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ABSTRACT: Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.
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Reordenamiento Génico , Proteínas Proto-Oncogénicas c-bcl-2 , Proteínas Proto-Oncogénicas c-myc , Humanos , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Linfoma de Células B/genética , Linfoma de Células B/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patologíaRESUMEN
PURPOSE: To report a case of primary vitreoretinal lymphoma masquerading as infectious retinitis that was diagnosed via a retinal biopsy. OBSERVATIONS: A 72-year-old female patient was referred to our ophthalmology clinic for evaluation of retinitis and vasculitis in the right eye (OD). On examination, best-corrected visual acuities (BCVAs) were hand motions OD and 20/20 in the left eye (OS). Fundus examination revealed optic disc edema and diffuse retinal whitening superior to the superotemporal arcade OD. Given the high suspicion of infectious retinitis, the patient was treated with intravitreal foscarnet, systemic acyclovir, and oral prednisone and underwent a comprehensive uveitis workup, which was unremarkable for viral and autoimmune entities. Given the patient's history of diffuse large B cell lymphoma with cutaneous involvement, vitreoretinal lymphoma was suspected, prompting pars plana vitrectomy with a retinal biopsy. Biopsy and immunohistochemistry results were consistent with B-cell lymphoma, and the patient was treated with high-dose methotrexate and rituximab. At 5-month follow-up, BCVAs were hand motions OD and 20/30 OS, and fundus examination demonstrated disc edema with resolution of retinal whitening OD. She responded well to the treatment with regression of vitreoretinal lymphoma on examination and is being monitored closely for lymphoma recurrence. CONCLUSIONS AND IMPORTANCE: Although uncommon, patients with vitreoretinal lymphoma may masquerade as infectious retinitis, and vitreoretinal lymphoma should be suspected when refractory to antiviral therapy and in the setting of a negative workup for viral etiologies. Vitrectomy with retinal biopsy may be considered to aid the diagnosis of vitreoretinal lymphoma although careful consideration of the risks and benefits is warranted.
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BACKGROUND: Patients with mantle cell lymphoma (MCL) exhibit a wide variation in clinical presentation and outcome. However, the commonly used prognostic models are outdated and inadequate to address the needs of the current multidisciplinary management of this disease. This study aims to investigate the clinical and pathological features of MCL in the immunochemotherapy era and improve the prognostic models for a more accurate prediction of patient outcomes. METHODS: The North American Mantle Cell Lymphoma Project is a multi-institutional collaboration of 23 institutions across North America to evaluate and refine prognosticators for front-line therapy. A total of 586 MCL cases diagnosed between 2000 and 2012 are included in this study. A comprehensive retrospective analysis was performed on the clinicopathological features, treatment approaches, and outcomes of these cases. The establishment of novel prognostic models was based on in-depth examination of baseline parameters, and subsequent validation in an independent cohort of MCL cases. RESULTS: In front-line strategies, the use of hematopoietic stem cell transplantation was the most significant parameter affecting outcomes, for both overall survival (OS, p < 0.0001) and progression-free survival (PFS, p < 0.0001). P53 positive expression was the most significant pathological parameter correlating with inferior outcomes (p < 0.0001 for OS and p = 0.0021 for PFS). Based on the baseline risk factor profile, we developed a set of prognostic models incorporating clinical, laboratory, and pathological parameters that are specifically tailored for various applications. These models, when tested in the validation cohort, exhibited strong predictive power for survival and showed a stratification resembling the training cohort. CONCLUSIONS: The outcome of patients with MCL has markedly improved over the past two decades, and further enhancement is anticipated with the evolution of clinical management. The innovative prognostic models developed in this study would serve as a valuable tool to guide the selection of more suitable treatment strategies for patients with MCL.
