RESUMEN
Follicular helper T-cell (TFH) lymphoma harbors recurrent mutations of RHOAG17V, IDH2R172, TET2, and DNMT3A. TET2 and DNMT3A mutations are the most frequently affected genes in clonal hematopoiesis (CH). The aim of our study was to investigate the frequency of CH in bone marrow biopsies (BMB) of TFH/angioimmunoblastic T-cell lymphoma (TFH-AITL) patients and its association with myeloid neoplasms. A total of 29 BMB from 22 patients with a diagnosis of TFH-AITL were analyzed by next-generation sequencing (NGS) with a custom panel. Morphologically, 5 BMB revealed that TFH-AITL infiltrates of >5% of bone marrow (BM) cellularity confirmed in 4 cases by NGS-based T-cell clonality. IDH2R172 was demonstrated only in 1 (3%) of 29, and RHOAG17V in 2 (7%) of 29 samples. TET2 and DNMT3A were identified in 24 (83%) of 29 and 17 (59%) of 29 BMB, respectively. In the parallel lymph node the frequencies of mutations were 27% (IDH2R172), 64% (RHOAG17V), 86% (TET2), and 50% (DNMT3A). TET2 and/or DNMT3A mutations identical in lymph node and BMB were present in 18 (82%) of 22 patients, regardless of BM infiltration. In 3 cases the CH mutations were detected 13, 41, and 145 months before TFH-AITL diagnosis. Cases with TET2/DNMT3A mutations and BM variant allele frequencies >40% (7/18, 39%) showed lower blood counts. However, only low platelet count was statistically significant (P = .024). Myeloid neoplasms and/or myelodysplastic syndrome-related mutations were identified in 4 cases (4/22; 18%); all with high TET2 variant allele frequencies (>40%; P = .0114). In conclusion, CH is present in 82% of TFH-AITL and can be demonstrated up to 145 months before TFH-AITL diagnosis. NGS T-cell clonality analysis is an excellent tool to confirm TFH-AITL BM infiltration. Concurrent myeloid neoplasms were identified in 18% of the cases and were associated with TET2 mutations with high allelic burden (>40%). We demonstrated that myeloid neoplasms might occur simultaneously or precede the diagnosis of TFH lymphoma.
Asunto(s)
Médula Ósea , Hematopoyesis Clonal , Mutación , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Hematopoyesis Clonal/genética , Médula Ósea/patología , Anciano de 80 o más Años , Adulto , Linfadenopatía Inmunoblástica/genética , Linfadenopatía Inmunoblástica/patología , Linfadenopatía Inmunoblástica/inmunología , Linfoma Folicular/genética , Linfoma Folicular/patología , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Colaboradores-Inductores/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento , ADN Metiltransferasa 3A/genética , Proteínas de Unión al ADN , DioxigenasasRESUMEN
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive lymphoid malignancy associated with a poor clinical prognosis. The AITL tumor microenvironment (TME) is unique, featuring a minority population of malignant CD4+ T follicular helper (TFH) cells inter-mixed with a diverse infiltrate of multi-lineage immune cells. While much of the understanding of AITL biology to date has focused on characteristics of the malignant clone, less is known about the many non-malignant populations that comprise the TME. Recently, mutational consistencies have been identified between malignant cells and non-malignant B cells within the AITL TME. As a result, a significant role for non-malignant populations in AITL biology has been increasingly hypothesized. In this study, we have utilized mass cytometry and single-cell transcriptome analysis to identify several expanded populations within the AITL TME. Notably, we find that B cells within the AITL TME feature decreased expression of key markers including CD73 and CXCR5. Furthermore, we describe the expansion of distinct CD8+ T cell populations that feature an exhausted phenotype and an underlying expression profile indicative of dysfunction, impaired cytotoxicity, and upregulation of the chemokines XCL2 and XCL1.
