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Cytogenomic characterization is crucial for the classification and risk stratification of acute myeloid leukemia (AML), thereby facilitating therapeutic decision-making. We examined the clinical utility of optical genome mapping (OGM) in 159 AML patients (103 newly diagnosed and 56 refractory/relapsed), all of whom also underwent chromosomal banding analysis (CBA), fluorescence in situ hybridization, and targeted next-generation sequencing. OGM detected nearly all clinically relevant cytogenetic abnormalities that SCG identified with >99% sensitivity, provided the clonal burden was above 20%. OGM identified additional cytogenomic aberrations and/or provided information on fusion genes in 77 (48%) patients, including eight patients with normal karyotypes and four with failed karyotyping. The most common additional alterations identified by OGM included chromoanagenesis (n = 23), KMT2A partial tandem duplication (n = 11), rearrangements involving MECOM (n = 7), NUP98 (n = 2), KMT2A (n = 2), JAK2 (n = 2), and other gene fusions in 17 patients, with 10 showing novel fusion gene partners. OGM also pinpointed fusion genes in 17 (11%) patients where chromosomal rearrangements were concurrently detected by OGM and CBA. Overall, 24 (15%) aberrations were identified exclusively by OGM and had the potential to alter AML classification, risk stratification, and/or clinical trial eligibility. OGM emerges as a powerful tool for identifying fusion genes and detecting subtle or cryptic cytogenomic aberrations that may otherwise remain undetectable by CBA.
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INTRODUCTION: NPM1-mutated (NPM1mut) myeloid neoplasms (MNs) with <20% bone marrow (BM) blasts (NPM1mut MNs<20) are uncommon, and their classification remains inconsistent. METHODS: The clinicopathologic features of 54 patients with NPM1mut MNs <20 were evaluated and compared with wild-type NPM1 MNs <20 and NPM1mut MNs≥20, respectively. RESULTS: NPM1mut MNs had similar features regardless of blast percentage, except for higher IDH2 (29% vs 7%, p = .023) and FLT3 (70% vs 11%, p < .001) frequency in patients with ≥20% BM blasts. Thirty-three (61%) patients with NPM1mut MNs <20 received low-intensity chemotherapy (LIC) and 12 (22%) received intensive chemotherapy (IC). Higher complete remission rates (75% vs 27%, p = .006) and median overall survival (mOS) (not reached vs 30.4 months, p = .06) were observed with IC compared to LIC. Young patients (age <60 years) did not reach mOS either when treated with LIC or IC. Stem cell transplant was associated with increased survival only in patients treated with LIC (HR, 0.24; p = .025). No differences in mOS were observed by BM blast strata (32.2 months, not reached and 46.9 months for <10%, 10%-19%, and ≥20% blasts, p = .700) regardless of treatment modality (LIC: p = .900; IC: p = .360). Twenty-three patients (43%) with NPM1mut MNs <20 had marrow blast progression to ≥20%. CONCLUSIONS: Overall, NPM1mut MNs define a unique entity independent of BM blast percentage.
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Protocolos de Quimioterapia Combinada Antineoplásica , Citarabina , Síndrome de Down , Leucemia Mieloide Aguda , Humanos , Síndrome de Down/tratamento farmacológico , Síndrome de Down/complicações , Citarabina/uso terapêutico , Citarabina/administração & dosagem , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Masculino , Lactente , Decitabina/farmacologia , Decitabina/uso terapêutico , Decitabina/administração & dosagem , Azacitidina/uso terapêutico , Azacitidina/administração & dosagem , Pré-Escolar , Antimetabólitos Antineoplásicos/uso terapêuticoRESUMO
Optical genome mapping (OGM) is a new DNA-based technology which provides comprehensive examination of the entire genome. We report two patients who presented with splenomegaly and leukocytosis with lymphocytosis including villous lymphocytes. Neither patient had lymphadenopathy. Bone marrow evaluation showed involvement by small B-cell lymphoma in a sinusoidal and interstitial distribution, and immunophenotypic analysis showed that the neoplastic cells were positive for B-cell markers and cyclin D1 but were negative for SOX11 and CD5. Initially, the clinicopathologic features in both patients were thought to be suspicious for hairy cell leukemia variant or splenic marginal zone lymphoma. However, OGM detected CCND1 rearrangement: t(2;11)/IGK::CCND1 in one case and t(11;14)/IGH::CCND1 in the other case. These cases illustrate the valuable role OGM can play in establishing the diagnosis of MCL. Case 1 also contributes to the paucity of literature on the rare occurrence of IGK::CCND1 in MCL.