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Linfoma de Células del Manto , Adulto , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/patología , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , América del NorteRESUMEN
PURPOSE: Peripheral T-cell lymphoma (PTCL) includes heterogeneous clinicopathologic entities with numerous diagnostic and treatment challenges. We previously defined robust transcriptomic signatures that distinguish common PTCL entities and identified two novel biologic and prognostic PTCL-not otherwise specified subtypes (PTCL-TBX21 and PTCL-GATA3). We aimed to consolidate a gene expression-based subclassification using formalin-fixed, paraffin-embedded (FFPE) tissues to improve the accuracy and precision in PTCL diagnosis. MATERIALS AND METHODS: We assembled a well-characterized PTCL training cohort (n = 105) with gene expression profiling data to derive a diagnostic signature using fresh-frozen tissue on the HG-U133plus2.0 platform (Affymetrix, Inc, Santa Clara, CA) subsequently validated using matched FFPE tissues in a digital gene expression profiling platform (nCounter, NanoString Technologies, Inc, Seattle, WA). Statistical filtering approaches were applied to refine the transcriptomic signatures and then validated in another PTCL cohort (n = 140) with rigorous pathology review and ancillary assays. RESULTS: In the training cohort, the refined transcriptomic classifier in FFPE tissues showed high sensitivity (> 80%), specificity (> 95%), and accuracy (> 94%) for PTCL subclassification compared with the fresh-frozen-derived diagnostic model and showed high reproducibility between three independent laboratories. In the validation cohort, the transcriptional classifier matched the pathology diagnosis rendered by three expert hematopathologists in 85% (n = 119) of the cases, showed borderline association with the molecular signatures in 6% (n = 8), and disagreed in 8% (n = 11). The classifier improved the pathology diagnosis in two cases, validated by clinical findings. Of the 11 cases with disagreements, four had a molecular classification that may provide an improvement over pathology diagnosis on the basis of overall transcriptomic and morphological features. The molecular subclassification provided a comprehensive molecular characterization of PTCL subtypes, including viral etiologic factors and translocation partners. CONCLUSION: We developed a novel transcriptomic approach for PTCL subclassification that facilitates translation into clinical practice with higher precision and uniformity than conventional pathology diagnosis.
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Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/genética , Transcriptoma , Reproducibilidad de los Resultados , Perfilación de la Expresión Génica , PronósticoRESUMEN
Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.
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Interferón gamma , Linfoma de Células T Periférico , Animales , Interferón gamma/genética , Linfoma de Células T Periférico/patología , Metiltransferasas/genética , Ratones , Mutación , Pronóstico , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
BACKGROUND: Pediatric myelodysplastic syndrome is a rare but life-threatening condition requiring prompt recognition and management. METHODS: We herein present the only reported case of a pediatric multi-organ transplant recipient developing myelodysplastic syndrome. RESULTS: The patient was a 14-year-old girl on chronic calcineurin inhibitor therapy who presented with peri-rectal pain approximately 13 years after liver, small bowel, and pancreas transplant. The initial workup revealed pancytopenia and parvovirus B19 viremia. Her definitive diagnosis was complicated by a lack of adequate bone marrow biopsy specimens and expert consultation that resulted in treatment for hemophagocytic lymphohistiocytosis. She was later diagnosed with high-grade myelodysplastic syndrome. Although curative treatment with chemotherapy and hematopoietic stem cell transplantation was strongly considered, it was not performed due to the child's rapid clinical progression, ventilator status, and active infections. The patient died approximately 6 months following symptom onset. CONCLUSIONS: This case emphasizes the importance of early recognition of myelodysplastic syndrome in multi-organ transplant recipients on chronic immunosuppression. Pancytopenia is a common presentation in the post-transplant period that requires thorough investigation. Multiple confounding considerations such as infection, immunosuppression, and systemic inflammation can delay the diagnosis of underlying hematological malignancies. Transplant care providers should be aware of myelodysplastic syndrome and advocate for a comprehensive evaluation, given early recognition and intervention can significantly improve outcomes.
