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Bone marrow aspiration (BMA) smear analysis is essential for diagnosis, treatment, and monitoring of a variety of benign and neoplastic hematological conditions. Currently, this analysis is performed by manual microscopy. We conducted a multicenter study to validate a computational microscopy approach with an artificial intelligence-driven decision support system. A total of 795 BMA specimens (615 Romanowsky-stained and 180 Prussian blue-stained) from patients with neoplastic and other clinical conditions were analyzed, comparing the performance of the Scopio Labs X100 Full Field BMA system (test method) with manual microscopy (reference method). The system provided an average of 1,385 ± 536 (range, 0-3,131) cells per specimen for analysis. An average of 39.98 ± 19.64 fields of view (range, 0-140) per specimen were selected by the system for analysis, of them 87% ± 21% (range, 0%-100%) were accepted by the qualified operators. These regions were included in an average of 17.62 ± 7.24 regions of interest (range, 1-50) per specimen. The efficiency, sensitivity, and specificity for primary and secondary marrow aspirate characteristics (maturation, morphology, and count assessment), as well as overall interuser agreement, were evaluated. The test method showed a high correlation with the reference method for comprehensive BMA evaluation, both on Romanowsky- (90.85% efficiency, 81.61% sensitivity, and 92.88% specificity) and Prussian blue-stained samples (90.0% efficiency, 81.94% sensitivity, and 93.38% specificity). The overall agreement between the test and reference methods for BMA assessment was 91.1%. For repeatability and reproducibility, all standard deviations and coefficients of variation values were below the predefined acceptance criteria both for discrete measurements (coefficient of variation below 20%) and differential measurements (SD below 5%). The high degree of correlation between the digital decision support system and manual microscopy demonstrates the potential of this system to provide a high-quality, accurate digital BMA analysis, expediting expert review and diagnosis of BMA specimens, with practical applications including remote BMA evaluation and possibly new opportunities for the research of normal and neoplastic hematopoiesis.
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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
Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.
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Linfoma de Células del Manto , Adulto , Humanos , Anciano , Linfoma de Células del Manto/patología , Rituximab/efectos adversos , Clorhidrato de Bendamustina/uso terapéutico , Biomarcadores , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
Although the majority of patients with chronic myeloid leukemia (CML) enjoy an excellent prognosis tyrosine kinase inhibitor (TKI) therapy, resistance remains a significant clinical problem. Resistance can arise from mutations in the kinase domain of ABL preventing drug binding, or due to ill-defined kinase-independent mechanisms. In this case report, we describe the case of a 27-year-old woman with a long-standing history of chronic phase (CP) CML who developed kinase-independent resistance with mutations in ASXL1 and RUNX1. As a consequence of uncontrolled disease, she progressed to a chronic myelomonocytic leukemia-like (CMML) accelerated phase (AP) disease with the acquisition of a mutation in IDH1. This disease progression was associated with the development of an inflammatory serositis, a phenomenon that has been described in CMML but not in AP-CML. This case presents key features of kinase-independent resistance with insight into potential mechanisms, highlights management challenges, and describes a novel systemic inflammatory response that occurred in this patient upon disease progression.
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A man in his 60s presented with a 5-year history of diffuse erythematous, edematous annular plaques, low-grade fevers, and mild leukopenia. What is your diagnosis?
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Leucopenia , Masculino , Humanos , Persona de Mediana Edad , Diagnóstico DiferencialRESUMEN
Myeloid sarcoma (MS) is currently considered equivalent to de novo acute myeloid leukemia (AML); however, the relationship between these entities is poorly understood. This retrospective multi-institutional cohort study compared 43 MS with NPM1 mutation to 106 AML with NPM1 mutation. Compared to AML, MS had more frequent cytogenetic abnormalities including complex karyotype (p = .009 and p = .007, respectively) and was enriched in mutations of genes involved in histone modification, including ASXL1 (p = .007 and p = .008, respectively). AML harbored a higher average number of gene mutations (p = .002) including more frequent PTPN11 mutations (p < .001) and mutations of DNA-methylating genes including DNMT3A and IDH1 (both p < .001). MS had significantly shorter overall survival (OS) than AML (median OS: 44.9 vs. 93.2 months, respectively, p = .037). MS with NPM1 mutation has a unique genetic landscape, and poorer OS, compared to AML with NPM1 mutation.
First study comparing genetic profiles of MS and AML with a common disease-defining lesion.NPM1Mut MS may be genetically distinct from NPM1Mut AML.NPM1Mut MS may have inferior overall survival compared to NPM1Mut AML.
