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1.
Int J Cancer ; 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-32212266

RESUMO

In humans, histiocytic sarcoma (HS) is an aggressive cancer involving histiocytes. Its rarity and heterogeneity explain that treatment remains a challenge. Sharing high clinical and histopathological similarities with human HS, the canine HS is conversely frequent in specific breeds and thus constitutes a unique spontaneous model for human HS to decipher the genetic bases and to explore therapeutic options. We identified sequence alterations in the MAPK pathway in at least 63.9% (71/111) of HS cases with mutually exclusive BRAF (0.9%; 1/111), KRAS (7.2%; 8/111) and PTPN11 (56.75%; 63/111) mutations concentrated at hotspots common to human cancers. Recurrent PTPN11 mutations are associated to visceral disseminated HS subtype in dogs, the most aggressive clinical presentation. We then identified PTPN11 mutations in 3/19 (15.7%) human HS patients. Thus, we propose PTPN11 mutations as key events for a specific subset of human and canine HS: the visceral disseminated form. Finally, by testing drugs targeting the MAPK pathway in eight canine HS cell lines, we identified a better anti-proliferation activity of MEK inhibitors than PTPN11 inhibitors in canine HS neoplastic cells. In combination, these results illustrate the relevance of naturally affected dogs in deciphering genetic mechanisms and selecting efficient targeted therapies for such rare and aggressive cancers in humans.

2.
Br J Haematol ; 188(3): 413-423, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31468517

RESUMO

The prognostic value of cell of origin (COO) classification and BCL2 expression is not well established in diffuse large B-cell lymphoma (DLBCL) patients with human immunodeficiency virus (HIV) infection in the recent era. Phenotypic patterns were determined by immunohistochemistry (IHC) of pathological samples from patients with HIV-associated DLBCL prospectively enrolled in the French AIDS and Viral Hepatitis CO16 Lymphovir cohort between 2008 and 2015. Molecular subgroup classification into germinal centre B-cell (GCB) and non-GCB subtypes was determined using the Hans algorithm. Among 52 samples of systemic DLBCL subjected to centralized pathological analysis, 25 of the 42 tested for BCL2 expression were positive. Samples were further classified into GCB (n = 19) and non-GCB (n = 16) subtypes and 17 remained unclassified. In multivariable analysis, BCL2 expression was an independent pejorative prognostic biomarker [4-year progression-free survival (PFS): 52% for BCL2+ vs. 88% for BCL2- , P = 0·02] and tended to reduce 4-year overall survival (OS) (63% for BCL2+ vs. 88% for BCL2- , P = 0·06). The difference between CGB and non-GCB subtypes on PFS and OS did not reach significance (4-year PFS: 79% for GCB vs. 53% for non-GCB, P = 0·24 and 4-year OS: 78% for GCB vs. 69% for non-GCB, P = 0·34). BCL2 expression determined by IHC is an independent pejorative prognostic biomarker in HIV-associated DLBCL in the recent era. This supports the investigation of new therapeutic strategies in patients with BCL2 expression.

4.
Biomark Res ; 7: 28, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31827799

RESUMO

Background: Immunotherapy is currently under investigation in B3 Thymoma (TB3) and Thymic Carcinoma (TC). PD-L1 expression has been evaluated on a limited number of patients with selected antibodies. We aimed to analyze cohort of TB3 and TC with a panel of antibodies to assess the prevalence of PD-L1 expression, its prognostic value and to set up a reproducible test. Methods: We retrospectively studied 103 patients samples of FFPE histologically confirmed TB3 (n = 53) and TC (n = 50) by expert pathologists within the RYTHMIC national network. We compared PD-L1, PD1, CD8 and PD-L2 expression and performed correlation with tumor types and patients outcomes. Four PD-L1 antibodies were tested, three of them validated as companion tests in lung cancer, one tested on two automates on whole section of tumors. We evaluated the percentage and intensity of both epithelial and immune stained cells. Results: TB3 epithelial cells had a higher and more diffuse expression of PD-L1 than TC regardless the antibodies tested (p < 0.0001). Three out of four antibodies targeting PD-L1 tested on the DAKO autostainer gave similar staining. Concordance between antibodies was lower for PD-L1 staining on immune cells with no significant difference between TB3 and TC except on E1L3N antibody. PD-L2 antibody stained no tumor epithelial cells. High PD-L1 expression was correlated with a better overall survival for TB3 and was not correlated with tumor staging. Conclusion: Frequent PD-L1 expression, particularly in TB3, paves the way for immunotherapy in TET (Thymic Epithelial Tumor). Otherwise, we have set up three reproducible LDT (laboratory-developed test) for four PD-L1 antibodies.