Asunto(s)
Biomarcadores de Tumor/genética , Linfadenopatía Inmunoblástica/patología , Linfoma de Células T/patología , Mutación , Análisis de la Célula Individual/métodos , Transcriptoma , Microambiente Tumoral , Estudios de Casos y Controles , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica , Humanos , Linfadenopatía Inmunoblástica/genética , Linfadenopatía Inmunoblástica/inmunología , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Fenotipo , Pronóstico , Células Tumorales CultivadasRESUMEN
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent small B-cell neoplasm that may transform into a clinically aggressive disease, namely Richter syndrome, usually as diffuse large B-cell lymphoma. Besides, CLL/SLL encompasses an increased risk of developing other secondary cancers, including a variety of T-cell lymphomas, often of the anaplastic large-cell type or with a cytotoxic phenotype. Here, we report a small series of patients with composite lymphomas consisting of CLL/SLL and angioimmunoblastic T-cell lymphoma (AITL), a hitherto unrecognized association. The 3 patients (1 male/2 females, 68 to 83 y) presented with high-grade-type symptoms. One patient was clinically suspicious for Richter syndrome, in the others CLL/SLL and AITL were concomitant de novo diagnoses. CLL/SLL and AITL were admixed in the same lymph nodes (3/3 cases) and in the bone marrow (1/2 cases). In all cases, the AITL comprised prominent clear cells with a strong T follicular helper immunophenotype and similar mutations consisting of TET2 or DNMT3A alterations, IDH2 R172K/M, and RHOA G17V. The 3 patients received chemotherapy. One died of early AITL relapse. The other 2 remained in complete remission of AITL, 1 died with recurrent CLL, and 1 of acute myeloid leukemia. These observations expand the spectrum of T-cell lymphoma entities that occur in association with CLL/SLL, adding AITL to the rare variants of aggressive neoplasms manifesting as Richter syndrome. Given that disturbances of T-cell homeostasis in CLL/SLL affect not only cytotoxic but also helper T-cell subsets, these may contribute to the emergence of neoplasms of T follicular helper derivation.
Asunto(s)
Linfoma Compuesto , Linfadenopatía Inmunoblástica , Leucemia Linfocítica Crónica de Células B , Linfoma de Células T , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Linfoma Compuesto/tratamiento farmacológico , Linfoma Compuesto/genética , Linfoma Compuesto/inmunología , Diagnóstico Diferencial , Resultado Fatal , Femenino , Reordenamiento Génico , Genes Codificadores de los Receptores de Linfocitos T , Humanos , Linfadenopatía Inmunoblástica/tratamiento farmacológico , Linfadenopatía Inmunoblástica/genética , Linfadenopatía Inmunoblástica/inmunología , Inmunoglobulinas/genética , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/inmunología , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Masculino , Valor Predictivo de las Pruebas , Recurrencia , Factores de Tiempo , Resultado del TratamientoRESUMEN
Follicular helper CD4 T (Tfh) cells play an essential role in the formation of germinal centers (GCs), where mature B cells proliferate, differentiate, and provide long-term protective humoral responses. Despite the extensive phenotypic characterization and identification of human Tfh cell subsets, their spatial positioning at tissue level is not well understood. Here, we describe a quantitative multiplexed immunofluorescence approach allowing for the comprehensive in situ characterization of Tfh cells in human tonsils and lymph nodes (LNs) from individuals with angioimmunoblastic T-cell lymphoma (AITL). We have developed eight multiplexed panels comprising a spectrum of Tfh cell markers, like PD-1, CXCR5, and ICOS, along with transcription factors (Bcl6, Tbet, GATA3), to assess their expression, frequencies, spatial distribution and co-localization in a quantitative manner. Combined analysis of relevant markers revealed the presence of several Tfh cell subsets at tissue level based on the differential expression of surface receptors, nuclear factors as well as their distinct localization within the follicular areas. Interestingly, we found a considerable amount of tonsillar Tfh cells expressing high levels of the Th2 regulator GATA3. The co-expression of GATA3, CXCR5, and BCL6, points to an important role of GATA3 for the generation of effector human Tfh cells. Furthermore, our data revealed significantly different Tfh cell profile signatures between health and disease. Therefore, our imaging platform generates meaningful information for the in situ characterization of human Tfh cells and could provide the base for future studies aiming to a comprehensive understanding of Tfh cell tissue heterogeneity.
