RESUMEN
T-cell large granular lymphocytic (T-LGL) leukemia is a rare, typically indolent neoplasm with a median age of onset above 60 years. Pathogenesis involves clonal T-cell expansion, and nearly all reported pediatric cases have been associated with concurrent autoimmune disease. Immunosuppressive therapy often mitigates sequelae, but definitive cure is not routinely achieved. Here we present an otherwise healthy 13-year-old with T-LGL leukemia refractory to all standard treatments. Our patient ultimately underwent allogeneic bone marrow transplant (BMT) and is now stable in remission 3 years post-BMT. BMT may offer a viable definitive cure for refractory T-LGL leukemia in very young patients.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Leucemia Linfocítica Granular Grande , Adolescente , Trasplante de Médula Ósea/efectos adversos , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Leucemia Linfocítica Granular Grande/terapia , Persona de Mediana Edad , Linfocitos T/patologíaRESUMEN
Follicular lymphoma (FL) is a common indolent B-cell malignancy with a variable clinical course. An unfavorable event in its course is histological transformation to a high-grade lymphoma, typically diffuse large B-cell lymphoma. Recent studies show that genetic aberrations of MYC or its overexpression are associated with FL transformation (tFL). However, the precise molecular mechanisms underlying tFL are unclear. Here we performed the first profiling of expression of microRNAs (miRNAs) in paired samples of FL and tFL and identified 5 miRNAs as being differentially expressed. We focused on one of these miRNAs, namely miR-150, which was uniformly downmodulated in all examined tFLs (â¼3.5-fold), and observed that high levels of MYC are responsible for repressing miR-150 in tFL by binding in its upstream region. This MYC-mediated repression of miR-150 in B cells is not dependent on LIN28A/B proteins, which influence the maturation of miR-150 precursor (pri-miR-150) in myeloid cells. We also demonstrated that low miR-150 levels in tFL lead to upregulation of its target, namely FOXP1 protein, which is a known positive regulator of cell survival, as well as B-cell receptor and NF-κB signaling in malignant B cells. We revealed that low levels of miR-150 and high levels of its target, FOXP1, are associated with shorter overall survival in FL and suggest that miR-150 could serve as a good biomarker measurable in formalin-fixed paraffin-embedded tissue. Overall, our study demonstrates the role of the MYC/miR-150/FOXP1 axis in malignant B cells as a determinant of FL aggressiveness and its high-grade transformation.
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Factores de Transcripción Forkhead/genética , Regulación Neoplásica de la Expresión Génica , Linfoma Folicular/genética , MicroARNs/genética , Proteínas Represoras/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Regulación hacia Abajo , Humanos , Linfoma Folicular/diagnóstico , Linfoma Folicular/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Pronóstico , Proteínas Proto-Oncogénicas c-myc/genética , Activación Transcripcional , Regulación hacia ArribaRESUMEN
AIMS: Little has been written on the frequency and nature of incidental splenic lesions diagnosed on histopathological examination of pancreatosplenectomy specimens. METHODS AND RESULTS: For 191 such specimens, incidental histological findings after haematopathologist re-review were tabulated. Cases suspicious for lymphoid malignancy underwent molecular analysis for immunoglobulin heavy and kappa light chain rearrangement. Follow-up was obtained on selected cases. In five cases (3%), the spleen was sampled but not mentioned in the original microscopic report; all were normal on re-review. Otherwise, most (171 of 186, 92%) were initially diagnosed as normal, with 160 (94%) remaining so on re-review. Findings on re-review not initially described (n = 11, 6%) included four cases with splenic morphology suspicious for possible leukaemia/lymphoma involvement. Additional findings included abscess formation, foamy macrophages, necrotising granulomas and simple cysts. Fifteen spleens were initially diagnosed as abnormal; the histopathological process was confirmed in all, including non-necrotising granulomas, cysts, Gamna-Gandy bodies, foamy macrophages, involvement by pancreatic neoplasm and involvement by known chronic lymphocytic leukaemia (CLL). Molecular analysis was performed on the five cases of known/suspected lymphoma and two were positive for monoclonal gene rearrangement, including the known CLL and a previously undiagnosed case with similar immunophenotype. CONCLUSIONS: Incidental splenic findings are not uncommon in pancreatosplenectomy specimens. While most are of limited clinical significance, low-grade lymphoproliferative disorders may go undetected if the spleen is overlooked. We recommend careful observation of splenic findings in these specimens, with a low threshold for haematopathological consultation when in doubt.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Trastornos Linfoproliferativos/diagnóstico , Bazo/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunofenotipificación , Hallazgos Incidentales , Leucemia Linfocítica Crónica de Células B/diagnóstico , Leucemia Linfocítica Crónica de Células B/patología , Linfoma/patología , Trastornos Linfoproliferativos/patología , Masculino , Persona de Mediana Edad , Páncreas/patología , Páncreas/cirugía , Pancreatectomía , Estudios Retrospectivos , Bazo/cirugía , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/patología , Adulto JovenAsunto(s)
Adenocarcinoma del Pulmón , Neoplasias Pulmonares , Linfoma Anaplásico de Células Grandes , Humanos , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/genética , Linfoma Anaplásico de Células Grandes/patología , Antígeno Ki-1 , Adenocarcinoma del Pulmón/diagnóstico , Adenocarcinoma del Pulmón/genética , Proteínas Tirosina Quinasas Receptoras/genética , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologíaRESUMEN
In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival.