5.
Blood ; 134(26): 2383-2387, 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31697834

RESUMO

The major weakness of most knock-in JAK2V617F mouse models is the presence of the JAK2 mutation in all rather than in a few hematopoietic stem cells (HSC), such as in human "early-stage" myeloproliferative neoplasms (MPN). Understanding the mechanisms of disease initiation is critical as underscored by the incidence of clonal hematopoiesis of indeterminate potential associated with JAK2V617F. Currently, such studies require competitive transplantation. Here, we report a mouse model obtained by crossing JAK2V617F/WT knock-in mice with PF4iCre transgenic mice. As expected, PF4iCre;JAK2V617F/WT mice developed an early thrombocytosis resulting from the expression of JAK2V617F in the megakaryocytes. However, these mice then developed a polycythemia vera-like phenotype at 10 weeks of age. Using mT/mG reporter mice, we demonstrated that Cre recombination was present in all hematopoietic compartments, including in a low number of HSC. The frequency of mutated cells increased along hematopoietic differentiation mimicking the clonal expansion observed in essential thrombocythemia and polycythemia vera patients. This model thus mimics the HSC compartment observed in early-stage MPN, with a small number of JAK2V617F HSC competing with a majority of JAK2WT HSC. PF4iCre;JAK2V617F/WT mice are a promising tool to investigate the mechanisms that regulate clonal dominance and progression to myelofibrosis.

6.
Haematologica ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31488561

RESUMO

Peripheral T-cell lymphoma comprises a heterogeneous group of mature non-Hodgkin lymphomas. Their diagnosis is challenging, with up to 30% of cases remaining unclassifiable and referred to as "not otherwise specified". We developed a reverse transcriptase-multiplex ligation-dependent probe amplification gene expression profiling assay to differentiate the main T-cell lymphoma entities and to study the heterogeneity of the "not specified" category. The test evaluates the expression of 20 genes, including 17 markers relevant to T-cell immunology and lymphoma biopathology, one EBV-related transcript, and variants of RHOA (G17V) and IDH2 (R172K/T). By unsupervised hierarchical clustering, our assay accurately identified 21/21 ALK-positive anaplastic large cell lymphomas, 16/16 extranodal NK/T-cell lymphomas, 6/6 hepatosplenic T-cell lymphomas, and 13/13 adult T-cell leukemia/lymphomas. ALK-negative anaplastic lymphomas (n=34) segregated into one cytotoxic cluster (n=10) and one non-cytotoxic cluster expressing Th2 markers (n=24) and enriched in DUSP22-rearranged cases. The 63 TFH-derived lymphomas divided in two subgroups according to a predominant TFH (n=50) or an enrichment in Th2 (n=13) signatures. We next developed a support vector machine predictor which attributed a molecular class to 27/77 not specified T-cell lymphomas: 17 TFH, 5 cytotoxic ALK-negative anaplastic, and 5 NK/T-cell lymphomas. Among the remaining cases, we identified two cell-of-origin subgroups corresponding to cytotoxic/Th1 (n=19) and Th2 (n=24) signatures. A reproducibility test on 40 cases yielded a 90% concordance between 3 independent laboratories. This study demonstrates the applicability of a simple gene expression assay for the classification of peripheral T-cell lymphomas. Its applicability to routinely-fixed samples makes it an attractive adjunct in diagnostic practice.

8.
Eur J Haematol ; 103(1): 35-42, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30985955

RESUMO

OBJECTIVE: Angioimmunoblastic T-cell lymphoma (AITL) is frequently associated with autoimmune cytopenia (AIC). Whether such patients have a particular phenotype and require particular management is unclear. METHOD: Angioimmunoblastic T-cell lymphoma patients from the multicentric database of the Lymphoma Study Association presenting with AIC during disease course were included and matched to AITL patients without AIC (1/5 ratio). RESULTS: At diagnosis, AIC patients (n = 28) had more spleen and bone marrow involvement (54% vs 19% and 71% vs 34%, P < 0.001), Epstein-Barr virus replication (89% vs 39%, P < 0.001), gamma globulin titers (median 23 vs 15 g/L, P = 0.002), and proliferating B cells and plasmablasts in biopsies, as compared to control patients (n = 136). The 28 AIC patients had 41 episodes of AIC, diagnosed concomitantly with AITL in 23 (82%) cases. After a median follow-up of 24 months (range 3-155), 10 patients relapsed, all associated with AITL relapse. CONCLUSION: Our results provide new insight into AIC associated with AITL by highlighting the significant interplay between AITL and B-cell activation leading to subsequent autoimmunity.