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Linfohistiocitosis Hemofagocítica , Síndromes Mielodisplásicos , Trasplante de Órganos , Pancitopenia , Adolescente , Médula Ósea/patología , Niño , Femenino , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico , Síndromes Mielodisplásicos/complicaciones , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Trasplante de Órganos/efectos adversos , Pancitopenia/diagnóstico , Pancitopenia/etiologíaRESUMEN
Composite classic Hodgkin lymphoma and follicular lymphoma (CHLFL) is a rare and poorly characterized entity. Herein, we report the clinicopathologic features of 22 cases of CHLFL from 3 institutions and we assess 27 additional cases reported in the literature. In our cohort (n=22), patients with CHLFL had a median age of 61 years and an equal male to female incidence. Most cases (95%) arose de novo with the remaining patients having a history of non-Hodgkin lymphoma. CHLFL always involved lymph nodes (100%) and most cases (95%) revealed 2 distinct areas separately diagnostic for CHL and FL. The CHL component represented a variable proportion of the overall neoplasm (5% to 90%) and was either mixed cellularity (82%) or nodular sclerosis (18%) type. The Hodgkin/Reed-Sternberg cells expressed CD30 (100%), PAX5 (100%), CD15 (62%), BCL6 (47%), BCL2 (29%), and EBER (25%), in a polymorphous inflammatory background typical of CHL. The FL component was low-grade in 55%, grade 3A in 36%, and grade 3B in 9% of cases. All 3 cases investigated by cytogenetic methods for a clonal relationship between the CHL and FL components were clonally related. These clinicopathologic features of our cohort are similar to those of cases reported in the literature. The 5-year overall survival in combined patients with CHLFL (n=49) was 48%, comparable to CHL but worse than FL in the elderly. In summary, CHLFL is a rare entity that most often occurs in older adults, involves lymph nodes, and most commonly presents de novo. In the small number of cases assessed, the CHL and FL components are usually clonally related suggesting that the CHL and FL components may share a common progenitor B-cell, likely a mutated germinal center B-cell.
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Enfermedad de Hodgkin , Linfoma Folicular , Anciano , Femenino , Enfermedad de Hodgkin/genética , Enfermedad de Hodgkin/patología , Humanos , Antígeno Ki-1 , Ganglios Linfáticos/patología , Linfoma Folicular/genética , Linfoma Folicular/patología , Masculino , Persona de Mediana Edad , Células de Reed-Sternberg/patologíaRESUMEN
PURPOSE: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin lymphomas with aggressive clinical behavior. We performed comprehensive miRNA profiling in PTCLs and corresponding normal CD4+ Th1/2 and TFH-like polarized subsets to elucidate the role of miRNAs in T-cell lymphomagenesis. EXPERIMENTAL DESIGN: We used nCounter (NanoString Inc) for miRNA profiling and validated using Taqman qRT-PCR (Applied Biosystems, Inc). Normal CD4+ T cells were polarized into effector Th subsets using signature cytokines, and miRNA significance was revealed using functional experiments. RESULTS: Effector Th subsets showed distinct miRNA expression with corresponding transcription factor expression (e.g., BCL6/miR-19b, -106, -30d, -26b, in IL21-polarized; GATA3/miR-155, miR-337 in Th2-polarized; and TBX21/miR-181a, -331-3p in Th1-polarized cells). Integration of miRNA signatures suggested activation of TCR and PI3K signaling in IL21-polarized cells, ERK signaling in Th1-polarized cells, and AKT-mTOR signaling in Th2-polarized cells, validated at protein level. In neoplastic counterparts, distinctive miRNAs were identified and confirmed in an independent cohort. Integrative miRNA-mRNA analysis identified a decrease in target transcript abundance leading to deregulation of sphingolipid and Wnt signaling and epigenetic dysregulation in angioimmunoblastic T-cell lymphoma (AITL), while ERK, MAPK, and cell cycle were identified in PTCL subsets, and decreased target transcript abundance was validated in an independent cohort. Elevated expression of miRNAs (miR-126-3p, miR-145-5p) in AITL was associated with poor clinical outcome. In silico and experimental validation suggest two targets (miR-126â SIPR2 and miR-145 â ROCK1) resulting in reduced RhoA-GTPase activity and T-B-cell interaction. CONCLUSIONS: Unique miRNAs and deregulated oncogenic pathways are associated with PTCL subtypes. Upregulated miRNA-126-3p and miR-145-5p expression regulate RhoA-GTPase and inhibit T-cell migration, crucial for AITL pathobiology.
