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A rare lymphoproliferative disorder involving thrombocytopenia (T), anasarca (A), fever (F), reticulin fibrosis (R), renal dysfunction (R), and organomegaly (O), called TAFRO syndrome, was first reported in 2010. Considered a variant of idiopathic multicentric Castleman's disease, the recent discovery and rarity of this syndrome pose challenges to diagnosis and management. Herein, we review three pediatric cases, including an infant, that illustrate the heterogeneity of TAFRO syndrome. Despite differences in presentation and treatment responses, all patients experienced excellent outcomes. This multi-institutional case series highlights the need to work toward earlier diagnosis and improved long-term management recommendations for patients with TAFRO syndrome.
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Enfermedad de Castleman , Trombocitopenia , Adolescente , Femenino , Humanos , Lactante , Masculino , Enfermedad de Castleman/patología , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/terapia , Edema/patología , Edema/etiología , Fiebre/etiología , Síndrome , Trombocitopenia/terapia , Trombocitopenia/diagnóstico , Trombocitopenia/patologíaRESUMEN
Little is known about the central nervous system (CNS) risk in high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). Hence, we sought to describe the rates of baseline CNS involvement, risk of CNS recurrence after primary therapy, and management strategies in HGBL, NOS. In this multicenter retrospective study, we included 160 adults with newly diagnosed HGBL, NOS treated between 2016 and 2021 at 20 US institutions. Eleven patients (7%) had baseline CNS involvement at diagnosis (leptomeningeal=6, parenchymal=4, and both=1). Baseline CNS involvement was significantly associated only with MYC rearrangement (OR=3.5) and testicular (in men) or female pelvic (in women) involvement (OR=8.1). There was no significant difference in survival outcomes between HGBL, NOS patients with (median PFS=4 years) or without (median PFS=2.4 years) baseline CNS involvement (p=0.45). The cumulative incidence of CNS recurrence at 3 years was 11%. Patients with baseline CNS involvement were at the highest risk (48.5% versus 8% for those without baseline CNS involvement) and were excluded from the risk factors analysis for CNS recurrence. The risk for CNS recurrence was significantly associated with blood or bone marrow involvement, CD5 expression, non-GCB subtype, and DEL phenotype, however, high CNS-IPI was not. The prognosis of relapsed HGBL, NOS was poor, regardless of whether recurrence was systemic or limited to the CNS, and with currently available salvage strategies, including autologous transplantation and CAR T-cell modalities, almost all patients with CNS recurrence ultimately succumbed to their disease. These patients represent an unmet need and should be prioritized for experimental approaches.
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Leucemia Megacarioblástica Aguda , Humanos , Leucemia Megacarioblástica Aguda/inmunología , Leucemia Megacarioblástica Aguda/genética , Leucemia Megacarioblástica Aguda/patología , Ratones , Animales , Niño , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Inmunoterapia Adoptiva , Femenino , Masculino , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/inmunología , Proteínas de Fusión Oncogénica/metabolismoRESUMEN
TP53 mutational status in myeloid neoplasms is prognostic and in acute myeloid leukaemia (AML) may lead to alternative induction therapy; therefore, rapid assessment is necessary for precision treatment. Assessment of multiple prognostic genes by next generation sequencing in AML is standard of care, but the turn-around time often cannot support rapid clinical decision making. Studies in haematological neoplasms suggest p53 immunohistochemistry (IHC) correlates with TP53 mutational status, but they have used variable criteria to define TP53 overexpression. p53 IHC was performed and interpreted on AZF-fixed, acid decalcified bone marrow biopsies on 47 cases of clonal myeloid neoplasms with TP53 mutations between 2016 and 2019 and 16 control samples. Results were scored by manual and digital analysis. Most TP53-mutated cases (81%) overexpressed p53 by digital analysis and manual analysis gave similar results. Among the nine TP53-mutated IHC-negative cases, seven (78%) were truncating mutations and two (22%) were single-hit missense mutations. Using a digital cut-off of at least 3% ≥1+ positive nuclei, the sensitivity and specificity are 81% and 100%; cases with loss-of-function mutations were more likely to be negative. In this cohort, p53 immunopositivity correlated with TP53 mutational status, especially missense mutations, with excellent specificity. Truncating TP53 mutations explain most IHC-negative cases, impacting the sensitivity. We demonstrate that p53 IHC can screen for TP53 mutations allowing quicker treatment decisions for most patients. However, not all patients will be identified, so molecular studies are required. Furthermore, cut-offs for positivity vary in the literature, consequently laboratories should independently validate their processes before adopting p53 IHC for clinical use. p53 IHC performs well to screen for TP53 mutations in AZF-fixed bone marrow. Performance in our setting differs from the literature, which shows variability of pre-analytic factors and cut-offs used to screen for TP53 mutations. Each laboratory should validate p53 IHC to screen for TP53 mutations in their unique setting.