Assuntos
Doenças Autoimunes/complicações , Linfadenopatia Imunoblástica/diagnóstico , Linfadenopatia Imunoblástica/terapia , Linfoma de Células T/diagnóstico , Linfoma de Células T/terapia , Pancitopenia/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças Autoimunes/diagnóstico , Biópsia , Gerenciamento Clínico , Suscetibilidade a Doenças , Feminino , Humanos , Linfadenopatia Imunoblástica/etiologia , Linfadenopatia Imunoblástica/mortalidade , Imunoglobulinas Intravenosas/uso terapêutico , Linfoma de Células T/etiologia , Linfoma de Células T/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pancitopenia/diagnóstico , Fenótipo , Estudos Retrospectivos , Avaliação de Sintomas , Resultado do Tratamento
10.
Front Immunol ; 10: 523, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30967864

RESUMO

The association of immune thrombocytopenia (ITP) with cancer has been reported, but the causality of tumor cells in paraneoplastic ITP pathogenesis and maintenance has never been established. We analyzed the unusual case of refractory ITP and coincident urothelial tumor of the kidney with circulating high titer anti-GPIIBIIIA autoantibodies. Intriguingly, after nephrectomy, the patient recovered fully and her anti-GPIIBIIIA autoantibodies disappeared. Proteomic and immunohistochemistry analyses revealed erratic GPIIB expression by the tumor cells, suggesting possible antigenic mimicry chronically stimulating the immune system and leading to this patient's refractory ITP. Such previously unreported findings provide proof-of-concept that requires further confirmation with the prospective study of a larger number of patients.

11.
J Thromb Haemost ; 17(5): 827-840, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801958

RESUMO

Essentials To reliably study the respective roles of blood and endothelial cells in hemostasis, mouse models with a strong and specific endothelial expression of the Cre recombinase are needed. Using mT/mG reporter mice and conditional JAK2V617F/WT mice, we compared Pdgfb-iCreERT2 and Cdh5(PAC)-CreERT2 with well-characterized Tie2-Cre mice. Comparison of recombination efficiency and specificity towards blood lineage reveals major differences between endothelial transgenic mice. Cre-mediated recombination occurs in a small number of adult hematopoietic stem cells in Pdgfb-iCreERT2;JAK2V617F/WT transgenic mice. SUMMARY: Background The vessel wall, and particularly blood endothelial cells (BECs), are intensively studied to better understand hemostasis and target thrombosis. To understand the specific role of BECs, it is important to have mouse models that allow specific and homogeneous expression of genes of interest in all BEC beds without concomitant expression in blood cells. Inducible Pdgfb-iCreERT2 and Cdh5(PAC)-CreERT2 transgenic mice are widely used for BEC targeting. However, issues remain in terms of recombination efficiency and specificity regarding hematopoietic cells. Objectives To determine which mouse model to choose when strong expression of a transgene is required in adult BECs from various organs, without concomitant expression in hematopoietic cells. Methods Using mT/mG reporter mice to measure recombination efficiency and conditional JAK2V617F/ WT mice to assess specificity regarding hematopoietic cells, we compared Pdgfb-iCreERT2 and Cdh5(PAC)-CreERT2 with well-characterized Tie2-Cre mice. Results Adult Cdh5(PAC)-CreERT2 mice are endothelial specific but require a dose of 10 mg of tamoxifen to allow constant Cre expression. Pdgfb-iCreERT2 mice injected with 5 mg of tamoxifen are appropriate for most endothelial research fields except liver studies, as hepatic sinusoid ECs are not recombined. Surprisingly, 2 months after induction of Cre-mediated recombination, all Pdgfb-iCreERT2;JAK2V617F/ WT mice developed a myeloproliferative neoplasm that is related to the presence of JAK2V617F in hematopoietic cells, showing for the first time that Cre-mediated recombination occurs in a small number of adult hematopoietic stem cells in Pdgfb-iCreERT2 transgenic mice. Conclusion This study provides useful guidelines for choosing the best mouse line to study the role of BECs in hemostasis and thrombosis.