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Leucemia Linfocítica Crônica de Células B , Linfoma de Células B , Linfoma de Célula do Manto , Adulto , Humanos , Linfoma de Célula do Manto/patologia , Leucemia Linfocítica Crônica de Células B/patologia , Linfócitos/patologia , Genômica , Ciclina D1/genéticaRESUMO
Most gastric cancers are adenocarcinomas, but other malignancies can arise in the stomach. Patients with leukemia may develop myeloid sarcoma (MS) in the gastrointestinal tract. Our patient was a 68-year-old woman who was initially diagnosed with acute myeloid leukemia and underwent a matched unrelated stem cell transplantation. She was in remission for 10 years before developing a rare case of gastric MS without acute myeloid leukemia. She had partial response to chemotherapy but ultimately died because of infection. Gastric MS has an incidence of less than 1%. Gastrointestinal involvement usually involves the small intestine and rarely the stomach.
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DDX41 is the most frequently mutated gene in myeloid neoplasms associated with germline predisposition including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We analyzed 3795 patients with myeloid neoplasms and identified 151 (4%) with DDX41 variants and a diagnosis of AML (n = 96), MDS (n = 52), and chronic myelomonocytic leukemia (n = 3). The most frequent DDX41 variants were the somatic variant p.R525H, followed by the germline variants p.M1I and p.D140fs. Most neoplasms had a normal karyotype (59%) and the most frequent co-mutations were TP53 (16%) and ASXL1 (15%). 30% of patients had no concomitant mutations besides DDX41 mutation. Patients with myeloid malignancies and DDX41 variants responded well to therapy, with an overall response rate for patients with treatment naïve AML and MDS of 87% and 84%, respectively. The median overall survival (mOS) of patients with treatment-naïve AML or MDS was 49 and 71 months, respectively. Patients with AML treated with low-intensity regimens including venetoclax had an improved survival (2-year OS 91% vs. 60%, p = .02) and lower cumulative incidence of relapse compared to those treated without venetoclax (10% vs. 56%, p = .03). In the 33% of patients receiving hematopoietic stem cell transplantation, the 2-year OS was 80% and 85% for AML and MDS, respectively.
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Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy, especially in pediatrics, that can involve the bone marrow, skin, lymph nodes, and central nervous system (CNS). Given its variable clinical presentation, coupled with an immunohistochemistry pattern (CD4, CD56, TCF4, TCL-1, and CD123 positivity) that differs from other myeloid neoplasms, the diagnosis of BPDCN can be missed. Limited data are available to guide the treatment of pediatric BPDCN. Herein, we report a case of a pediatric patient who had BPDCN with central nervous system, orbital, and skin involvement. This patient achieved complete remission after receiving modified hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone with venetoclax and intrathecal chemotherapy. He remains disease-free 200 days after receiving a stem cell transplant. This represents the first known published pediatric case using a modified hyper-CVAD plus venetoclax regimen for treating a pediatric BPDCN patient in the frontline setting.
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Neoplasias Hematológicas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Masculino , Humanos , Criança , Células Dendríticas/patologia , Neoplasias Cutâneas/patologia , Pele/patologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Neoplasias Hematológicas/patologiaRESUMO
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that can involve the bone marrow, peripheral blood, skin, lymph nodes, and the central nervous system. Though more common in older adults, BPDCN has been reported across all age groups, including infants and children. The incidence of pediatric BPDCN is extremely low and little is known about the disease. Pediatric BPDCN is believed to be clinically less aggressive but often with more dissemination at presentation than adult cases. Unlike adults who almost always proceed to a hematopoietic stem cell transplantation in first complete remission if transplant-eligible, the majority of children can be cured with a high-risk acute lymphoblastic leukemia-like regimen. Hematopoietic stem cell transplantation is recommended for children with high-risk disease, the definition of which continues to evolve, or those in relapse and refractory settings where outcomes continue to be dismal. Novel agents used in other hematologic malignancies and CD123 targeted agents, including chimeric antigen receptor T-cells and monoclonal/bispecific antibodies, are being brought into research and practice. Our goal is to provide a comprehensive review of presentation, diagnosis, and treatment by review of pediatric cases reported for the last 20 years, and a review of novel targeted therapies and therapies under investigation for adult and pediatric patients.
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Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Transtornos Mieloproliferativos , Neoplasias Cutâneas , Criança , Humanos , Adolescente , Adulto Jovem , Idoso , Células Dendríticas/patologia , Neoplasias Hematológicas/patologia , Neoplasias Cutâneas/patologia , Transtornos Mieloproliferativos/patologiaRESUMO
The development of therapy-related myeloid neoplasms (t-MN) is a rare complication that can occur in myeloma patients treated primarily with novel therapies. To better understand t-MNs in this context, we reviewed 66 such patients and compared them with a control group of patients who developed t-MN after cytotoxic therapies for other malignancies. The study group included 50 men and 16 women, with a median age of 68 years (range, 48-86 years). Therapies included proteasome inhibitors, immunomodulatory agents, and high-dose melphalan-based autologous stem cell transplantation (HDM-ASCT) in 64 (97%), 65 (98.5%), and 64 (97%) patients, respectively; 29 (43.9%) patients were exposed to other cytotoxic drugs besides HDM. The latency interval from therapy to t-MN was 4.9 years (range, 0.6-21.9 years). Patients who received HDM-ASCT in addition to other cytotoxic therapies had a longer latency period to t-MN compared with patients who only received HDM-ASCT (6.1 vs 4.7 years, P = .009). Notably, 11 patients developed t-MN within 2 years. Therapy-related myelodysplastic syndrome was the most common type of neoplasm (n = 60), followed by therapy-related acute myeloid leukemia (n = 4) and myelodysplastic syndrome/myeloproliferative neoplasm (n = 2). The most common cytogenetic aberrations included complex karyotypes (48.5%), del7q/-7 (43.9%), and/or del5q/-5 (40.9%). The most frequent molecular alteration was TP53 mutation, in 43 (67.2%) patients and the sole mutation in 20 patients. Other mutations included DNMT3A, 26.6%; TET2, 14.1%; RUNX1, 10.9%; ASXL1, 7.8%; and U2AF1, 7.8%. Other mutations in less than 5% of cases included SRSF2, EZH2, STAG2, NRAS, SETBP, SF3B1, SF3A1, and ASXL2. After a median follow-up of 15.3 months, 18 patients were alive and 48 died. The median overall survival after the diagnosis of t-MN in the study group was 18.4 months. Although the overall features are comparable to the control group, the short interval to t-MN (<2 years) underscores the unique vulnerable status of myeloma patients.
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Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Mieloma Múltiplo , Síndromes Mielodisplásicas , Doenças Mieloproliferativas-Mielodisplásicas , Masculino , Humanos , Feminino , Gravidez , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Mieloma Múltiplo/genética , Mieloma Múltiplo/terapia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante Autólogo/efeitos adversos , Melfalan/efeitos adversos , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/induzido quimicamente , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/terapiaRESUMO
T-cell neoplasms are a highly heterogeneous group of leukaemias and lymphomas that represent 10-15% of all lymphoid neoplasms. Traditionally, our understanding of T-cell leukaemias and lymphomas has lagged behind that of B-cell neoplasms, in part due to their rarity. However, recent advances in our understanding of T-cell differentiation, based on gene expression and mutation profiling and other high throughput methods, have better elucidated the pathogenetic mechanisms of T-cell leukaemias and lymphomas. In this review, we provide an overview of many of the molecular abnormalities that occur in various types of T-cell leukaemia and lymphoma. Much of this knowledge has been used to refine diagnostic criteria that has been included in the fifth edition of the World Health Organization. This knowledge is also being used to improve prognostication and identify novel therapeutic targets, and we expect this progress will continue, eventually resulting in improved outcomes for patients with T-cell leukaemias and lymphomas.
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Leucemia , Linfoma de Células B , Linfoma , Humanos , Linfoma/diagnóstico , Linfoma/genética , Linfoma/patologia , Linfoma de Células B/patologia , Leucemia/patologia , Linfócitos T/patologia , MutaçãoRESUMO
T-prolymphocytic leukemia (T-PLL) is a rare, aggressive T-cell leukemia, and patients typically present with marked peripheral blood lymphocytosis. Approximately 15-20 % of patients may present with moderate and relative stable lymphocytosis and an indolent clinical course that can persist for a few years. However, eventually these patients go on to develop marked lymphocytosis and rapidly progressive disease. We report a 72-year-old man who presented with multicompartmental lymphadenopathy and a normal complete blood count. Excision of left and right cervical lymph nodes showed replacement of the lymph node architecture by a small T-cell neoplasm positive for CD3, CD4, CD5, CD7 and TCL-1, and negative for CD8, CD20, CD30 and ALK. Subsequent bone marrow evaluation showed minimal bone marrow involvement by a T-cell neoplasm associated with TCL1A rearrangement in 11 % of cells supporting the diagnosis of T-PLL. Despite treatment, he showed progressive lymphadenopathy while remarkably maintaining normal white blood cell counts until he eventually developed leukocytosis of 110.9 × 103/uL 26 months later. Review of the literature identified only a single abstract reporting a patient with a similar lymphoma-like presentation and normal white blood cell count; however, that case showed significant bone marrow involvement in stark contrast to the current case. In summary, we report a highly unusual case of T-PLL can initially presenting with an aleukemic or lymphoma-like clinical picture, which can make establishing the diagnosis challenging.
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Leucemia Prolinfocítica de Células T , Leucemia Prolinfocítica , Linfadenopatia , Linfocitose , Masculino , Humanos , Idoso , Linfocitose/patologia , Leucemia Prolinfocítica/patologia , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/patologia , Medula Óssea/patologia , Linfadenopatia/patologiaAssuntos
Linfoma de Células B , Neoplasias de Plasmócitos , Macroglobulinemia de Waldenstrom , Humanos , Paraproteínas , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/patologia , Linfoma de Células B/patologia , Neoplasias de Plasmócitos/diagnóstico , Neoplasias de Plasmócitos/patologia , Diferenciação Celular , Imunoglobulina G , Plasmócitos/patologiaRESUMO
Lymphoplasmacytic lymphoma (LPL) with IgG or IgA paraprotein is rare and a subset of cases can mimic a plasma cell neoplasm (PCN). We studied 29 such cases to explore their clinicopathological features and the best diagnostic approaches with a focus on bone marrow findings. The cohort included 18 men and 11 women with a median age of 68 years. The median M protein was 3.1 g/dL, IgG in 19 patients (66%), IgA in 9 (31%), and dual IgG/IgA in 1 (3%). All patients had bone marrow involvement with CD138+ plasma cells (PCs) ranging from 1 to 35% (median, 10%). Two patients also had amyloidosis. Immunoglobulin light chain concordant monotypic PCs and monotypic B cells were identified in 96% of cases assessed by flow cytometry. Notably, the neoplastic PCs were consistently positive for CD45 (dim, 100%), CD19 (96%), CD81 (89%), CD27 (83%), rarely and only weakly or partially express CD56 (16%), whereas CD117 was consistently negative. Eleven cases analyzed by fluorescence in situ hybridization were negative for CCND1::IGH and myeloma-related aberrations. MYD88 mutation was detected in 17 of 24 cases (71%), and CXCR4 mutation was identified in 6 of 19 cases (32%), of which 4 had concurrent MYD88 mutation. In conclusion, the results highlight a potential diagnostic pitfall of LPL associated with marked plasmacytic differentiation and an IgG or IgA paraprotein that can resemble a PCN. Useful features in favor of LPL against PCN include the characteristic immunophenotypic profile of the PCs in LPL, absence of CCND1::IGH, and the presence of MYD88 and/or CXCR4 mutations.
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Linfoma de Células B , Mieloma Múltiplo , Plasmocitoma , Macroglobulinemia de Waldenstrom , Masculino , Humanos , Feminino , Idoso , Paraproteínas/genética , Hibridização in Situ Fluorescente , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/genética , Mieloma Múltiplo/patologia , Imunoglobulina GRESUMO
Resumen Introducción: Estudios previos han relacionado la presencia de fibrilación auricular (FA) con una tasa de filtrado glomerular estimada (TFGe) reducida. Objetivo: comparar la evolución de la TFGe en pacientes con FA persistente tras cardioversión eléctrica (CVE) programada en función de la existencia o no de recurrencias, así como la evolución de varios biomarcadores. Materiales y métodos: Cohorte prospectiva de pacientes con FA persistente remitidos a nuestro centro para CVE programada con seguimiento de un año. La TFGe se obtuvo mediante la fórmula CKD-EPI en el momento basal y a los 3 y 12 meses. Se midieron biomarcadores antes de la CVE y a los 12 meses. Resultados: Se incluyeron 92 pacientes con FA persistente, edad media de 64 ± 11 años. Al año de seguimiento y en el total de pacientes, la TFGe se redujo de 86,5 [74,6-97,6 a 84,5 [71,7-95,1 ml/min/1,73 m2 (p = 0,002) y la creatinina aumentó de 0,80 [0,72-0,94] mg/dl a 0,83 [0,74-0,97] mg/dl (p = 0,005). La TFGe se redujo al final del seguimiento, sin diferencia estadísticamente significativa entre los pacientes que presentaron recurrencia a los 12 meses y los que no. Las cifras de BNP y corina mejoraron a los 12 meses, mientras que las de galectina-3 no cambiaron, sin relación con la TFGe. Conclusiones: En los pacientes con FA persistente tratados con CVE programada se observó un empeoramiento de la TFGe al año de seguimiento. Los niveles de BNP y corina mejoraron al año de seguimiento. No hubo diferencias en los niveles de galectina-3.
Abstract Introduction: Previous studies have linked the presence of atrial fibrillation (AF) with a reduced estimated glomerular filtration rate (eGFR). Objective: to compare the evolution of eGFR in patients with persistent AF after elective electrical cardioversion (ECV) based on the existence or not of recurrences, as well as the evolution of various biomarkers. Materials and methods: Prospective cohort of patients with persistent AF referred to our center for elective EVC with a 1-year follow-up. The eGFR was obtained using the CKD-EPI formula at baseline and at 3 and 12 months. Biomarkers were measured before ECV and at 12 months. Results: 92 patients with persistent AF were included, mean age 64 ± 11 years. At one year of follow-up and in all patients, the eGFR decreased from 86.5 [74.6-97.6 to 84.5 [71.7-95.1 ml/min/1.73 m2 (p = 0.002) and creatinine increased from 0.80 [0.72-0.94] mg/dl to 0.83 [0.74-0.97] mg/dl (p = 0.005). The eGFR was reduced at the end of the follow-up, with no statistically significant difference between the patients who had recurrence at 12 months and those who did not. BNP and corin levels improved at 12 months, while galectin-3 did not change, unrelated to eGFR. Conclusions: In patients with persistent AF treated with elective ECV, a worsening of eGFR was observed at one year of follow-up. BNP and corin levels improve at one year of follow-up, there were no differences in galectin-3 levels.
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EZH2 coding mutation (EZH2MUT), resulting in loss-of-function, is an independent predictor of overall survival in MDS. EZH2 function can be altered by other mechanisms including copy number changes, and mutations in other genes and non-coding regions of EZH2. Assessment of EZH2 protein can identify alterations of EZH2 function missed by mutation assessment alone. Precise evaluation of EZH2 function and gene-protein correlation in clinical MDS cohorts is important in the context of upcoming targeted therapies aimed to restore EZH2 function. In this study, we evaluated the clinicopathologic characteristics of newly diagnosed MDS patients with EZH2MUT and correlated the findings with protein expression using immunohistochemistry. There were 40 (~6%) EZH2MUT MDS [33 men, seven women; median age 74 years (range, 55-90)]. EZH2 mutations spanned the entire coding region. Majority had dominant EZH2 clone [median VAF, 30% (1-92)], frequently co-occurring with co-dominant TET2 (38%) and sub-clonal ASXL1 (55%) and RUNX1 (43%) mutations. EZH2MUT MDS showed frequent loss-of-expression compared to EZH2WT (69% vs. 27%, p = 0.001). Interestingly, NINE (23%) EZH2WT MDS also showed loss-of-expression. EZH2MUT and loss-of-expression significantly associated with male predominance and chr(7) loss. Further, only EZH2 loss-of-expression patients showed significantly lower platelet counts, a trend for higher BM blast% and R-IPSS scores. Over a 14-month median follow-up, both EZH2MUT (p = 0.027) and loss-of-expression (p = 0.0063) correlated with poor survival, independent of R-IPSS, age and gender. When analyzed together, loss-of-expression showed a stronger correlation than mutation (p = 0.061 vs. p = 0.43). In conclusion, immunohistochemical assessment of EZH2 protein, alongside mutation, is important for prognostic workup of MDS.
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Proteína Potenciadora do Homólogo 2 de Zeste , Síndromes Mielodisplásicas , Idoso , Idoso de 80 Anos ou mais , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/patologia , Prognóstico , Fatores de Transcrição/genéticaRESUMO
The development of clonally related hematologic neoplasms in the setting of primary mediastinal germ cell tumors (PMGCTs) has been recognized previously and is associated with a dismal prognosis. However, the presentation of hematologic neoplasms as chronic myelomonocytic leukemia (CMML) and hemophagocytic lymphohistiocytosis (HLH) has been rarely reported. Here we report two patients with PMGCTs and hematologic neoplasms. The PMGCT was composed mostly of yolk sac tumor whereas the hematologic neoplasms had morphologic features that resembled CMML and HLH. The hematologic neoplasms from both patients harbored isochromosome 12p [i(12p)] and TP53 mutations, supporting a clonal relationship between these tumors. This association represents a unique clinical syndrome that likely contributes to the poor clinical outcome of these patients.
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Neoplasias Hematológicas , Isocromossomos , Neoplasias do Mediastino , Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Neoplasias Hematológicas/genética , Humanos , Masculino , Neoplasias do Mediastino/genética , Neoplasias do Mediastino/patologia , Mutação , Neoplasias Embrionárias de Células Germinativas/genética , Proteína Supressora de Tumor p53/genéticaAssuntos
Imunoterapia Adotiva , Linfoma de Células B , Anticorpos Monoclonais Humanizados , Antígenos CD19 , Epitopos , Humanos , Imunoterapia Adotiva/efeitos adversos , Linfoma de Células B/diagnóstico , Linfoma de Células B/patologia , Linfoma de Células B/terapia , Receptores de Antígenos de Linfócitos TRESUMO
Epstein-Barr virus (EBV) is associated with hematologic and solid tumors. We utilized a hybridization capture-based next-generation sequencing (NGS) platform targeting 400 genes associated with hematological malignancies to detect and quantify nontargeted viral-derived EBV reads that aligned to the EBV reference contig (NC_007605). We evaluated 5234 samples from 3636 unique patients with hematological neoplasms and found that 100 samples (1.9%) in 93 unique patients had ≥6 EBV reads (range, 6 to 32,325; mean, 827.5; median, 54). Most (n = 73, 73%) represented known EBV-associated conditions, and the most common was post-transplant lymphoproliferative disorders (n = 21, 29%). Documented EBV viremia was found in 4 of 27 samples with a moderate quantity of EBV reads and conditions not known to be EBV associated, whereas suspected viremia or low-level activation was likely in the remaining 23 samples. A good correlation (Spearman r = 0.8; 95% CI, 0.74-0.85) was found between EBV reads by NGS and systematic semiquantitative EBV-encoded RNA in situ hybridization in 162 available samples, particularly at greater EBV involvement. An optimal threshold for significant morphologic EBV involvement was found to be ≥10 reads by the receiver operating characteristic analysis (area under the curve, 0.990; 95% CI, 0.9974%-1.000%). Thus, in addition to mutational analysis, hybrid-capture-based NGS panels can detect and quantitate off-target EBV-derived viral DNA, which correlates well with morphology.