Asunto(s)
Linfadenopatía Inmunoblástica/metabolismo , Ganglios Linfáticos/metabolismo , Linfoma de Células T/metabolismo , Microscopía Fluorescente , Tonsila Palatina/metabolismo , Células T Auxiliares Foliculares/metabolismo , Biomarcadores/metabolismo , Técnica del Anticuerpo Fluorescente , Humanos , Procesamiento de Imagen Asistido por Computador , Linfadenopatía Inmunoblástica/inmunología , Linfadenopatía Inmunoblástica/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Linfoma de Células T/inmunología , Linfoma de Células T/patología , Tonsila Palatina/inmunología , Tonsila Palatina/patología , Fenotipo , Proteoma , Proteómica , Células T Auxiliares Foliculares/inmunologíaRESUMEN
Angioimmunoblastic T-cell lymphoma (AITL) is a neoplastic proliferation of T follicular helper cells with clinical and histological presentations suggesting a role of antigenic drive in its development. Genetically, it is characterized by a stepwise acquisition of somatic mutations, with early mutations involving epigenetic regulators (TET2, DNMT3A) and occurring in haematopoietic stem cells, with subsequent changes involving signaling molecules (RHOA, VAV1, PLCG1, CD28) critical for T-cell biology. To search for evidence of potential oncogenic cooperation between genetic changes and intrinsic T cell receptor (TCR) signaling, we investigated somatic mutations and T-cell receptor ß (TRB) rearrangement in 119 AITL, 11 peripheral T-cell lymphomas with T follicular helper phenotype (PTCL-TFH), and 25 PTCL-NOS using Fluidigm polymerase chain reaction (PCR) and Illumina MiSeq sequencing. We confirmed frequent TET2, DNMT3A, and RHOA mutations in AITL (72%, 34%, 61%) and PTCL-TFH (73%, 36%, 45%) and showed multiple TET2 mutations (2 or 3) in 57% of the involved AITL and PTCL-TFH. Clonal TRB rearrangement was seen in 76 cases with multiple functional rearrangements (2-4) in 18 cases (24%). In selected cases, we confirmed bi-clonal T-cell populations and further demonstrated that these independent T-cell populations harboured identical TET2 mutations by using BaseScope in situ hybridization, suggesting their derivation from a common TET2 mutant progenitor cell population. Furthermore, both T-cell populations expressed CD4. Finally, in comparison with tonsillar TFH cells, both AITL and PTCL-TFH showed a significant overrepresentation of several TRB variable family members, particularly TRBV19*01. Our findings suggest the presence of parallel neoplastic evolutions from a common TET2 mutant haematopoietic progenitor pool in AITL and PTCL-TFH, albeit to be confirmed in a large series of cases. The biased TRBV usage in these lymphomas suggests that antigenic stimulation may play an important role in predilection of T cells to clonal expansion and malignant transformation. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Asunto(s)
Proteínas de Unión al ADN/genética , Linfadenopatía Inmunoblástica/inmunología , Linfoma de Células T/inmunología , Proteínas Proto-Oncogénicas/genética , Anciano , Alelos , Dioxigenasas , Frecuencia de los Genes , Humanos , Linfadenopatía Inmunoblástica/genética , Linfadenopatía Inmunoblástica/patología , Linfoma de Células T/genética , Linfoma de Células T/patología , Persona de Mediana Edad , Mutación , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patologíaAsunto(s)
Antígenos de Neoplasias/genética , Linfadenopatía Inmunoblástica/terapia , Inmunoterapia Adoptiva/métodos , Linfoma de Células T/terapia , Linfocitos T/inmunología , Anciano , Antígenos de Neoplasias/inmunología , Células Clonales , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfadenopatía Inmunoblástica/genética , Linfadenopatía Inmunoblástica/inmunología , Activación de Linfocitos , Linfoma de Células T/genética , Linfoma de Células T/inmunología , Masculino , Linfocitos T/trasplante , Trasplante HaploidénticoRESUMEN
Cutaneous manifestations of Epstein-Barr virus (EBV)-driven B-cell lymphoid proliferations occur rarely as a result of severe immunodeficiency. To date, only a few cases of extranodal EBV-associated B-cell lymphomas arising in patients with angioimmunoblastic T-cell lymphoma (AITL) have been reported, and less common is a cutaneous presentation. AITL is a rare aggressive tumor that carries a poor prognosis and prompt diagnosis, and recognition of EBV-associated diffuse B-cell lymphoma is essential in these patients to instigate the correct treatment.