12.
Histopathology ; 74(7): 1067-1080, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30715765

RESUMO

AIMS: We applied the 2017 World Health Organization (WHO) classification criteria to categorise a series of 64 primary cutaneous large B-cell lymphomas (PCLBCLs), containing a majority (≥80%) of large cells and a proliferative rate of ≥40%, raising the problem of the differential diagnosis between PCLBCL, leg type (PCLBCL-LT) and primary cutaneous follicle centre lymphoma, large cell (PCFCL-LC). The aims were to determine the reproducibility and prognostic relevance of the 2017 WHO criteria. METHODS AND RESULTS: Morphology and phenotype identified 32 PCLBCLs-LT and 25 PCFCLs-LC; seven cases (11%) remained unclassified. Morphology was less reproducible than immunophenotype. Pertinent markers for the differential diagnosis were MUM1, FOXP1, CD10, and IgM. bcl-2 and bcl-6 were expressed by both PCFCLs-LC and PCLBCLs-LT at substantial levels. Neither Ki67 expression nor p63 expression was of diagnostic value. MYD88 was found to be mutated only in PCLBCLs-LT (n = 22, 69%). According to Hans/Hans modified algorithms, 23 of 25 PCFCLs-LC had germinal centre (GC) status, and the 32 PCLBCLs-LT had non-GC status. Overall survival was poorer for PCLBCLs-LT than PCFCLs-LC (P = 0.0002). Non-GC cases had poorer overall survival than GC cases (P = 0.0007). In PCLBCLs-LT, MYC expression was associated with cutaneous relapses (P = 0.014). When GC/non-GC status was applied to unclassified cases, only a single case remained discordant. CONCLUSIONS: Our results support the 2017 WHO classification criteria for PCLBCL diagnosis. The Hans modified algorithm using CD10 and MUM1 distinguished PCFCLs-LC from PCLBCLs-LT with optimal diagnostic value without requiring bcl-6 immunolabelling (poorly reproducible). Rare unclassified cases may constitute a provisionally heterogeneous subgroup for which GC/non-GC status (relevant for prognosis) may guide therapeutic decisions.


Assuntos
Biomarcadores Tumorais/análise , Linfoma de Células B/classificação , Linfoma Folicular/classificação , Neoplasias Cutâneas/classificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Feminino , Centro Germinativo/patologia , Humanos , Imunofenotipagem , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma Folicular/diagnóstico , Linfoma Folicular/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Reprodutibilidade dos Testes , Pele/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Organização Mundial da Saúde
13.
Pediatr Blood Cancer ; 66(5): e27571, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30637917

RESUMO

BACKGROUND: Although a prognosis of recurrent or refractory childhood Hodgkin lymphoma (HL) is associated with poor outcomes despite intensive therapy, the immune checkpoint inhibitors PD-1/PD-L1 appear to be therapeutic alternatives for advanced adult cases. However, these pharmacotherapies are yet to be studied in a pediatric population. PROCEDURE: The present study measured the expression of PD-1/PD-L1 in diagnostic samples of children with classical HL, according to the disease course. This study included two groups of patients treated at the Department of Pediatric Oncology, Bordeaux University Hospital-a group of cured or in-remission cases and a group of relapsed or refractory cases. Immunohistochemical analyses of anti-PD-1 and anti-PD-L1 (clone 28-8, companion test for nivolumab) were performed on baseline and follow-up biopsies. RESULTS: Of the 42 included patients, 31 were cured or in remission and 11 were categorized as relapsed or refractory. At the time of diagnosis, PD-1 expression was low (1-3% of intratumoral lymphocytes labeled) in <20% of cases, whereas PD-L1 was expressed by tumor cells in all cases, and strongly (≥50%) in most cases. There were no significant differences in the expression levels of the two checkpoint molecules between the groups. Initial biopsies showed strong expression of PD-L1, whereas expression of PD-1 was rare. CONCLUSIONS: The identical labeling profiles of the cured and relapsed/refractory patients suggest that comparable responses to inhibitors of the PD1/PDL1 immunological checkpoints could be expected in patients undergoing first-, second-, or third-line therapy.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Doença de Hodgkin/metabolismo , Imunoterapia , Recidiva Local de Neoplasia/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/patologia , Humanos , Masculino , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Prognóstico , Indução de Remissão
14.
Am J Surg Pathol ; 43(3): 341-351, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30540571