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Regulación Neoplásica de la Expresión Génica , Estudio de Asociación del Genoma Completo , Linfoma de Células T Periférico/genética , MicroARNs/genética , Humanos , Células Tumorales CultivadasRESUMEN
INTRODUCTION: The diagnosis of myelodysplastic syndromes (MDS) and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) is based on morphology and cytogenetics/FISH findings per 2017 WHO classification. With rare exceptions, somatic mutations have not been incorporated as the diagnostic criteria. METHODS: We analyzed the utility of mutational analysis with a targeted 54-gene or 40-gene next-generation sequencing (NGS) panel in the diagnosis of MDS and MDS/MPN. RESULTS: We retrospectively collected 92 patients who presented with unexplained cytopenia with or without cytosis, including 32 low-grade MDS (MDS-L), 18 high-grade MDS (MDS-H), 5 therapy-related MDS (MDS-TR), 19 MDS/MPN, and 18 negative cases. Of 92 patients, 197 somatic mutations involving 38 genes were detected and had variant allele frequency (VAF) ranging from 3% to 99%. The most common mutated genes were TET2, ASXL1, RUNX1, TP53, SRSF2, and SF3B1. MDS-L, MDS-H, MDS-TR, and MDS/MPN showed an average number of somatic mutations with a mean VAF of 1.9/33%, 2.6/30%, 2/36%, and 4/41%, respectively. SF3B1 mutations were exclusively observed in MDS-L and MDS/MPN. TP53 gene mutations were more frequently seen in MDS-H and MDS-TR. Among 34 patients with a diagnosis of MDS or MDS/MPN with normal cytogenetics, 31 patients (91%) had at least 1 mutation and 24 patients (71%) had ≥2 mutations with ≥10% VAF. CONCLUSION: A myeloid mutational panel provides additional evidence of clonality besides cytogenetics/FISH studies in the diagnosis of cytopenia with or without cytosis. Two or more mutations with ≥10% VAF highly predicts MDS and MDS/MPN with a positive predictive value of 100%.
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Biomarcadores de Tumor , Predisposición Genética a la Enfermedad , Pruebas Genéticas , Mutación , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Enfermedades Mielodisplásicas-Mieloproliferativas/diagnóstico , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Alelos , Análisis Mutacional de ADN , Manejo de la Enfermedad , Estudios de Asociación Genética , Pruebas Genéticas/métodos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Fenotipo , Estudios RetrospectivosRESUMEN
This commentary highlights the article by Grumaz et al that describes the use of molecular sequencing for fast detection of pathogens directly from blood samples from septic patients.
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Secuenciación de Nucleótidos de Alto Rendimiento , Linfocitos T , HumanosRESUMEN
Splenic marginal zone lymphoma (SMZL) is a rare, indolent non-Hodgkin's lymphoma that affects 0. 13 per 100,000 persons annually. Overall survival of SMZL is estimated to reach 8-11 years in most cases, but up to 30% of SMZL cases develop aggressive presentations resulting in greatly diminished time of survival. SMZL presents with a very heterogeneous molecular profile, making diagnosis problematic, and accurate prognosis even less likely. The study herein has identified a potential diagnostic gene expression signature with highly specific predictive utility, coined the SMZL-specific Gene Expression Signature (SSGES). Additionally, five of the most impactful markers identified within the SSGES were selected for a five-protein panel, for further evaluation among control and SMZL patient samples. These markers included EME2, ERCC5, SETBP1, USP24, and ZBTB32. When compared with control spleen and other B-cell lymphoma subtypes, significantly higher expression was noticed in SMZL samples when stained for EME2 and USP24. Additionally, ERCC5, SETBP1, USP24, and ZBTB32 staining displayed indications of prognostic value for SMZL patients. Delineation of the SSGES offers a unique SMZL signature that could provide diagnostic utility for a malignancy that has historically been difficult to identify, and the five-marker protein panel provides additional support for such findings. These results should be further investigated and validated in subsequent molecular investigations of SMZL so it may be potentially incorporated into standard oncology practice for improving the understanding and outlook for SMZL patients.