Asunto(s)
Médula Ósea/patología , Microambiente Celular , Células Madre Hematopoyéticas/patología , Síndromes Mielodisplásicos/patología , Animales , Médula Ósea/metabolismo , Modelos Animales de Enfermedad , Células Madre Hematopoyéticas/metabolismo , Proteínas de Homeodominio/genética , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Síndromes Mielodisplásicos/genética , Proteínas de Complejo Poro Nuclear/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción/genética , TransgenesRESUMEN
The diagnosis of myelodysplastic syndrome (MDS) can be challenging, and may be facilitated by correlation with cytogenetic testing. Microarray analysis using comparative genomic hybridization and/or single-nucleotide polymorphism array can detect chromosomal abnormalities not seen by standard metaphase cytogenetics. We examined the ability of combined comparative genomic hybridization and single-nucleotide polymorphism analysis (hereafter referred to as 'combined array') to detect changes among 83 patients with unexplained cytopenias undergoing pathologic evaluation for MDS and compared results with 18 normal bone marrow controls. Thirty-seven patients (45%) were diagnosed with MDS, 12 patients (14%) were demonstrated to have 'indeterminate dyspoiesis' (insufficient for classification of MDS), 27 (33%) were essentially normal, and 7 patients (8%) had alternative pathologic diagnoses. Twenty-one MDS patients (57% of diagnoses) had effectively normal metaphase cytogenetics, but combined array showed that 5 of these (13% of MDS patients) harbored major cryptic chromosomal aberrations. Furthermore, nearly half of patients with 'indeterminate dyspoiesis' and 1 with normal morphology had clonal cytopenia(s) of undetermined significance by combined array analysis. Cryptic array findings among MDS patients and those with clonal cytopenias(s) included large-scale copy-neutral loss of heterozygosity (up to 118 Mb) and genomic deletion of loci implicated in MDS pathogenesis (eg, TET2 (4q22) and NUP98 (11p15)). By comparison, in MDS patients with abnormal metaphase cytogenetics, microarray mostly recapitulated findings seen by routine karyotype. Combined array analysis has considerable diagnostic yield in detecting cryptic chromosomal aberrations in MDS and in demonstrating aberrant clonal hematopoiesis in cytopenic patients with indeterminate morphologic dysplasia.
Asunto(s)
Hibridación Genómica Comparativa/métodos , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
A patient with relapsed and refractory chronic lymphocytic leukaemia with Richter transformation was treated with chimeric antigen receptor (CAR)-modified T cells targeted for CD19 but later relapsed with a clonally related plasmablastic lymphoma. The loss of most routine markers of pre-plasma cell or B lymphoid differentiation (including CD19) highlights the ability of such mature lymphomas to evade lineage-specific targeted immunotherapy by differentiating along pathways comparable to their normal cellular counterparts. Molecular genetic evaluation demonstrated multiple independent lines of CD19-negative disease that eventually evolved in this single patient. Such plasticity represents potential challenges for antigen-directed CAR-T cell therapy, while serving as a testament to the selective pressure exerted by these engineered T cells over time.