Asunto(s)
Infecciones por Virus de Epstein-Barr/virología , Herpesvirus Humano 4/crecimiento & desarrollo , Linfadenopatía Inmunoblástica/inmunología , Huésped Inmunocomprometido , Linfoma de Células B Grandes Difuso/virología , Linfoma de Células T/inmunología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/virología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ciclofosfamida/efectos adversos , Doxorrubicina/efectos adversos , Infecciones por Virus de Epstein-Barr/inmunología , Herpesvirus Humano 4/inmunología , Humanos , Linfadenopatía Inmunoblástica/tratamiento farmacológico , Linfadenopatía Inmunoblástica/patología , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/inmunología , Linfoma de Células B Grandes Difuso/patología , Linfoma de Células T/tratamiento farmacológico , Linfoma de Células T/patología , Masculino , Persona de Mediana Edad , Prednisona/efectos adversos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Resultado del Tratamiento , Vincristina/efectos adversos , Replicación ViralAsunto(s)
Linfadenopatía Inmunoblástica/patología , Linfoma Cutáneo de Células T/patología , Neoplasias Cutáneas/patología , Anciano , Femenino , Humanos , Linfadenopatía Inmunoblástica/complicaciones , Linfadenopatía Inmunoblástica/inmunología , Mordeduras y Picaduras de Insectos , Linfoma Cutáneo de Células T/complicaciones , Linfoma Cutáneo de Células T/inmunología , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/inmunologíaRESUMEN
Angioimmunoblastic T-cell lymphoma is a peripheral T-cell lymphoma derived from follicular T-helper cells. High-throughput genomic sequencing studies have shown that angioimmunoblastic T-cell lymphoma carries frequent mutations in RHOAG17V and IDH2R172 genes. The clinico-pathological features of angioimmunoblastic T-cell lymphoma cases with RHOAG17V mutations have been addressed; however, similar studies for IDH2 mutated cases are lacking. Therefore, the aim of the present study was to evaluate the pathological features of angioimmunoblastic T-cell lymphoma with IDH2 mutations. In order to identify cases with IDH2 mutations, 50 cases previously diagnosed as angioimmunoblastic T-cell lymphoma were subjected to next-generation sequencing analysis using a custom panel covering four genes frequently mutated in angioimmunoblastic T-cell lymphoma including DNMT3A, TET2, IDH2 and RHOA. All cases were analyzed for PD1, ICOS, CXCL13, CD10, BCL6, CD21, CD23 and EBER in situ hybridization. Mutational analysis recognized three groups. Group 1: IDH2R172 mutations were identified in 20 cases (40%). All cases carried RHOAG17V mutations. Group 2: RHOAG17V mutations without IDH2R172 mutation were identified in 16 cases (32%), and Group 3: 14 cases (28%) without RHOAG17V or IDH2R172 mutations. Morphologically, angioimmunoblastic T-cell lymphoma cases with IDH2R172 mutations were characterized by the presence of medium to large clear cells (p = 0.00001), and a follicular T-helper phenotype with the particular feature of strong CD10 (p = 0.0268) and CXCL13 expression (p = 0.0346). Interestingly, TET2 mutations were identified in 32 of 33 (97%) cases with IDH2R172 and/or RHOAG17V mutations whereas only 55% of angioimmunoblastic T-cell lymphoma cases wild-type for these two genes carried TET2 mutations (p = 0.0022). In contrast, DNMT3A mutations were found in 48% of the cases and were equally distributed in the three groups. In conclusion, our results support the results of gene expression profiling studies suggesting that IDH2R172 mutations define a unique subgroup within angioimmunoblastic T-cell lymphoma with strong follicular T-helper-like phenotype and characteristic morphological features.