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OBJECTIVE. Primary CNS posttransplant lymphoproliferative disorder (PTLD) may present as multiple contrast-enhancing intraaxial lesions, often with central necrosis and surrounding edema. This imaging appearance is similar to the pattern seen in brain metastases. The purpose of this study was to find differences in the radiologic features of primary CNS PTLD lesions and brain metastases. MATERIALS AND METHODS. We retrospectively reviewed the radiologic findings of 51 primary CNS PTLD lesions in 10 patients and 156 metastatic brain lesions in 25 patients. Lesion size, multifocality, location, necrosis, hemorrhage, perilesional vasogenic edema, contrast enhancement, and diffusion and perfusion features were evaluated. We used the chi-square test or Fisher exact test when appropriate to compare the findings between primary CNS PTLD lesions and brain metastases. RESULTS. Primary CNS PTLD lesions occur in the deep gray matter and periventricular locations more frequently than brain metastases (p < 0.0001) and are not present at the gray and white matter junctions and vascular border zones as commonly as brain metastases are (p < 0.0001). Primary CNS PTLD tends to have less frequent hemorrhage (p < 0.0001), more restricted diffusion (p = 0.001), and lower perfusion (p = 0.002) than brain metastases. We did not find statistically significant differences between primary CNS PTLD and brain metastases for lesion size, multifocality, necrosis, and perilesional edema. CONCLUSION. The imaging characteristics of primary CNS PTLD overlap considerably with those of brain metastases, but there are significant differences between primary CNS PTLD lesions and brain metastases in lesion location, diffusion and perfusion features, and tendency to hemorrhage.
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Encefalopatías/diagnóstico por imagen , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/secundario , Trastornos Linfoproliferativos/diagnóstico por imagen , Neuroimagen/métodos , Trasplante de Órganos , Complicaciones Posoperatorias/diagnóstico por imagen , Adolescente , Adulto , Anciano , Niño , Preescolar , Medios de Contraste , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/patología , Estudios RetrospectivosRESUMEN
Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL-not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.
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Biomarcadores de Tumor , Linfoma de Células T Periférico/diagnóstico , Linfoma de Células T Periférico/etiología , Adulto , Anciano , Algoritmos , Biología Computacional/métodos , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Inmunofenotipificación , Linfoma de Células T Periférico/metabolismo , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: Central nervous system post-transplant lymphoproliferative disorder (CNS-PTLD) is a rare disease that presents with non-specific signs and symptoms. The purpose of this article is to present the imaging appearances of CNS-PTLD by magnetic resonance imaging. We highlight the differential diagnostic considerations including primary central nervous system lymphoma, glioblastoma, cerebral abscess, and metastatic disease. This is an important topic to review since in daily practice the diagnosis of CNS-PTLD is often not initially considered when present due to its rarity and the lack of radiologists' familiarity with the disease. CONCLUSION: Knowing the unique imaging features of CNS-PTLD narrows the differential diagnosis, facilitates the diagnostic work-up, and optimizes making the diagnosis. Advanced MRI data for CNS PTLD is limited but is promising for helping with narrowing the differential diagnosis.
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Incorporating genetic variant data into the electronic health record (EHR) in discrete computable fashion has vexed the informatics community for years. Genetic sequence test results are typically communicated by the molecular laboratory and stored in the EHR as textual documents. Although text documents are useful for human readability and initial use, they are not conducive for data retrieval and reuse. As a result, clinicians often struggle to find historical gene sequence results on a series of oncology patients within the EHR that might influence the care of the current patient. Second, identification of patients with specific mutation results in the EHR who are now eligible for new and/or changing therapy is not easily accomplished. Third, the molecular laboratory is challenged to monitor its sequencing processes for nonrandom process variation and other quality metrics. A novel approach to address each of these issues is presented and demonstrated. The authors use standard Health Level 7 laboratory result message formats in conjunction with international standards, Systematized Nomenclature of Medicine Clinical Terms and Human Genome Variant Society nomenclature, to represent, communicate, and store discrete gene sequence data within the EHR in a scalable fashion. This information management plan enables the support of the clinician at the point of care, enhances population management, and facilitates audits for maintaining laboratory quality.