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Leucemia Prolinfocítica Tipo Células B/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adenina/análogos & derivados , Anciano , Femenino , Humanos , Leucemia Prolinfocítica Tipo Células B/mortalidad , Masculino , Piperidinas , Análisis de SupervivenciaRESUMEN
The secreted M1 protein of murine gammaherpesvirus 68 (MHV68) promotes effector Vß4(+) CD8(+) T cell expansion to impact virus control and immune-mediated pathologies in C57BL/6 mice, but not BALB/c mice. We report a striking increase in the number of genome-positive, IgD(-) B cells during chronic infection of both mouse strains. This suggests a novel role for M1 in influencing long-term maintenance in a major latency reservoir irrespective of the degree of Vß4(+) CD8(+) T cell expansion.
Asunto(s)
Linfocitos B/virología , Inmunoglobulina D/inmunología , Rhadinovirus/inmunología , Rhadinovirus/patogenicidad , Proteínas Virales/metabolismo , Latencia del Virus , Animales , Linfocitos B/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Proteínas Virales/inmunologíaRESUMEN
The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, χ(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.
Asunto(s)
Carcinoma Intraductal no Infiltrante/patología , Neoplasias de la Próstata/patología , Diagnóstico Diferencial , Encuestas Epidemiológicas , Humanos , Masculino , Clasificación del Tumor , Variaciones Dependientes del Observador , Médicos , Pronóstico , Neoplasia Intraepitelial Prostática/patología , Reproducibilidad de los ResultadosRESUMEN
Gamma delta (γδ) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) is a rare, aggressive subtype of T-lymphoid leukemia that accounts for only 9-12% of all T-ALL cases. Herein, we report the case of an 8-year-old boy who presented with facial swelling, shortness of breath, and progressive cervical and axillary lymphadenopathy. Pathological examination, flow cytometry (Navios, Beckman Coulter ClearLLab 10C 10-color T-cell panel [containing FITC-labeled TCR γδ antibody]), chromosomal analysis, interphase FISH, and targeted DNA-based NGS (34-gene Illumina TruSeq Myeloid Panel) were performed. Flow cytometry evaluation of a lymph node biopsy specimen revealed an immature T-cell population positive for CD4, CD3, CD2 (subset positive), CD5, CD7, CD38, CD1a, cytoplasmic terminal deoxynucleotidyl transferase (cyto-TdT), CD30 (subset positive), and T-cell receptor (TCR) gamma delta (γδ). Microscopic examination of an enlarged lymph node and bone marrow showed involvement by a dense, diffuse, neoplastic infiltrate. Interphase FISH revealed a copy number loss of PDGFRB (5q32) in 90.5% of interphase nuclei. Targeted DNA-based NGS detected a tier II oncogenic variant in NOTCH1 (c.7375C > T, p.Gln2459Ter) at a VAF of 21%. This case of γδ T-ALL highlights a rare entity and adds to the literature, albeit scant, which may aid in better recognition and classification.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores de Antígenos de Linfocitos T gamma-delta , Humanos , Masculino , Niño , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Inmunofenotipificación , Ganglios Linfáticos/patología , Citometría de FlujoRESUMEN
CONTEXT.: Unicentric Castleman disease (UCD) is a dynamic entity with a wide spectrum of morphologic findings. UCD can be further subdivided into hyaline-vascular and mixed/plasmacytic variants. Hyaline-vascular UCD has both follicular and interfollicular (stromal) changes, and occasionally these lesions show a skewed representation of either the follicular or stromal compartments. Plasmacytosis is usually minimal in the hyaline-vascular variant. The mixed/plasmacytic variant of UCD is composed of sheets of plasma cells often associated with a variable number of follicles with regressive changes. OBJECTIVE.: To illustrate the differential diagnosis of UCD, as it is quite broad and includes lymphomas, plasma cell neoplasms, stromal neoplasms such as follicular dendritic cell sarcoma and vascular neoplasms, immunoglobulin G4-related disease, infections, and other rare lesions. An additional objective is to enhance awareness of the morphologic features of UCD in excisional and in small core-needle biopsy specimens, the latter of which may inadvertently target follicle- or stroma-rich areas, causing diagnostic challenges. DATA SOURCES.: In this review, we provide readers a concise illustration of the morphologic spectrum of UCD that we have encountered in our practice and a brief discussion of entities in the differential diagnosis. CONCLUSIONS.: UCD exhibits a broad spectrum of morphologic changes, and awareness of these morphologic variations is key to avoid misdiagnosis.
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Enfermedad de Castleman , Sarcoma de Células Dendríticas Foliculares , Mieloma Múltiple , Humanos , Enfermedad de Castleman/diagnóstico , Enfermedad de Castleman/patología , Diagnóstico Diferencial , Células Plasmáticas/patología , Mieloma Múltiple/diagnósticoRESUMEN
Acute myeloid leukemia (AML) is fatal in the majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the 'fittest hit' to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.
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Proliferación Celular , Leucemia Mieloide Aguda , Proteínas Activadoras de ras GTPasa , Humanos , Proteínas Activadoras de ras GTPasa/metabolismo , Proteínas Activadoras de ras GTPasa/genética , Proteínas Activadoras de ras GTPasa/antagonistas & inhibidores , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/genética , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Simulación por Computador , Antineoplásicos/farmacología , Dominios Proteicos , Animales , Proteómica/métodosRESUMEN
The potential for more than one distinct hematolymphoid neoplasm to arise from a common mutated stem or precursor cell has been proposed based on findings in primary human malignancies. Particularly, angioimmunoblastic T-cell lymphoma (AITL), which shares a somatic mutation profile in common with other hematopoietic malignancies, has been reported to occur alongside myeloid neoplasms or clonal B-cell proliferations, with identical mutations occurring in more than one cell lineage. Here we report such a case of an elderly woman who was diagnosed over a period of 8 years with diffuse large B-cell lymphoma, polycythemia vera, and AITL, each harboring identical somatic mutations in multiple genes. Overall, at least five identical nucleotide mutations were shared across multiple specimens, with two identical mutations co-occurring at variable variant allele frequencies in all three specimen types. These findings lend credence to the theory that a common mutated stem cell could give rise to multiple neoplasms through parallel hematopoietic differentiation pathways.
Asunto(s)
Neoplasias Hematológicas , Linfoma de Células B , Linfoma de Células T , Policitemia Vera , Anciano , Femenino , Humanos , Policitemia Vera/genética , Linfoma de Células T/genética , Diferenciación Celular , Linfoma de Células B/genéticaRESUMEN
INTRODUCTION: Splenic B-cell lymphomas are rare and understudied entities. Splenectomy is frequently required for specific pathological diagnosis in patients with splenic B-cell lymphomas other than classical hairy cell leukemia (cHCL), and can be effective and durable therapy. Our study investigated the diagnostic and therapeutic role of splenectomy for non-cHCL indolent splenic B-cell lymphomas. METHODS: Observational study of patients with non-cHCL splenic B-cell lymphoma undergoing splenectomy between 1 August 2011 and 1 August 2021 at the University of Rochester Medical Center. The comparison cohort was patients categorized as having non-cHCL splenic B-cell lymphoma who did not undergo splenectomy. RESULTS: Forty-nine patients (median age 68 years) had splenectomy (SMZL n = 33, HCLv n = 9, SDRPL n = 7) with median follow up of 3.9 years post splenectomy. One patient had fatal post-operative complications. Post-operative hospitalization was ≤ 4 days for 61% and ≤ 10 days for 94% of patients. Splenectomy was initial therapy for 30 patients. Of the 19 patients who had previous medical therapy, splenectomy changed their lymphoma diagnosis in 5 (26%). Twenty-one patients without splenectomy were clinically categorized as having non-cHCL splenic B-cell lymphoma. Nine required medical treatment for progressive lymphoma and of these 3 (33%) required re-treatment for lymphoma progression compared to 16% of patients following first line splenectomy. CONCLUSION: Splenectomy is useful for the diagnosis of non-cHCL splenic B-cell lymphomas with comparable risk/benefit profile and remission duration to medical therapy. Patients with suspected non-cHCL splenic lymphomas should be considered for referral to a high-volume center with experience in performing splenectomies for definitive diagnosis and treatment.
