every 8 weeks for six cycles and, if completed, a second year of maintenance therapy of additional CT-P10 (every 8 weeks for six cycles) was offered. The study was partially unmasked after database lock (Feb 23, 2018) for all data up to 7 months (before cycle 3 of the maintenance period). The primary endpoint was the proportion of patients who achieved an overall response by 7 months in the intention-to-treat population. Efficacy equivalence was shown if the two-sided 90% CIs for the treatment difference in the proportion of responders between CT-P10 and rituximab was within the equivalence margin of 17%. This trial is registered with ClinicalTrials.gov, number NCT02260804. FINDINGS: Between Nov 9, 2015, and Jan 4, 2018, 402 patients were assessed for eligibility, of whom 258 were randomly assigned: 130 to CT-P10 and 128 to rituximab. 108 (83%) of 130 patients assigned to CT-P10 and 104 (81%) of 128 assigned to rituximab achieved an overall response by month 7 (treatment difference estimate 1·8%; 90% CI -6·43 to 10·20). Therapeutic equivalence was shown (90% CIs were within the prespecified margin of 17%). The most common grade 3 or 4 treatment-emergent adverse events were decreased neutrophil count (two grade 3 in the CT-P10 group) and neutropenia (one in each group); all other grade 3 or 4 treatment-emergent adverse events occurred in one patient each. Six (5%) of 130 patients who received CT-P10 and three (2%) of 128 who received rituximab experienced at least one treatment-emergent serious adverse event. INTERPRETATION: CT-P10 was equivalent to rituximab in terms of efficacy and was well tolerated. CT-P10 monotherapy is suggested as a new therapeutic option for patients with low-tumour-burden follicular lymphoma. FUNDING: Celltrion, Inc.


Assuntos
Anticorpos Monoclonais Murinos/farmacocinética , Anticorpos Monoclonais Murinos/uso terapêutico , Linfoma Folicular/tratamento farmacológico , Linfoma Folicular/patologia , Rituximab/uso terapêutico , Segurança , Carga Tumoral , Anticorpos Monoclonais Murinos/efeitos adversos , Anticorpos Monoclonais Murinos/farmacologia , Medicamentos Biossimilares/efeitos adversos , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/farmacologia , Medicamentos Biossimilares/uso terapêutico , Intervalo Livre de Doença , Método Duplo-Cego , Feminino , Humanos , Linfoma Folicular/metabolismo , Masculino , Pessoa de Meia-Idade , Rituximab/efeitos adversos , Rituximab/farmacocinética , Rituximab/farmacologia , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos
12.
Diagn Pathol ; 13(1): 78, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30322385

RESUMO

BACKGROUND: Transformation of follicular lymphoma most typically occurs as diffuse large B-cell lymphoma, however other forms of transformation such as classic Hodgkin lymphoma and lymphoblastic transformation can occur. Secondary malignant histiocytosis also represents a rare form of transformation, which is thought to occur due to a process of transdifferentiation whereby the lymphoma cells exhibit lineage plasticity and lose all evidence of B-cell phenotype and instead acquire the phenotype of a histiocytic neoplasm. Little is known about the underlying genetic alterations that occur during this unusual process. Comparative genetic analysis of pre- and post-transformation/transdifferentiation would be one tool by which we could better understand how this phenomenon occurs. CASE PRESENTATION: Here we report the clinical, immunophenotypic and genetic features of a rare case of secondary malignant histiocytosis, Langerhans cell-type (Langerhans cell sarcoma) arising from a previous low grade follicular lymphoma. FISH analysis confirmed the presence of IgH/BCL2 rearrangement in both the low grade follicular lymphoma (FL) and transformed Langerhans cells sarcoma (LCS) samples, demonstrating a clonal relationship. Comparative whole exome sequencing was then performed, which identified a KRAS p.G13D mutation in the LCS that was not present in the FL. CONCLUSIONS: This report highlights genetic alterations, in particular an acquired somatic KRAS mutation, that may occur during transdifferentiation, with additional significance of KRAS mutation as a possible therapeutic target in cases which otherwise would have limited treatment options.