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Registros Electrónicos de Salud , Patología Molecular/normas , Análisis de Secuencia de ADN/normas , Secuencia de Bases , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estándares de Referencia , Terminología como AsuntoRESUMEN
Peripheral T-cell lymphoma (PTCL) is a group of complex clinicopathological entities, often associated with an aggressive clinical course. Angioimmunoblastic T-cell lymphoma (AITL) and PTCL-not otherwise specified (PTCL-NOS) are the 2 most frequent categories, accounting for >50% of PTCLs. Gene expression profiling (GEP) defined molecular signatures for AITL and delineated biological and prognostic subgroups within PTCL-NOS (PTCL-GATA3 and PTCL-TBX21). Genomic copy number (CN) analysis and targeted sequencing of these molecular subgroups revealed unique CN abnormalities (CNAs) and oncogenic pathways, indicating distinct oncogenic evolution. PTCL-GATA3 exhibited greater genomic complexity that was characterized by frequent loss or mutation of tumor suppressor genes targeting the CDKN2A /B-TP53 axis and PTEN-PI3K pathways. Co-occurring gains/amplifications of STAT3 and MYC occurred in PTCL-GATA3. Several CNAs, in particular loss of CDKN2A, exhibited prognostic significance in PTCL-NOS as a single entity and in the PTCL-GATA3 subgroup. The PTCL-TBX21 subgroup had fewer CNAs, primarily targeting cytotoxic effector genes, and was enriched in mutations of genes regulating DNA methylation. CNAs affecting metabolic processes regulating RNA/protein degradation and T-cell receptor signaling were common in both subgroups. AITL showed lower genomic complexity compared with other PTCL entities, with frequent co-occurring gains of chromosome 5 (chr5) and chr21 that were significantly associated with IDH2 R172 mutation. CN losses were enriched in genes regulating PI3K-AKT-mTOR signaling in cases without IDH2 mutation. Overall, we demonstrated that novel GEP-defined PTCL subgroups likely evolve by distinct genetic pathways and provided biological rationale for therapies that may be investigated in future clinical trials.
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Variaciones en el Número de Copia de ADN , Linfoma de Células T Periférico/genética , Oncogenes , Femenino , Factor de Transcripción GATA3/genética , Perfilación de la Expresión Génica , Humanos , Linfadenopatía Inmunoblástica/genética , Linfoma de Células T Periférico/clasificación , Masculino , Mutación , Proteínas de Dominio T Box/genéticaRESUMEN
Although generally curable with intensive chemotherapy in resource-rich settings, Burkitt lymphoma (BL) remains a deadly disease in older patients and in sub-Saharan Africa. Epstein-Barr virus (EBV) positivity is a feature in more than 90% of cases in malaria-endemic regions, and up to 30% elsewhere. However, the molecular features of BL have not been comprehensively evaluated when taking into account tumor EBV status or geographic origin. Through an integrative analysis of whole-genome and transcriptome data, we show a striking genome-wide increase in aberrant somatic hypermutation in EBV-positive tumors, supporting a link between EBV and activation-induced cytidine deaminase (AICDA) activity. In addition to identifying novel candidate BL genes such as SIN3A, USP7, and CHD8, we demonstrate that EBV-positive tumors had significantly fewer driver mutations, especially among genes with roles in apoptosis. We also found immunoglobulin variable region genes that were disproportionally used to encode clonal B-cell receptors (BCRs) in the tumors. These include IGHV4-34, known to produce autoreactive antibodies, and IGKV3-20, a feature described in other B-cell malignancies but not yet in BL. Our results suggest that tumor EBV status defines a specific BL phenotype irrespective of geographic origin, with particular molecular properties and distinct pathogenic mechanisms. The novel mutation patterns identified here imply rational use of DNA-damaging chemotherapy in some patients with BL and targeted agents such as the CDK4/6 inhibitor palbociclib in others, whereas the importance of BCR signaling in BL strengthens the potential benefit of inhibitors for PI3K, Syk, and Src family kinases among these patients.