Asunto(s)
Biomarcadores de Tumor/genética , Linfadenopatía Inmunoblástica/genética , Isocitrato Deshidrogenasa/genética , Linfoma de Células T Periférico/genética , Mutación , Animales , Análisis Mutacional de ADN , Perfilación de la Expresión Génica , Predisposición Genética a la Enfermedad , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Linfadenopatía Inmunoblástica/inmunología , Linfadenopatía Inmunoblástica/patología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Linfoma de Células T Periférico/inmunología , Linfoma de Células T Periférico/patología , Fenotipo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patología , TranscriptomaRESUMEN
Methotrexate-associated lymphoproliferative disorders are categorized as "other immunodeficiency-associated lymphoproliferative disorders in the WHO classification. Methotrexate-associated lymphoproliferative disorder is mainly a B-cell lymphoproliferative disorders or Hodgkin lymphoma type, whereas T-cell lymphoproliferative disorders are relatively rare (4-8%). Only a small number of methotrexate-associated T-cell lymphoproliferative disorders have been detailed thus far. Because of the rarity, methotrexate-associated T-cell lymphoproliferative disorder has not been well studied and its clinicopathological characteristics are unknown. A total of 28 cases of methotrexate-associated T-cell lymphoproliferative disorders were retrospectively analyzed. Histologically and immunohistochemically, they were divided into three main types: angioimmunoblastic T-cell lymphoma (n = 19), peripheral T-cell lymphoma, NOS (n = 6), and CD8+ cytotoxic T-cell lymphoma (n = 3). Among the 28 cases, only one CD8+ cytotoxic T-cell lymphoma case was Epstein-Barr virus-positive. The other 27 cases were negative for Epstein-Barr virus on tumor cells, but scattered Epstein-Barr virus-infected B-cells were detected in 24 cases (89%), implying the reactivation of Epstein-Barr virus caused by immunodeficient status of the patients. After the diagnosis of methotrexate-associated T-cell lymphoproliferative disorder, methotrexate was immediately withdrawn in 26 cases. Twenty (77%) cases presented with spontaneous regression. Compared to methotrexate-associated B-cell lymphoproliferative disorder, patients with methotrexate-associated T-cell lymphoproliferative disorder had a significantly higher proportion of males (p = 0.035) and presence of B-symptoms (p = 0.036), and lower proportion of Epstein-Barr virus+ tumor cells (p < 0.001). Although the difference was not significant, the methotrexate-associated T-cell lymphoproliferative disorder also had more frequent spontaneous regression (p = 0.061). In conclusion, methotrexate-associated T-cell lymphoproliferative disorder was divided into three main types: angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma, NOS, and CD8+ cytotoxic T-cell lymphoma. Angioimmunoblastic T-cell lymphoma was the most common type. Methotrexate-associated T-cell lymphoproliferative disorder was characterized by a high rate of spontaneous regression after methotrexate cessation. Epstein-Barr virus positivity was relatively rare in methotrexate-associated T-cell lymphoproliferative disorder, significantly less frequent than methotrexate-associated B-cell lymphoproliferative disorder, suggesting different pathogenesis.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Inmunosupresores/efectos adversos , Trastornos Linfoproliferativos/inducido químicamente , Metotrexato/efectos adversos , Subgrupos de Linfocitos T/efectos de los fármacos , Anciano , Anciano de 80 o más Años , Femenino , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Linfadenopatía Inmunoblástica/inducido químicamente , Linfadenopatía Inmunoblástica/inmunología , Linfadenopatía Inmunoblástica/patología , Linfoma de Células T Periférico/inducido químicamente , Linfoma de Células T Periférico/inmunología , Linfoma de Células T Periférico/patología , Trastornos Linfoproliferativos/inmunología , Trastornos Linfoproliferativos/patología , Trastornos Linfoproliferativos/virología , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Estudios Retrospectivos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/patología , Subgrupos de Linfocitos T/virología , Linfocitos T Citotóxicos/efectos de los fármacos , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/patologíaRESUMEN
A 68-year-old woman was referred to our hospital due to fever and rash on the neck and extremities. Laboratory findings revealed hepatic dysfunction and positivity for anti-mitochondrial M2 antibody (AMA-M2). Hepatosplenomegaly and systemic lymphadenopathy were detected by enhanced computed tomography. One week after her first visit, hypoxemia, ascites, and Coomb test-positive autoimmune hemolytic anemia had newly appeared in addition to worsened fever, hepatosplenomegaly, and lymphadenopathy. Results of axillary lymph node, skin, and bone-marrow biopsies led to the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), for which CEPP therapy (cyclophosphamide, etoposide, procarbazine, and prednisolone) was initiated. Her serum levels of hepatobiliary enzymes normalized and AMA-M2 became negative after treatment. The unexpected positivity for AMA-M2 might have been caused by AITL cell-activated intrahepatic immune cells or the tumor cells themselves inflicting bile duct injury that mimicked primary biliary cholangitis. Alternatively, cross reactivity due to the overproduction of immunoglobulins may have caused this phenomenon. The present case may shed light on of the mechanisms of liver dysfunction accompanying AITL.