Assuntos
Linfócitos B/patologia , Sarcoma Histiocítico/metabolismo , Células de Langerhans/patologia , Linfoma Folicular/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Sarcoma Histiocítico/patologia , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Imunofenotipagem/métodos , Hibridização in Situ Fluorescente/métodos , Sarcoma de Células de Langerhans/patologia , Linfoma Folicular/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo
13.
Semin Oncol ; 45(5-6): 291-302, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30360879

RESUMO

The molecular pathogenesis of follicular lymphoma (FL) was partially revealed 3 decades ago, with the discovery of the translocation that brings BCL2 under the influence of immunoglobulin heavy chain enhancers in a vast majority of cases. Despite the importance of this seminal observation, it has become increasingly clear that additional genetic alterations need to occur to trigger neoplastic transformation and disease progression. The evolution of FL involves developmental arrest and disruption of the normal function of one or more of epigenetic regulators including KMT2D/MLL2, EZH2, CBP/CREBBP, p300/EP300, and HIST1H1 in >95% of cases. B-cells "arrested" in germinal centers acquire dozens of additional genetic aberrations that influence key pathways controlling their physiological development including B Cell Receptor (BCR) signaling, PI3K/AKT, TLR, mTOR, NF-κB, JAK/STAT, MAPK, CD40/CD40L, chemokine, and interleukin signaling. Additionally, most cases of FL do not result from linear accumulation of genomic aberrations, but rather evolve from a common progenitor cell population by diverse evolution, creating multiple FL subclones in one patient. Moreover, one of the subclones might acquire a combination of aberrations involving genes controlling cell survival and proliferation including MDM2, CDKN2A/B, BCL6, MYC, TP53, ß2M, FOXO1, MYD88, STAT3, or miR-17-92, and this can lead to the transformation of an initially indolent FL to an aggressive lymphoma (2%-3% risk per year). The complexity of the disease is also underscored by the importance of its interactions with the microenvironment that can substantially influence disease development and prognosis. Interpreting individual aberrations in relation to their impact on normal processes, their frequency, position in the disease evolution, and the consequences of their (co)occurrence, are the basis for understanding FL pathogenesis. This is necessary for the identification of patients with risk of early progression or transformation, for the development of novel targeted therapies, and for personalized treatment approaches. In this review, we summarize recent knowledge of molecular pathways and microenvironmental components involved in FL biology, and discuss them in the context of physiological B-cell development, FL evolution, and targeted therapies.


Assuntos
Linfoma Folicular/etiologia , Linfoma Folicular/metabolismo , Animais , Biomarcadores , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma Folicular/patologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , RNA não Traduzido/genética , Receptores de Antígenos de Linfócitos B/metabolismo , Transdução de Sinais
14.
Clin Lab ; 64(7): 1311-1315, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30146835

RESUMO

BACKGROUND: Diffuse large B cell lymphoma (DLBCL) and follicular cell lymphoma (FL) synchronously occurring in the same individual is unusual. The authors describe a rare case of DLBCL coexisting with FL at diagnosis in a male patient, with intestinal and lymph node involvement. METHODS: Hematologic investigation, intestinal tumor biopsy, bone marrow examination, cytogenetic analysis, and PCR were performed. RESULTS: The patient received three courses of R-CHOP regimen chemotherapy, the mesentery lymph nodes were reduced to 2.7 x 1.4 cm compared to 5.4 x 5.0 cm at diagnosis. However, the mesentery lymph nodes were increased to 4.7 x 3.5 cm after four additional courses R-CHOP treatment. Unfortunately, the patient refused chemotherapy treatment or hematopoietic stem cell transplantation (HSCT) and was lost to follow-up. CONCLUSIONS: The presence of DLBCL coexisting with FL at diagnosis is rare and has generally been the subject of isolated case reports. Further studies are required to better understand the biological insights of the disease and to propose an optimal management strategy for this type of lymphoma.


Assuntos
Linfoma Folicular/diagnóstico , Linfoma Difuso de Grandes Células B/diagnóstico , Adulto , Antígenos CD20/análise , Antígenos CD79/análise , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Linfoma Folicular/complicações , Linfoma Folicular/metabolismo , Linfoma Difuso de Grandes Células B/complicações , Linfoma Difuso de Grandes Células B/metabolismo , Masculino , Neprilisina/análise , Proteínas Proto-Oncogênicas c-bcl-2/análise , Proteínas Proto-Oncogênicas c-bcl-6/análise
15.
J Clin Exp Hematop ; 58(3): 128-135, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30012920

RESUMO

Follicular lymphoma (FL) is genetically characterized by BCL2/IGH translocation. Some FL cases histologically transform to high-grade lymphoma, and the majority of cases transform to diffuse large B-cell lymphoma. We report herein an unusual FL case that transformed to plasmablastic lymphoma (PBL) with MYC gene rearrangement as early as 12 months after FL diagnosis. IGH/MYC translocation, the most common cytogenetic abnormality seen in de novo PBL, was also detected in the transformed tumor (double-hit lymphoma). The patient became resistant to chemotherapy and died 4 months after transformation. We speculate that the "second hit" of MYC rearrangement played a crucial role in PBL transformation (PBL-T) in this case. Highly specific three-color FISH analysis demonstrated the presence of BCL2/IGH/MYC triple fusion signals on a single chromosome as we expected, but BCL2/IGH and IGH/MYC fusion signals also coexisted in a single nucleus. The PBL-T tumor was genetically heterogeneous, despite being histologically quite homogeneous PBL. Surprisingly, three-color FISH analysis revealed that the preceding FL tumor was also genetically heterogeneous, simultaneously harboring BCL2/IGH, IGH/MYC and BCL2/IGH/MYC fusion signals (i.e. double-hit lymphoma), despite being histologically quite homogeneous FL. This suggests that MYC rearrangement played a partial role in PBL-T. Genetic instability including MYC rearrangement in the preceding FL tumor would contribute to PBL-T and poor outcome in this case. This study will broaden our understanding of the pathogenesis of high-grade transformation of FL and help improve patient outcome.


Assuntos
Rearranjo Gênico , Linfoma Folicular/genética , Proteínas de Fusão Oncogênica/genética , Linfoma Plasmablástico/genética , Proteínas Proto-Oncogênicas c-myc/genética , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica/metabolismo , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismo
16.
Blood ; 131(21): 2297-2306, 2018 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-29666116

RESUMO

The development of follicular lymphoma (FL) from a founder B cell with an upregulation of B-cell lymphoma 2 (BCL2), via the t(14;18) translocation, to a proliferating clone, poised to undergo further transformation to an aggressive lymphoma, illustrates the opportunistic Darwinian process of tumorigenesis. Protection against apoptosis allows an innocent cell to persist and divide, with dangerous accumulation of further mutational changes, commonly involving inactivation of chromatin-modifying genes. But this is not all. FL cells reflect normal B cells in relying on expression of surface immunoglobulin. In doing so, they add another supportive mechanism by exploiting the natural process of somatic hypermutation of the IGV genes. Positive selection of motifs for addition of glycan into the antigen-binding sites of virtually all cases, and the placement of unusual mannoses in those sites, reveals a posttranslational strategy to engage the microenvironment. A bridge between mannosylated surface immunoglobulin of FL cells and macrophage-expressed dendritic cell-specific ICAM-3-grabbing nonintegrin produces a persistent low-level signal that appears essential for life in the hostile germinal center. Early-stage FL therefore requires a triad of changes: protection from apoptosis, mutations in chromatin modifiers, and an ability to interact with lectin-expressing macrophages. These changes are common and persistent. Genetic/epigenetic analysis is providing important data but investigation of the posttranslational landscape is the next challenge. We have one glimpse of its operation via the influence of added glycan on the B-cell receptor of FL. The consequential interaction with environmental lectins illustrates how posttranslational modifications can be exploited by tumor cells, and could lead to new approaches to therapy.


Assuntos
Suscetibilidade a Doenças , Linfoma Folicular/etiologia , Animais , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Variação Genética , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/metabolismo , Linfoma Folicular/terapia , Gradação de Tumores , Lesões Pré-Cancerosas , Processamento de Proteína Pós-Traducional , Receptores de Antígenos de Linfócitos B/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
17.
Blood ; 132(1): 49-58, 2018 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-29666118

RESUMO

In follicular lymphoma (FL), no prognostic index has been built based solely on a cohort of patients treated with initial immunochemotherapy. There is currently a need to define parsimonious clinical models for trial stratification and to add on biomolecular factors. Here, we confirmed the validity of both the follicular lymphoma international prognostic index (FLIPI) and the FLIPI2 in the large prospective PRIMA trial cohort of 1135 patients treated with initial R-chemotherapy ± R maintenance. Furthermore, we developed a new prognostic tool comprising only 2 simple parameters (bone marrow involvement and ß2-microglobulin [ß2m]) to predict progression-free survival (PFS). The final simplified score, called the PRIMA-PI (PRIMA-prognostic index), comprised 3 risk categories: high (ß2m > 3 mg/L), low (ß2m ≤ 3 mg/L without bone marrow involvement), and intermediate (ß2m ≤ 3 mg/L with bone marrow involvement). Five-year PFS rates were 69%, 55%, and 37% in the low-, intermediate-, and high-risk groups, respectively (P < .0001). In addition, achieving event-free survival (EFS) or not at 24 months (EFS24) was a strong posttreatment prognostic parameter for subsequent overall survival, and the PRIMA-PI was correlated with EFS24. The results were confirmed in a pooled external validation cohort of 479 patients from the FL2000 LYSA trial and the University of Iowa/Mayo Clinic Lymphoma Specialized Program of Research Excellence Molecular Epidemiology Resource. Five-year EFS in the validation cohort was 77%, 57%, and 44% in the PRIMA-PI low-, intermediate-, and high-risk groups, respectively (P < .0001). The PRIMA-PI is a novel and easy-to-compute prognostic index for patients initially treated with immunochemotherapy. This could serve as a basis for building more sophisticated and integrated biomolecular scores.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imunoterapia , Linfoma Folicular , Idoso , Medula Óssea/metabolismo , Medula Óssea/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/mortalidade , Linfoma Folicular/patologia , Linfoma Folicular/terapia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/metabolismo , Taxa de Sobrevida , Microglobulina beta-2/metabolismo
18.
J Pathol Clin Res ; 4(2): 124-134, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29665320

RESUMO

Cytokine production is essential for follicular dendritic cell (FDC) maintenance and organization of germinal centres. In follicular lymphoma, FDCs are often disarrayed and may lack antigens indicative of terminal differentiation. We investigated the in situ distribution of cells producing lymphotoxin-beta (LTB), lymphotoxin-alpha (LTA), and tumour necrosis factor-alpha (TNFA) transcripts in human reactive lymph nodes and in follicular lymphomas with follicular or diffuse growth pattern. LTB was the cytokine most abundantly produced in germinal centres. LTB was present in nearly 90% of germinal centre cells whereas LTA and TNFA were detected in 30 and 50%, respectively. Moreover, the amount of LTB expressed in reactive germinal centre cells was 80-fold higher than that of LTA and 20-fold higher than that of TNFA. LTB-positive cells were more numerous in the germinal centre dark zone, whereas expression of the FDC proteins CD21, CD23, VCAM, and CXCL13 was more intense in the light zone. Tumour cells of follicular lymphomas produced less LTB than reactive germinal centre cells. The results of the in situ study were confirmed by RT-PCR; LTB was significantly more abundant in reactive lymph nodes than in follicular lymphoma, with the lowest values detected in predominantly diffuse follicular lymphoma. In neoplastic follicles, low production of LTB by tumour B cells was associated with weaker expression of CD21+/CD23+ by FDCs. Our findings detail for the first time the distribution of LTA-, LTB-, and TNFA-producing cells in human reactive germinal centres and in follicular lymphoma. They suggest the possibility that impaired tumour-cell LTB production may represent a determinant of FDC phenotype loss and for defective follicular organization in follicular lymphoma.


Assuntos
Linfoma Folicular/metabolismo , Linfotoxina-beta/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Células Dendríticas Foliculares/metabolismo , Feminino , Centro Germinativo/metabolismo , Humanos , Imuno-Histoquímica , Hibridização In Situ , Linfonodos/metabolismo , Linfoma Folicular/patologia , Linfotoxina-alfa/genética , Linfotoxina-alfa/metabolismo , Linfotoxina-beta/genética , Masculino , Pessoa de Meia-Idade , Fenótipo
20.
Expert Rev Hematol ; 11(5): 403-410, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29542329

RESUMO

INTRODUCTION: Advanced follicular lymphoma (FL) remains an incurable disease, at least with conventional therapy. Despite the long remission and disease-free periods that can be currently achieved with treatment, the disease will ultimately relapse in most of the patients. Areas covered: This article reviews the current spectrum of therapies for patients with relapsed FL in the rituximab area. It will revisit current therapies, approaches to therapeutic decision making and novel agents under investigation. Expert commentary: At present, rituximab or second generation anti-CD20 antibodies either as single agent or in combination with chemotherapy, anti-CD20 maintenance therapy and stem cell transplant remain effective treatment options for relapsed patients. A plethora of new targeted agents and novel approaches such as immunotherapy are currently under investigation,thus the landscape is rapidly evolving. In this context, therapeutic decisions for individual patients in a disease which is increasingly becoming a chronic condition require a tailored approach integrating multiple clinical parameters with particular considerations of patients' preferences and quality of life.


Assuntos
Linfoma Folicular/terapia , Rituximab/uso terapêutico , Transplante de Células-Tronco , Aloenxertos , Humanos , Linfoma Folicular/metabolismo , Linfoma Folicular/patologia , Recidiva
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