RESUMO

Gray-zone lymphoma (GZL) with features intermediate between classic Hodgkin lymphoma (cHL) and large B-cell lymphoma (LBCL) was introduced as a provisional entity into the World Health Organization classification in 2008. However, as diagnostic criteria are imprecise, reliable identification of GZL cases remains challenging. Here, we describe the histopathologic features of 139 GZL cases from a retrospective Lymphoma Study Association (LYSA) study with the goal to improve classification accuracy. Inclusion criteria were based on literature review and an expert consensus opinion of the LYSA hematopathologist panel. We observed 86 cases with a morphology more closely related to cHL, but with an LBCL immunophenotype based on strong and homogenous B-cell marker expression (CD20 and/or CD79a, OCT2, BOB1, PAX5) on all tumor cells (cHL-like GZL). Fifty-three cases were morphologically more closely related to LBCL but harbored a cHL immunophenotype (LBCL-like GZL). Importantly, we observed a continuous morphologic and immunophenotypic spectrum within these 2 GZL categories. The majority of cases presented genetic immune escape features with CD274/PDCD1LG2 and/or CIITA structural variants by fluorescence in situ hybridization. Patients without mediastinal involvement at diagnosis (17%) were older than those with mediastinal tumors (median: 56 vs. 39 y). Cases associated with Epstein-Barr virus (24%) presented with similar patient characteristics and outcome as Epstein-Barr virus negative cases. In summary, we provide refined diagnostic criteria that contribute to a more precise pathologic and clinical characterization of GZL within a broad spectrum from cHL-like to LBCL-like disease.


Assuntos
Linfoma/classificação , Linfoma/patologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
16.
Ann Pathol ; 39(1): 29-35, 2019 Feb.
Artigo em Francês | MEDLINE | ID: mdl-30554835

RESUMO

Herein we report the case of a 41-year-old woman who presented with pelvic pain. Magnetic Resonance Imaging exhibited a single pelvic mass, measuring 50mm long axis, alongside the right iliac vessels. Histological examination of the excision specimen showed a lymphoid tumor with features of localized Castleman disease, hyaline vascular type. Moreover we identified multiple interfollicular dark clusters, composed of cells morphologically resembling cortical thymocytes. Their immunophenotype was consistent with an intermediate stage of T-cell differentiation, with the expression of CD3, CD4, CD8, TdT, CD1a, CD99, CD2, CD5, CD7 and CD10, with 40% Ki67. After integration of clinical and molecular data, the retained diagnosis was an indolent T-cell lymphoblastic proliferation associated with hyaline vascular localized Castleman disease. The clinical course confirmed the indolent nature of the proliferation, despite a late local recurrence at 7 years of the initial diagnosis, without histological modification, due to an incomplete initial resection surgery.


Assuntos
Hiperplasia do Linfonodo Gigante/patologia , Linfócitos T/patologia , Adulto , Proliferação de Células , Feminino , Humanos , Transtornos Linfoproliferativos/patologia
17.
Clin Immunol ; 197: 130-138, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30219667

RESUMO

Common variable immunodeficiency (CVID) is characterized by low levels of circulating immunoglobulins and defects in B cell maturation leading to an increased susceptibility to infections. Some patients develop complications such as autoimmune diseases, enteropathy, and lymphoproliferation, resulting in higher morbidity and mortality. Follicular helper T (Tfh) cells are specialized in helping B cell differentiation into Ig-producing cells. Three subsets have been described, namely non B-cell helper Tfh1 and the two B-helper cell subsets Tfh2 and Tfh17. We determined that circulating Tfh cells were elevated in CVID patients and skewed toward a Tfh1 profile. Interestingly, elevated levels of Tfh1 cells were significant only in patients harboring non-infectious complications regardless of the type of complication and inversely correlated with switched memory B cells. Moreover, CXCR3+ cells are increased in splenic CVID germinal centers. Our observations suggest that the altered balance in Tfh subsets in CVID is linked to a more severe disease.


Assuntos
Linfócitos B/imunologia , Imunodeficiência de Variável Comum/imunologia , Memória Imunológica/imunologia , Células Th1/imunologia , Adulto , Doenças Autoimunes/imunologia , Estudos de Casos e Controles , Feminino , Centro Germinativo/citologia , Centro Germinativo/imunologia , Humanos , Enteropatias/imunologia , Linfopoese/imunologia , Transtornos Linfoproliferativos/imunologia , Masculino , Pessoa de Meia-Idade , Receptores CXCR3 , Sarcoidose/imunologia , Baço/citologia , Baço/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Células Th17/imunologia , Células Th2/imunologia
18.
Am J Surg Pathol ; 42(3): 401-412, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29200102

RESUMO

Immune thrombocytopenia (ITP) is an acquired antibody-mediated disease, for which splenectomy remains a curative treatment. We analyzed histology and phenotypes of ITP-splenectomy specimens from 41 adult patients, with different previous ITP-specific treatments, including B-cell-depleting rituximab (RTX) or not, in an attempt to predict splenectomy success or failure on the basis of day 56 postoperative platelet counts. RTX-naive ITP-spleen samples, compared with those from a 20-patient control trauma cohort, contained the following nonspecific, ITP-evocative, white-pulp lesions: follicular helper T-cell (programmed death-1 and inducible T-cell COStimulator) expansion in reactive follicles (P=0.01 and 0.03, respectively) and regulatory T-cell (FOXP3) expansion in the T-cell zone (P=0.049). On comparing ITP-splenectomy samples that would be successful with those that would be failures, only marginal zone hyperplasia differed (P=0.017). Indeed, 13/21 (61.9%) successful splenectomy samples exhibited marginal zone hyperplasia, as opposed to 1/9 (11.1%) failed splenectomy specimens. RTX impact on ITP-splenectomy samples was characterized by white-pulp (P=0.03) and marginal zone atrophies (P=0.01), and periarteriolar T-cell-zone hyperplasia (P<0.0001). The results of this novel comparative study of the histologic patterns of 41 ITP patients' evocative splenic lesions enabled clear description of different ITP morphologies and phenotypes, as a function of prior treatment and splenectomy success or failure.


Assuntos
Fatores Imunológicos/uso terapêutico , Púrpura Trombocitopênica Idiopática/terapia , Rituximab/uso terapêutico , Baço/efeitos dos fármacos , Baço/cirurgia , Esplenectomia , Adulto , Idoso , Biópsia , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Fenótipo , Contagem de Plaquetas , Púrpura Trombocitopênica Idiopática/sangue , Púrpura Trombocitopênica Idiopática/imunologia , Púrpura Trombocitopênica Idiopática/patologia , Baço/imunologia , Baço/patologia , Esplenectomia/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
19.
Am J Surg Pathol ; 41(12): 1581-1592, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28945625

RESUMO

Skin biopsies of 41 angioimmunoblastic T-cell lymphoma patients were retrospectively analyzed for the expression of follicular helper T-cell (TFH) markers, Epstein-Barr virus (EBV), and the presence of RHOA (p.G17V) and IDH2 (p.R172K/S) mutations using allele-specific polymerase chain reaction. We categorized cases into 4 distinctive patterns: (1) low-density lymphocytic perivascular infiltrates (n=11), (2) dense perivascular infiltrates with atypical cells and occasional inflammatory cells (n=13), (3) diffuse infiltrates reminiscent of angioimmunoblastic T-cell lymphoma (n=4), or (4) other aspects (n=13). Two EBV and 2 plasmacytoid lymphoproliferative disorders were seen. We observed variable expression of TFH markers (CD10 [50%], BCLB6 [84%], PD1 [94%], CXCL13 [84%], and ICOS [97.5%]), and EBV B-blasts (26%). A TFH phenotype was identified in 82% and 73%, respectively, of cases with the most challenging patterns 1 and 2. TFH markers and EBV can thus help for diagnosis and are detected in samples with low-density infiltrates. We found RHOA G17V and IDH2 R172K/S mutations in the skin in 14/18 (78%) and 3/16 (19%) cases, respectively. The RHOA G17V mutation was identified in a proportion of biopsies with patterns 1 and 2, which represent a diagnostic challenge. The RHOA G17V mutation was detected both in the skin and lymph node (LN) biopsies in 7/9 (64%) cases, and in only the skin or the LN of 1 sample each. The frequency of RHOA G17V mutation was similar to that reported in LNs. It may represent a sensitive diagnostic marker in the skin, helpful in cases with low-density infiltrates.