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Leucemia de Células Pilosas , Linfoma de Células B de la Zona Marginal , Neoplasias del Bazo , Humanos , Anciano , Esplenectomía/efectos adversos , Neoplasias del Bazo/diagnóstico , Neoplasias del Bazo/cirugía , Neoplasias del Bazo/patología , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma de Células B de la Zona Marginal/cirugíaRESUMEN
Autologous and allogeneic hematopoietic stem cell transplantation (HSCT) has revolutionized the therapy of hematolymphoid malignancies. Yet, how to best detect or predict the emergence of HSCT-related complications remain unresolved. Here, we describe a case of donor-derived, transient Alpha Beta (αß) T-cell large granular clonal lymphocytosis and cytopenia that emerged post-HSCT in a patient with a history of gamma delta (γδ) T-cell large granular lymphocytic leukemia (T-LGLL). Clonal unrelatedness of post-transplant T-LGL lymphocytosis to the patient's pretransplant T-LGLL was first identified by T-cell receptor (TCR) PCR showing different sized fragments of rearranged gamma chains, in addition to shift from γδ to αß TCR expression by flow cytometry analyses. Donor-derivation of the patient's post-transplant clonal lymphocytosis was confirmed by serial chimerism analyses of recipient's blood specimens demonstrating 100% donor DNA. Moreover, oncogenic DNMT3A and RUNX1 mutations were detected by next-generation sequencing (NGS) only in post-transplant specimens. Intriguingly, despite continued increase in DNMT3A and RUNX1 mutation load, the patient's clonal lymphocytosis and anemia eventually largely resolved; yet, the observed mutation profile with persistent thrombocytopenia indicated secondary clonal cytopenia of undetermined significance (CCUS) in the absence of overt morphologic evidence of myeloid neoplasm in the marrow. This case illustrates the utility of longitudinal chimerism analysis and NGS testing combined with flow cytometric immunophenotyping to evaluate emerging donor-derived hematolymphoid processes and to properly interpret partial functional engraftment. It may also support the notion that driver mutation-induced microenvironmental changes may paradoxically contribute to reestablishing tissue homeostasis.
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Leucemia Linfocítica Granular Grande , Linfocitosis , Humanos , Leucemia Linfocítica Granular Grande/genética , Linfocitosis/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal , Hematopoyesis Clonal , Metilasas de Modificación del ADN , Linfocitos TRESUMEN
CONTEXT.: It is known that a subset of cases of classic Hodgkin lymphoma (CHL) with B-cell-rich nodules (lymphocyte-rich CHL) exhibits morphologic and immunophenotypic features that overlap with nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL), raising diagnostic difficulties that can be resolved in most cases by performing an adequate battery of immunohistochemical studies. OBJECTIVE.: To fully characterize cases of T-cell-rich Hodgkin lymphoma where a specific diagnosis of NLPHL (ie, pattern D) or CHL could not be made even after complete immunophenotypic investigation. DESIGN.: The clinical, immunomorphologic, and molecular (when applicable) presentation of 3 cases of T-cell-rich Hodgkin lymphoma was thoroughly investigated. RESULTS.: These 3 cases harbored lymphocyte-predominant-like and Hodgkin and Reed-Sternberg-like cells that partially expressed B-cell and CHL markers and were negative for Epstein-Barr virus-encoded small RNA, in a T-cell-rich background with residual follicular dendritic cell meshworks; 1 case had frequent and the other 2 cases scant/absent eosinophils and plasma cells. Two patients with advanced-stage (III or IV) disease presented with axillary and supraclavicular lymphadenopathy, respectively, and without B symptoms. These patients underwent NLPHL-like therapeutic management with 6 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride [hydroxydaunorubicin], vincristine sulfate [Oncovin], and prednisone) chemotherapy; both are in complete remission 7 years posttherapy. One patient presented with stage I disease involving an internal mammary lymph node without B-symptoms and was treated with surgical excision alone; this patient is also in complete remission 1 year later. CONCLUSIONS.: These cases illustrate overlapping features of T-cell-rich NLPHL and CHL with neoplastic cells expressing both B-cell program and CHL markers. This underrecognized overlap has not been fully illustrated in the literature, although it portrays a therapeutic challenge. These neoplasms may deserve in-depth investigation in the future that may bring up diagnostic or theragnostic implications.
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Cuerpos de Inclusión , Fallo Hepático Agudo , Monocitos , Neutrófilos , Adolescente , Adulto , Anciano , Femenino , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Fallo Hepático Agudo/sangre , Fallo Hepático Agudo/mortalidad , Fallo Hepático Agudo/patología , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Monocitos/patología , Neutrófilos/metabolismo , Neutrófilos/patologíaRESUMEN
This report highlights the value of flow cytometry analysis, particularly in the setting of myeloproliferative neoplasms showing features of progression, as neoplastic plasmacytoid dendritic cell (PDC) proliferations may be present, representing either a clonal expansion of mature PDCs related to the underlying myeloproliferative neoplasm or transformation to blastic plasmacytoid dendritic cell neoplasm (BPDCN). BPDCN should always be considered in patients with myeloid neoplasms in progression and/or who develop new cutaneous findings, as it may prompt change of management.