Asunto(s)
Autoanticuerpos/sangre , Linfadenopatía Inmunoblástica/inmunología , Linfoma de Células T/inmunología , Mitocondrias/inmunología , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ciclofosfamida/uso terapéutico , Etopósido/uso terapéutico , Femenino , Hepatomegalia/etiología , Humanos , Linfadenopatía Inmunoblástica/complicaciones , Linfadenopatía Inmunoblástica/tratamiento farmacológico , Hígado/enzimología , Linfoma de Células T/complicaciones , Linfoma de Células T/tratamiento farmacológico , Prednisona/uso terapéutico , Procarbazina/uso terapéutico , Esplenomegalia/etiologíaRESUMEN
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.
Asunto(s)
Biomarcadores de Tumor/genética , Linfadenopatía Inmunoblástica/genética , Isocitrato Deshidrogenasa/genética , Linfoma Cutáneo de Células T/genética , Mutación , Neoplasias Cutáneas/genética , Linfocitos T Colaboradores-Inductores , Proteína de Unión al GTP rhoA/genética , Biomarcadores de Tumor/análisis , Quimiocina CXCL13/análisis , Análisis Mutacional de ADN/métodos , Predisposición Genética a la Enfermedad , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Linfadenopatía Inmunoblástica/enzimología , Linfadenopatía Inmunoblástica/inmunología , Linfadenopatía Inmunoblástica/patología , Inmunohistoquímica , Proteína Coestimuladora de Linfocitos T Inducibles/análisis , Linfoma Cutáneo de Células T/enzimología , Linfoma Cutáneo de Células T/inmunología , Linfoma Cutáneo de Células T/patología , Neprilisina/análisis , Fenotipo , Reacción en Cadena de la Polimerasa , Receptor de Muerte Celular Programada 1/análisis , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Linfocitos T Colaboradores-Inductores/enzimología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/patologíaRESUMEN
The presence of Hodgkin and Reed-Sternberg (HRS)-like B-cells in peripheral T-cell lymphoma (PTCL) is rare and its clinicopathological features still remain unclear. Here, we describe 30 cases of PTCL with HRS-like B-cells from Japan. Twenty-three cases (77%) presented evidence of follicular T-helper phenotype (TFH) derivation: 12 were angioimmunoblastic T-cell lymphoma and 11 PTCL with TFH phenotype (PTCL-TFH). The remaining seven cases were diagnosed as PTCL, not otherwise specified (PTCL-NOS). Epstein-Barr virus (EBV) reactivation was detected in 25 cases (83%), but HRS-like B-cells were EBER in only 20 cases (67%). The median age at diagnosis was 77 years (range, 39-91 y), including 24 patients (80%) were older than 60 years of age. Most of the patients presented at an advanced clinical stage and were associated with higher risk according to the International Prognostic Index. The 3-year overall and progression-free survival rates were 44% and 27%, respectively. No significant clinicopathological differences were detected between PTCL-TFH, PTCL-NOS and the angioimmunoblastic cases. Cases with EBER HRS-like B-cells were associated with inferior overall and progression-free survival compared to those with EBER HRS-like B-cells, but the difference was not significant. In conclusion, HRS-like B-cells were found in a subset of T-cell lymphomas, especially in association with the TFH phenotype and EBV reactivation. These cells have a tendency to affect elderly patients and to be associated with advanced clinical stages and dismal prognosis. The EBV status of HRS-like B-cells does not seem to affect the clinicopathological features of this group of PTCLs.