Assuntos
Biomarcadores Tumorais/genética , Linfadenopatia Imunoblástica/genética , Isocitrato Desidrogenase/genética , Linfoma Cutâneo de Células T/genética , Mutação , Neoplasias Cutâneas/genética , Linfócitos T Auxiliares-Indutores , Proteína rhoA de Ligação ao GTP/genética , Biomarcadores Tumorais/análise , Quimiocina CXCL13/análise , Análise Mutacional de DNA/métodos , Predisposição Genética para Doença , Herpesvirus Humano 4/isolamento & purificação , Humanos , Linfadenopatia Imunoblástica/enzimologia , Linfadenopatia Imunoblástica/imunologia , Linfadenopatia Imunoblástica/patologia , Imuno-Histoquímica , Proteína Coestimuladora de Linfócitos T Induzíveis/análise , Linfoma Cutâneo de Células T/enzimologia , Linfoma Cutâneo de Células T/imunologia , Linfoma Cutâneo de Células T/patologia , Neprilisina/análise , Fenótipo , Reação em Cadeia da Polimerase , Receptor de Morte Celular Programada 1/análise , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia , Linfócitos T Auxiliares-Indutores/enzimologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia
20.
J Dermatol Sci ; 88(2): 238-246, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28838616

RESUMO

BACKGROUND: Immunophenotype of primary cutaneous diffuse large B-cell lymphoma, leg-type (PCLBCL-LT) suggests a germinal center-experienced B lymphocyte (BCL2+ MUM1+ BCL6+/-). OBJECTIVES: As maturation history of B-cell is "imprinted" during B-cell development on the immunoglobulin gene sequence, we studied the structure and sequence of the variable part of the genes (IGHV, IGLV, IGKV), immunoglobulin surface expression and features of class switching in order to determine the PCLBCL-LT cell of origin. METHODS: Clonality analysis with BIOMED2 protocol and VH leader primers was done on DNA extracted from frozen skin biopsies on retrospective samples from 14 patients. The clonal DNA IGHV sequence of the tumor was aligned and compared with the closest germline sequence and homology percentage was calculated. Superantigen binding sites were studied. Features of selection pressure were evaluated with the multinomial Lossos model. RESULTS: A functional monoclonal sequence was observed in 14 cases as determined for IGHV (10), IGLV (2) or IGKV (3). IGV mutation rates were high (>5%) in all cases but one (median:15.5%), with superantigen binding sites conservation. Features of selection pressure were identified in 11/12 interpretable cases, more frequently negative (75%) than positive (25%). Intraclonal variation was detected in 3 of 8 tumor specimens with a low rate of mutations. Surface immunoglobulin was an IgM in 12/12 cases. FISH analysis of IGHM locus, deleted during class switching, showed heterozygous IGHM gene deletion in half of cases. The genomic PCR analysis confirmed the deletions within the switch µ region. IGV sequences were highly mutated but functional, with negative features of selection pressure suggesting one or more germinal center passage(s) with somatic hypermutation, but superantigen (SpA) binding sites conservation. Genetic features of class switch were observed, but on the non functional allele and co-existing with primary isotype IgM expression. CONCLUSION: These data suggest that cell-of origin is germinal center experienced and superantigen driven selected B-cell, in a stage between germinal center B-cell and plasma cell.


Assuntos
Genes de Imunoglobulinas/genética , Centro Germinativo/patologia , Região Variável de Imunoglobulina/genética , Linfoma de Células B/genética , Neoplasias Cutâneas/genética , Superantígenos/imunologia , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Linfócitos B/patologia , Biópsia , Evolução Clonal/genética , Evolução Clonal/imunologia , Análise Mutacional de DNA/métodos , Feminino , Genes de Imunoglobulinas/imunologia , Centro Germinativo/imunologia , Humanos , Switching de Imunoglobulina/genética , Switching de Imunoglobulina/imunologia , Região Variável de Imunoglobulina/imunologia , Perna (Membro) , Linfoma de Células B/imunologia , Linfoma de Células B/patologia , Masculino , Pessoa de Meia-Idade , Mutação , Plasmócitos/imunologia , Plasmócitos/patologia , Estudos Retrospectivos , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/patologia
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