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Biomarcadores de Tumor/genética , Linfoma de Burkitt/genética , Infecciones por Virus de Epstein-Barr/complicaciones , Genes de Inmunoglobulinas , Genoma Humano , Mutación , Transcriptoma , Adolescente , Adulto , Linfoma de Burkitt/patología , Linfoma de Burkitt/virología , Niño , Preescolar , Estudios de Cohortes , Citidina Desaminasa/genética , Infecciones por Virus de Epstein-Barr/genética , Infecciones por Virus de Epstein-Barr/virología , Femenino , Estudios de Seguimiento , Herpesvirus Humano 4/aislamiento & purificación , Humanos , Lactante , Recién Nacido , Masculino , Fenotipo , Pronóstico , Adulto JovenRESUMEN
OBJECTIVES: We developed a simple and effective rinsing technique (RT) of needle biopsies to produce cell suspensions for flow cytometry (FCM) and evaluated whether the RT is comparable to the conventional tissue cell suspension (TCS) technique. METHODS: We retrieved 93 needle core biopsy cases employing the RT for FCM and 25 needle biopsy cases using TCS for FCM. RESULTS: The diagnostic concordance between the FCM results and the morphologic diagnoses of both groups was compared. The diagnostic concordance was comparable in the RT group (92.6%) to the TCS group (71.4%). Furthermore, the diagnostic concordance in the RT group was associated with number of isolated cells. The diagnostic accuracy increased significantly when the cell number was above 30,000 in the RT group. CONCLUSIONS: The RT for FCM not only maximizes the tissue utilization, but also is a simple and effective method to obtain cell suspension as compared to traditional cell suspension technique. © 2018 International Clinical Cytometry Society.
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Biopsia con Aguja Gruesa , Citometría de Flujo , Leucemia Linfoide/diagnóstico , Leucemia Linfoide/patología , Humanos , Persona de Mediana Edad , Estudios RetrospectivosAsunto(s)
Inhibidores Enzimáticos/farmacología , Linfoma de Células del Manto , Proteínas de Neoplasias , Proteína de Unión al GTP rac1 , Línea Celular Tumoral , Humanos , Linfoma de Células del Manto/tratamiento farmacológico , Linfoma de Células del Manto/enzimología , Linfoma de Células del Manto/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Proteína de Unión al GTP rac1/antagonistas & inhibidores , Proteína de Unión al GTP rac1/metabolismoRESUMEN
The World Health Organization classification of lymphoma recommends the subdivision of follicular lymphoma (FL) into 3 grades (FL1-3) based on the average number of centroblasts per high-power field in the neoplastic follicles, but does not recognize a form of FL characterized by a predominance of large cleaved cells (centrocytes) without enough centroblasts to meet the World Health Organization criteria for FL3. We have classified such cases as follicular large cleaved cell lymphoma (FLC) and, herein, describe the pathologic and clinical features of 72 cases of this entity. The features of FLC include a follicular growth pattern with pale follicles at low magnification and frequent follicular and/or interfollicular fibrosis. Cytologically, the cells are predominantly large cleaved cells with moderately coarse to fine chromatin, absent or inconspicuous nucleoli, and small to moderate amounts of pale cytoplasm. The mean nuclear diameter of the large cleaved cells was 10.1µ, approximately twice that of small lymphocytes and similar to centroblasts. The t(14;18) was present in 83% of the cases, and a high proportion expressed BCL2 (84%), BCL6 (100%), and CD10 (88%) and had high Ki67 proliferation (81%). The clinical features of patients with FLC were similar to those with other types of FL, and survival was excellent with anthracycline-based chemotherapy plus rituximab. FLC is a variant of follicular lymphoma which should be recognized in future lymphoma classifications because the diagnosis of FLC may be important for the selection of therapy.