Asunto(s)
Linfocitos B/patología , Linfadenopatía Inmunoblástica/patología , Linfoma de Células T Periférico/patología , Células de Reed-Sternberg/patología , Linfocitos T Colaboradores-Inductores/patología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/inmunología , Linfocitos B/virología , Antígeno B7-H1/análisis , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Biopsia , Supervivencia sin Enfermedad , Femenino , Herpesvirus Humano 4/genética , Humanos , Linfadenopatía Inmunoblástica/inmunología , Linfadenopatía Inmunoblástica/terapia , Linfadenopatía Inmunoblástica/virología , Inmunohistoquímica , Japón , Estimación de Kaplan-Meier , Linfoma de Células T Periférico/inmunología , Linfoma de Células T Periférico/terapia , Linfoma de Células T Periférico/virología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Fenotipo , ARN Viral/genética , Células de Reed-Sternberg/inmunología , Células de Reed-Sternberg/virología , Factores de Riesgo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/virología , Factores de Tiempo , Resultado del Tratamiento , Activación ViralAsunto(s)
Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Linfadenopatía Inmunoblástica/inmunología , Linfocitosis/inmunología , Neumonía por Pneumocystis/inmunología , Anciano , Células Dendríticas Foliculares/patología , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/complicaciones , Síndrome Inflamatorio de Reconstitución Inmune/patología , Linfadenopatía Inmunoblástica/complicaciones , Linfadenopatía Inmunoblástica/patología , Ganglios Linfáticos/patología , Linfocitos/patología , Linfocitosis/complicaciones , Linfocitosis/patología , Neumonía por Pneumocystis/complicaciones , Neumonía por Pneumocystis/microbiología , Neumonía por Pneumocystis/patología , Tórax/diagnóstico por imagen , Tórax/patologíaRESUMEN
The molecular pathogenesis of peripheral T-cell lymphoma (PTCL) has gradually been clarified in terms of genomic abnormalities. Insights into these genomic abnormalities have provided clues to understanding the pathogenesis of PTCL. Furthermore, the origins of lymphoma cells have been clarified by investigating the distribution of genomic abnormalities in tumor cells and non-tumor blood cells. Multistep tumorigenesis has been suggested to be a fundamental mechanism underlying the development of angioimmunoblastic T-cell lymphoma (AITL), a distinct subtype of PTCL: premalignant cells evolve from hematopoietic progenitors via mutations in epigenetic regulators. These cells then further differentiate into tumor cells via the addition of tumor-specific G17V RHOA mutations. Meanwhile, AITL are composed of various infiltrating cells as well as tumor cells. Most notably, AITL tissues are characterized by massive infiltration of B cells partially infected by Epstein-Barr virus, follicular dendritic cells, and high endothelial venules. Infiltration of these cell types has been thought to be a reactive process, promoted by cytokines and chemokines released from tumor cells. Considering the multistep mechanisms of AITL allows us to analyze whether these infiltrating cells are also derived from premalignant cells. Indeed, the mechanisms underlying massive infiltration of bystander cells might be more complicated than previously imagined.