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Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Humanos , Proteína p53 Supresora de Tumor/genética , Médula Ósea/patología , Inmunohistoquímica , Mutación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , BiopsiaRESUMEN
CONTEXT.: Gene editing-based therapies are currently in development in the areas of oncology, inherited disease, and infectious disease. These potentially life-altering therapies are derived from decades of research in both academic and industry settings that developed technologies rooted in principles and products of nature. However, with such technologic developments come many important considerations, including adverse risks, high cost, and ethical questions. OBJECTIVE.: To educate pathologists about gene editing technologies, inform them of potential indications and risks, outline regulatory and practical issues that could affect hospital-based practice and laboratory testing, and advocate that pathologists need to be present at discussions among industry and regulators pertaining to gene editing-based therapies. DESIGN.: A Gene Editing Workgroup, facilitated by the College of American Pathologists Personalized Health Care Committee and consisting of pathologists of various backgrounds, was convened to develop an educational paper to serve as a stimulus to increase pathologist involvement and inquiry in gene editing therapeutic and diagnostic implementation. RESULTS.: Through multiple discussions and literature review, the workgroup identified potential gaps in pathologists' knowledge of gene editing. Additional topics that could impact pathology and laboratory medicine were also identified and summarized in order to facilitate pathologists as stakeholders in gene editing therapy administration and monitoring and potential use in diagnostics. CONCLUSIONS.: Gene editing therapy is a complex but potentially transformative area of medicine. This article serves as an introduction to pathologists to assist them in future discussions with colleagues and potentially identify and alter pathology practices that relate to gene editing.
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CONTEXT: Gene editing-based therapies are currently in development in the areas of oncology, inherited disease, and infectious disease. These potentially life-altering therapies are derived from decades of research in both academic and industry settings that developed technologies rooted in principles and products of nature. However, with such technologic developments come many important considerations, including adverse risks, high cost, and ethical questions. OBJECTIVE: To educate pathologists about gene editing technologies, inform them of potential indications and risks, outline regulatory and practical issues that could affect hospital-based practice and laboratory testing, and advocate that pathologists need to be present at discussions among industry and regulators pertaining to gene editing-based therapies. DESIGN: A Gene Editing Workgroup, facilitated by the College of American Pathologists Personalized Health Care Committee and consisting of pathologists of various backgrounds, was convened to develop an educational paper to serve as a stimulus to increase pathologist involvement and inquiry in gene editing therapeutic and diagnostic implementation. RESULTS: Through multiple discussions and literature review, the workgroup identified potential gaps in pathologists' knowledge of gene editing. Additional topics that could impact pathology and laboratory medicine were also identified and summarized in order to facilitate pathologists as stakeholders in gene editing therapy administration and monitoring and potential use in diagnostics. CONCLUSIONS: Gene editing therapy is a complex but potentially transformative area of medicine. This article serves as an introduction to pathologists to assist them in future discussions with colleagues and potentially identify and alter pathology practices that relate to gene editing.
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In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.
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Linfoma de Células B Grandes Difuso , Humanos , Persona de Mediana Edad , Rituximab/uso terapéutico , Estudios Retrospectivos , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Prednisona/uso terapéutico , Vincristina/uso terapéutico , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Etopósido , Lactato DeshidrogenasasRESUMEN
The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML) and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G-fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, folate receptor α (FOLR1), and demonstrated their preclinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.
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Receptor 1 de Folato , Inmunoterapia Adoptiva , Leucemia Megacarioblástica Aguda , Proteínas de Fusión Oncogénica , Animales , Niño , Preescolar , Humanos , Lactante , Modelos Animales de Enfermedad , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Leucemia Megacarioblástica Aguda/genética , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Linfocitos T , Transcriptoma , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Vacuoles, E1, X-linked, autoimmunity, somatic (VEXAS) syndrome is characterized by a pathogenic mutation in UBA1, which leads to protean complications including autoimmunity and myelodysplasia. A 56-year-old man with steroid-dependent, later steroid-refractory cutaneous polyarteritis nodosa and Sweet syndrome developed recurrent daily fever, macrocytic anemia, thrombocytopenia, acute hypoxic respiratory failure, and anasarca. He was eventually diagnosed with Epstein-Barr virus (EBV) viremia and hemophagocytic lymphohistiocytosis (HLH). He improved clinically with rituximab, ruxolitinib, and increased glucocorticoids before expiring from Pseudomonas sepsis. UBA1 exon 3 mutational analysis in myeloid enriched peripheral blood revealed a c.122T>C (p.Met41Thr) pathogenic variant, consistent with VEXAS syndrome. We describe the first case of EBV-associated HLH in a patient diagnosed with VEXAS syndrome. Early identification of this syndrome will be important in order to offer potential therapies before life-threatening complications arise.
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Infecciones por Virus de Epstein-Barr , Linfohistiocitosis Hemofagocítica , Síndromes Mielodisplásicos , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Virus de Epstein-Barr/tratamiento farmacológico , Herpesvirus Humano 4 , Humanos , Linfohistiocitosis Hemofagocítica/complicaciones , Linfohistiocitosis Hemofagocítica/diagnóstico , Linfohistiocitosis Hemofagocítica/tratamiento farmacológico , Masculino , Persona de Mediana Edad , RituximabRESUMEN
Unusual presentations of otherwise common hematopoietic neoplasms are a well-recognized diagnostic challenge. Herein, we present a case study of a previously healthy 64 year old woman with myeloid sarcoma whose diagnosis was delayed by an unusual immunohistochemical staining pattern, including cytokeratin expression, by the neoplastic cells and by possible anchoring bias introduced by radiographic and flow cytometric immunophenotyping reports. This case study emphasizes the need to integrate clinical, radiographic, histologic, and immunophenotyping data for rapid and accurate tissue diagnoses while being wary of the lack of specificity for many common immunophenotypic markers.
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Sarcoma Mieloide , Biomarcadores de Tumor , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Inmunofenotipificación , Queratinas , Persona de Mediana Edad , Sarcoma Mieloide/diagnósticoRESUMEN
Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children's Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (<0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD- patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.
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Antimetabolitos Antineoplásicos/uso terapéutico , Citarabina/uso terapéutico , Síndrome de Down/complicaciones , Leucemia Mieloide/complicaciones , Leucemia Mieloide/tratamiento farmacológico , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/efectos adversos , Preescolar , Citarabina/administración & dosificación , Citarabina/efectos adversos , Relación Dosis-Respuesta a Droga , Síndrome de Down/genética , Femenino , Humanos , Lactante , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Masculino , Neoplasia Residual/diagnóstico , Neoplasia Residual/genética , Pronóstico , Resultado del TratamientoRESUMEN
The gastrointestinal (GI) tract is home to a significant portion of the immune system, which interacts daily with the antigenic milieu of its contents. Therefore, the presence of white blood cells within the walls of the GI tract upon histologic examination is a familiar sight on GI biopsies-both in health and disease. The GI tract is the most common site of extranodal lymphomas, most of which are B-cell neoplasms. Here, we review common and uncommon B-cell neoplasms of the GI tract - extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma), mantle cell lymphoma, duodenal-type follicular lymphoma, diffuse large B-cell lymphoma, plasmablastic lymphoma, EBV-positive mucocutaneous ulcer, and post-transplant lymphoproliferative disorders - with special focus on literature published during the past five years. Along with the other articles in this edition of Seminars in Diagnostic Pathology, it is the authors' hope that this review proves to be a useful resource in the workup of the array of hematopoietic processes that can involve the GI tract.
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Neoplasias Gastrointestinales , Linfoma de Células B de la Zona Marginal , Trastornos Linfoproliferativos , Neoplasias Gástricas , Adulto , Linfocitos B , HumanosRESUMEN
BACKGROUND: Peripheral blood smears are performed to evaluate a variety of hematologic and non-hematologic disorders. At the authors' institutions, clinician requests for pathologist-performed blood smear reviews have increased in recent years. Blood smears may contribute significantly to pathologists' workloads, yet their clinical value is variable, and professional reimbursement rates are low. This study aimed to identify clinical scenarios in which smear review is likely to provide value beyond automated laboratory testing. METHODS: Blood smear review practices at three institutions were examined, and the indications for and interpretations of clinician-initiated smears were reviewed to determine the percentage of smears with potential added clinical value. A smear review was classified as having added clinical value if the pathologist's interpretation included a morphologic abnormality that had the potential to impact patient management, and that could not be diagnosed by automated complete blood count with white blood cell differential or automated iron studies alone. RESULTS: Among 515 consecutive clinician-requested smears performed during the study timeframes, 23% yielded interpretations with potential added clinical value. When sorted by indication, 25, 19, and 13% of smear reviews requested for white blood cell abnormalities, red blood cell abnormalities, and platelet abnormalities, respectively, had findings with potential added clinical value. The proportion of smears with potential clinical value differed significantly across these three categories (p = 0.0375). CONCLUSIONS: Smear review ordering practices across three institutions resulted in a minority of smears with potential added clinical value. The likelihood of value varied according to the indication for which the smear was requested. Given this, efforts to improve the utilization and efficiency of smear review are worthwhile. Solutions are discussed, including engaging laboratory staff, educating clinicians, and modifying technology systems.
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Células Sanguíneas/patología , Neoplasias del Cuello Uterino/diagnóstico , Neoplasias del Cuello Uterino/patología , Frotis Vaginal , Técnicas de Laboratorio Clínico/métodos , Pruebas Diagnósticas de Rutina/métodos , Eficiencia , Femenino , Humanos , Frotis Vaginal/métodosAsunto(s)
Atovacuona/administración & dosificación , Azitromicina/administración & dosificación , Babesia microti/metabolismo , Babesiosis , Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva , Aloinjertos , Babesiosis/sangre , Babesiosis/tratamiento farmacológico , Babesiosis/etiología , Humanos , Leucemia Mielógena Crónica BCR-ABL Positiva/complicaciones , Leucemia Mielógena Crónica BCR-ABL Positiva/parasitología , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Masculino , Persona de Mediana EdadRESUMEN
CONTEXT.: Cancer immunotherapy provides unprecedented rates of durable clinical benefit to late-stage cancer patients across many tumor types, but there remains a critical need for biomarkers to accurately predict clinical response. Although some cancer immunotherapy tests are associated with approved therapies and considered validated, other biomarkers are still emerging and at various states of clinical and translational exploration. OBJECTIVE.: To provide pathologists with a current and practical update on the evolving field of cancer immunotherapy testing. The scientific background, clinical data, and testing methodology for the following cancer immunotherapy biomarkers are reviewed: programmed death ligand-1 (PD-L1), mismatch repair, microsatellite instability, tumor mutational burden, polymerase δ and ε mutations, cancer neoantigens, tumor-infiltrating lymphocytes, transcriptional signatures of immune responsiveness, cancer immunotherapy resistance biomarkers, and the microbiome. DATA SOURCES.: Selected scientific publications and clinical trial data representing the current field of cancer immunotherapy. CONCLUSIONS.: The cancer immunotherapy field, including the use of biomarker testing to predict patient response, is still in evolution. PD-L1, mismatch repair, and microsatellite instability testing are helping to guide the use of US Food and Drug Administration-approved therapies, but there remains a need for better predictors of response and resistance. Several categories of tumor and patient characteristics underlying immune responsiveness are emerging and may represent the next generation of cancer immunotherapy predictive biomarkers. Pathologists have important roles and responsibilities as the field of cancer immunotherapy continues to develop, including leadership of translational studies, exploration of novel biomarkers, and the accurate and timely implementation of newly approved and validated companion diagnostics.
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Biomarcadores de Tumor/análisis , Inmunoterapia/métodos , Neoplasias/terapia , HumanosRESUMEN
BACKGROUND: The Verigene Enteric Pathogens Test (Luminex Corporation) is a polymerase chain reaction (PCR)/nucleic acid microarray-based assay targeting 8 bacterial and viral pathogens that cause diarrhea. OBJECTIVE: To compare traditional enteric culture methods with stool testing by Verigene EP (PCR/microarray). METHODS: Tests were performed using PCR/microarray between February and August 2016. All specimens also underwent culture for Salmonella and Shigella; specimens that tested positive for bacterial pathogen(s) had confirmatory cultures. RESULTS: Valid results were obtained for 99.3% of the 3795 stool specimens. Among these, 497 (13.2%) specimens tested positive for at least 1 pathogen by PCR/microarray; 45.5% of these tested positive for 1 or more bacterial pathogens. Agreement between positive bacterial PCR/microarray results and culture-based testing was 85.3%. Compared with cultures, PCR/microarray demonstrated 95.2% and 87.5% sensitivity and 99.8% and 99.8% specificity for Salmonella and Shigella, respectively. CONCLUSIONS: The Verigene EP generated evaluable results for most stool specimens tested and demonstrated good agreement with bacterial cultures.
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Automatización de Laboratorios/métodos , Infecciones Bacterianas/diagnóstico , Diarrea/diagnóstico , Análisis por Micromatrices/métodos , Técnicas de Diagnóstico Molecular/métodos , Reacción en Cadena de la Polimerasa/métodos , Virosis/diagnóstico , Heces/microbiología , Heces/virología , Estudios Prospectivos , Sensibilidad y EspecificidadRESUMEN
Urinary tract blastomycosis is an uncommon manifestation of disseminated Blastomyces infection. Here, we report a 50-year-old male with common variable immunodeficiency who presented with urinary symptoms and a renal mass concerning for a kidney neoplasm. Urine cytology revealed typical broad-based budding yeasts with thick-walled refractile capsules, leading to diagnosis of urinary tract blastomycosis. In this case, urine cultures were negative, and urine cytology was the main method of diagnosis of blastomycosis. Thus, urine cytology represents a rapid and reliable method of diagnosing blastomycosis, which in the current case led to prompt treatment of this potentially life threatening infection.