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Leucemia Mieloide Aguda , Sarcoma Mieloide , Humanos , Médula Ósea/patología , Proteínas Nucleares/genética , Nucleofosmina , Sarcoma Mieloide/diagnóstico , Sarcoma Mieloide/genética , Sarcoma Mieloide/patología , Estudios Retrospectivos , Estudios de Cohortes , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , PronósticoRESUMEN
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
Acute myeloid leukemia (AML) with NUP98 rearrangement (AML-NUP98) has been uncommonly reported in adults, and its incidence in our institution is â¼2.5%. There were four men and five women with a median age of 49 years, among which six cases were de novo AML and three were therapy-related. Five cases were AML with minimal differentiation or without maturation, followed by four with monocytic differentiation. NUP98 rearrangement was confirmed in all cases by FISH, and five cases showed cryptic translocations. The median overall survival (OS) was 13 months, shorter than that of AML-NPM1 (p < 0.05), and similar to that in AML-KMT2A patients in our institution. The unfavorable OS was further confirmed by comparing to AML patients in TCGA database. In conclusion, adult AML-NUP98 is associated with cryptic translocations and an unfavorable outcome. Our study suggests that incorporating the NUP98 probe into AML FISH panels are warranted to improve clinical management.
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Leucemia Mieloide Aguda , Aberraciones Cromosómicas , Femenino , Reordenamiento Génico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Proteínas de Complejo Poro Nuclear/genética , Translocación GenéticaRESUMEN
ABSTRACT: Cutaneous/systemic plasmacytosis (C/SP) is a plasma cell disorder characterized by reddish-brown patches, lymphadenopathy, and hypergammaglobulinemia. The degree to which C/SP overlaps with other plasma cell proliferative disorders and neoplasms is incompletely understood. We present the case of a patient with a several-year history of cutaneous plasmacytosis and evidence of systemic involvement with concurrent idiopathic multicentric Castleman disease (iMCD) involving a lymph node. There have been only a few reports of systemic iMCD preceded by a long, asymptomatic phase of cutaneous manifestations. We discuss the relationship between C/SP and iMCD and elaborate on the pathophysiological overlap of these 2 conditions and potential similarities in their pathogenesis. We suggest that the 2 diseases may represent the same entity presenting on a spectrum, with individuals diagnosed with C/SP at risk for progression to iMCD.
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Enfermedad de Castleman/diagnóstico , Células Plasmáticas/patología , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Enfermedad de Castleman/tratamiento farmacológico , Enfermedad de Castleman/patología , Diagnóstico Diferencial , Femenino , Humanos , Persona de Mediana EdadRESUMEN
AML, frequently showing megakaryocytic differentiation, is known to arise in MGCT and has a dismal prognosis. Close inspection of MGCT is required to identify concurrent AML.
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Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated condition defined by the presence of a somatic mutation in a leukemia-associated gene in individuals who otherwise have no evidence of a hematologic malignancy. In the allogeneic hematopoietic cell transplantation (HCT) setting, clonal hematopoiesis (CH) mutations present in donor stem cells can be transferred to recipients at the time of HCT. Given that the consequences of donor-derived CH in HCT recipients are not entirely clear, we sought to investigate clinical outcomes in patients with engrafted donor-derived CH using a matched cohort analysis of both related and unrelated donors. Of 209 patients with next-generation sequencing performed before and after HCT, donor-derived CH mutations were detected in 15 (5.2%). DNMT3A was the most commonly mutated gene (9 of 15; 60%); mutations in SF3B1, CSF3R, STAT3, CBLB, TET2, and ASXL1 were also identified. Donor-derived CH was not associated with delayed neutrophil or platelet engraftment, and there was no impact on conversion to full donor chimerism. No patients with donor-derived CH experienced relapse, in contrast to 15.6% (7 of 45) in the matched control cohort without CH (P = .176). Donor-derived CH was not associated with worse overall survival; however, patients with donor-derived CH were more likely to develop chronic graft-versus-host disease (GVHD) necessitating systemic immunosuppressive therapy (IST) (P = .045) and less likely to discontinue IST (P = .03) compared with controls without donor-derived CH. We conclude that donor-derived CH does not have an adverse impact on relapse, survival, or engraftment outcomes but may potentiate a graft-versus-leukemia effect, as reflected by increased chronic GVHD necessitating IST.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Hematopoyesis Clonal , Enfermedad Injerto contra Huésped/genética , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Recurrencia , Trasplante Homólogo , Donante no EmparentadoRESUMEN
Chimeric antigen receptor T-cell therapy (CAR T) is a novel intervention for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) and other hematologic malignancies. However, it is associated with prolonged hematologic toxicity (PHT) that is unpredictable and can significantly impair patients' quality of life. Reported here is a single-center experience with PHT in adult patients with R/R DLBCL who received commercial CAR T-cell therapy between March 1, 2018 and May 30, 2020. Prolonged hematologic toxicity was defined as ≥ grade 3 neutropenia or thrombocytopenia at day +30 after CAR T-cell therapy. Of the 31 patients identified, 18 patients (58%) developed PHT. Patients with PHT had a shorter 1-year overall survival (OS) than patients without PHT (36% vs. 81%, P < .05). There were no differences in the median time to ANC recovery for those with PHT compared to patients without PHT (16 days vs. 15 days). Several risk factors were identified to be associated with PHT including CRS (P = .002), receipt of tocilizumab (P = .002) or steroids (P = .033), peak ferritin >5000 ng/ml (P = .048), peak C-reactive protein (CRP) > 100 mg/L (P = .007), and ferritin greater than the upper limit of normal at day +30. Seven patients with PHT underwent a bone marrow biopsy after CAR T-cell therapy; all showed complete aplasia or were hypocellular with cellularity ranging from <5% to 10%. These findings identify PHT as a significant toxicity associated with CAR T-cell therapy and highlight the critical need for further investigations to describe PHT in larger cohorts and identify standards for management of this condition.
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Inmunoterapia Adoptiva/efectos adversos , Linfoma de Células B Grandes Difuso/terapia , Neutropenia/etiología , Trombocitopenia/etiología , Corticoesteroides/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Médula Ósea/patología , Terapia Combinada , Ciclofosfamida/administración & dosificación , Femenino , Ferritinas/sangre , Humanos , Infecciones/etiología , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/sangre , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Vidarabina/administración & dosificación , Vidarabina/análogos & derivados , Adulto JovenRESUMEN
The COVID-19 outbreak caused by the novel coronavirus, SARS-CoV-2, typically presents with symptoms including fever, cough, headache, myalgia, asthenia, anosmia, diarrhea, and sometimes pneumonia, which can be fatal. Recently, new dermatologic findings have been described in association with the disease that can potentially be a distinguishing feature of infection. One such feature resembles chilblains and this case report represents a presentation of this feature with a 48-year-old female with violaceous lesions with surrounding pink erythema on her toes who tested negative for COVID-19.
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Eritema Pernio/virología , Infecciones por Coronavirus/complicaciones , Neumonía Viral/complicaciones , Enfermedades de la Piel/virología , Animales , Betacoronavirus , COVID-19 , Gatos , Femenino , Humanos , Persona de Mediana Edad , Pandemias , SARS-CoV-2 , Dedos del Pie/patologíaAsunto(s)
Dolor Abdominal/diagnóstico , Medios de Contraste/administración & dosificación , Mastocitoma/diagnóstico , Vómitos/diagnóstico , Dolor Abdominal/etiología , Dolor Abdominal/patología , Adulto , Medios de Contraste/efectos adversos , Rubor/diagnóstico , Rubor/etiología , Rubor/patología , Humanos , Masculino , Mastocitos/patología , Mastocitoma/complicaciones , Mastocitoma/diagnóstico por imagen , Mastocitoma/patología , Ultrasonografía , Vómitos/etiología , Vómitos/patologíaRESUMEN
A fever of unknown origin is often pursued diagnostically under the framework of infectious, rheumatologic, and neoplastic causes. When encephalopathy ensues, the differential diagnosis narrows, but can remain elusive, particularly when dealing with rare diseases. We present the case of a patient with fever of unknown origin and intermittent encephalopathy that spanned multiple hospital admissions and ultimately yielded a diagnosis of intravascular large B cell lymphoma complicated by hemophagocytic lymphohistiocytosis. We review the varying presentations of this disease, when to consider this as a diagnosis, and how to most accurately make the diagnosis.
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Linfohistiocitosis Hemofagocítica , Linfoma de Células B Grandes Difuso , Diagnóstico Diferencial , Fiebre , Humanos , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfoma de Células B Grandes Difuso/complicaciones , Linfoma de Células B Grandes Difuso/diagnóstico , PielRESUMEN
Anti-low-density lipoprotein receptor-related lipoprotein 2 (LRP2) nephropathy/anti-brush border antibody disease is rare and characterized by tubular basement membrane, Bowman's capsule and glomerular subepithelial immune deposits on kidney biopsy. No reported cases have occurred in patients with lymphoproliferative disorders or monoclonal gammopathies. We present two cases of anti-LRP2 nephropathy that occurred in patients with progressive low-grade B-cell lymphoma and had concurrent kidney infiltration by lymphoma on biopsy. We speculate that underlying immune dysregulation related to lymphoma may contribute to the development of this rare autoimmune kidney disease in some patients.