Asunto(s)
Linfadenopatía Inmunoblástica/metabolismo , Linfoma de Células T/metabolismo , Linfocitos B/inmunología , Transformación Celular Neoplásica , Humanos , Linfadenopatía Inmunoblástica/diagnóstico , Linfadenopatía Inmunoblástica/inmunología , Linfoma de Células T/diagnóstico , Linfoma de Células T/patología , Invasividad NeoplásicaRESUMEN
Lennert lymphoma (LeL) is a variant of peripheral T-cell lymphoma, not otherwise specified. Few clinicopathologic studies have investigated LeL, which is a rare disease. Here, we analyzed the clinicopathologic features of 26 patients with LeL to identify potential prognostic factors. Neoplastic cells positive for CD4, CD8, CD4/CD8, TIA-1, and granzyme B were observed in 21 (80.8%), 4 (15.4%), 1 (3.8%), 4 (15.3%), and 0 (0.0%) patients, respectively. Regarding follicular helper T-cell (TFH) markers, neoplastic cells positive for programmed cell death-1 (PD-1), CXCL13, CD10, and BCL6 were observed in 14 (53.8%), 13 (50.0%), 1 (3.8%), and 0 (0.0%) patients, respectively. Patients with positivity for at least 1 TFH cell marker (PD-1, CXCL13, CD10, and/or BCL6) were defined as being TFH cell marker-positive (n=15) and had a worse prognosis than TFH cell marker-negative patients (n=11) (P=0.011). Clinicopathologic characteristics did not differ significantly between TFH cell marker-positive and marker-negative LeL patients. Moreover, prognosis did not differ significantly between TFH cell marker-positive LeL patients and patients with angioimmunoblastic T-cell lymphoma (AITL) (n=42). Nevertheless, as compared with AITL, TFH cell marker-positive LeL was associated with significantly lower frequencies of B symptoms, skin rash, high-intermediate-risk or high-risk international prognostic index values, expanded follicular dendritic cell meshworks, polymorphic infiltrate, clear cells, and positivity for CD10 and BCL6. Although it may be difficult to definitively distinguish between TFH cell marker-positive LeL and AITL, our results suggest that TFH cell markers are useful for identifying LeL patients who will experience unfavorable outcomes.
Asunto(s)
Linfoma de Células T Periférico/inmunología , Linfoma de Células T Periférico/patología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Southern Blotting , Análisis Citogenético , Femenino , Humanos , Linfadenopatía Inmunoblástica/inmunología , Linfadenopatía Inmunoblástica/patología , Inmunohistoquímica , Inmunofenotipificación , Hibridación in Situ , Estimación de Kaplan-Meier , Linfoma de Células T Periférico/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
Angioimmunoblastic T-cell lymphoma (AITL) and other lymphomas derived from follicular T-helper cells (TFH) represent a large proportion of peripheral T-cell lymphomas (PTCLs) with poorly understood pathogenesis and unfavorable treatment results. We investigated a series of 85 patients with AITL (n = 72) or other TFH-derived PTCL (n = 13) by targeted deep sequencing of a gene panel enriched in T-cell receptor (TCR) signaling elements. RHOA mutations were identified in 51 of 85 cases (60%) consisting of the highly recurrent dominant negative G17V variant in most cases and a novel K18N in 3 cases, the latter showing activating properties in in vitro assays. Moreover, half of the patients carried virtually mutually exclusive mutations in other TCR-related genes, most frequently in PLCG1 (14.1%), CD28 (9.4%, exclusively in AITL), PI3K elements (7%), CTNNB1 (6%), and GTF2I (6%). Using in vitro assays in transfected cells, we demonstrated that 9 of 10 PLCG1 and 3 of 3 CARD11 variants induced MALT1 protease activity and increased transcription from NFAT or NF-κB response element reporters, respectively. Collectively, the vast majority of variants in TCR-related genes could be classified as gain-of-function. Accordingly, the samples with mutations in TCR-related genes other than RHOA had transcriptomic profiles enriched in signatures reflecting higher T-cell activation. Although no correlation with presenting clinical features nor significant impact on survival was observed, the presence of TCR-related mutations correlated with early disease progression. Thus, targeting of TCR-related events may hold promise for the treatment of TFH-derived lymphomas.
Asunto(s)
Genes Codificadores de los Receptores de Linfocitos T/genética , Linfadenopatía Inmunoblástica/genética , Linfoma Folicular/genética , Linfoma de Células T Periférico/genética , Mutación/genética , Transducción de Señal , Linfocitos T Colaboradores-Inductores/inmunología , Proteína de Unión al GTP rhoA/genética , Biomarcadores de Tumor/genética , Estudios de Cohortes , Estudios de Seguimiento , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Linfadenopatía Inmunoblástica/inmunología , Linfadenopatía Inmunoblástica/patología , Linfoma Folicular/inmunología , Linfoma Folicular/patología , Linfoma de Células T Periférico/inmunología , Linfoma de Células T Periférico/patología , Estadificación de Neoplasias , PronósticoRESUMEN
Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63-year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated.