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Extranodal marginal zone lymphoma (EMZL) is the most common subtype of ocular lymphomas. Diffuse large B-cell lymphoma (DLBCL) and EMZL with large-cell transformation present diagnostic challenges. Radiotherapy is the standard treatment for ocular lymphomas, but complications and relapse are common. Diagnostic utility in challenging cases, as well as treatment options using immune checkpoint inhibitors, are unclear in ocular lymphomas. We herein investigated the PD-1, PD-L1, and IDO1 staining patterns in 20 cases of ocular lymphomas, including EMZL (n=14), EMZL with increased large cells (n=2), and DLBCL (n=4). PD-1, PD-L1, and IDO1 staining was not detected in lymphoma cells in any cases but was observed within the tumor microenvironment in all cases. Positivity for PD-1, PD-L1, and IDO1 in inflammatory cells was seen either intratumorally or peritumorally. In all 6 cases with significantly more large B cells, the density of PD-1, PD-L1, and IDO1 expression in the tumor microenvironment was higher than that of the remaining 14 cases without large B cells (P-value<0.0001), whereas other clinicopathologic features showed no statistical correlation. Increased expression of PD-1, PD-L1, and IDO1 in the inflammatory milieu in cases with large cells may provide diagnostic utility in small biopsies as well as therapeutic potential.
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Primary renal involvement by T lymphoblasts is rare among adults with T acute lymphoblastic leukaemia. We report a 28-year-old man presenting with acute renal failure due to infiltration by T lymphoblasts and his response to paediatric-inspired modified BFM-90 protocol. The patient achieved an initial complete remission (CR) but developed central nervous system relapse. He achieved CR2 with cranial irradiation and intrathecal chemotherapy. He underwent a haploidentical transplant in CR2 and remains in remission post-transplant day 330. An early kidney biopsy helped confirm the diagnosis. Such presentations remain responsive to modified BFM-90. An early allotransplant in CR2 remains the standard of care.
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Anaplastic lymphoma kinase (ALK) positive large B-cell lymphoma (ALK+ LBCL) is an aggressive and rare subtype of B-cell lymphoma. Patients typically present with advanced clinical stage disease and do not respond to conventional chemotherapy; the median overall survival is 1.8 years. The genetic landscape of this entity remains poorly understood. Here we report a unique case of ALK+ LBCL harbouring a rare TFG::ALK fusion. Targeted next-generation sequencing showed no significant single nucleotide variants, insertions/deletions, or other structural variants beyond the TFG::ALK fusion; deep deletions of FOXO1, PRKCA, and the MYB locus were also detected. Our case report draws attention to this rare disease, highlights a need for larger genetic profiling studies, and focuses on the pathogenesis and potential therapeutic targets of this aggressive disease. To our knowledge, this is the first report of a TFG::ALK fusion in ALK+ LBCL.
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BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematopoietic disease derived from plasmacytoid dendritic lineage cells. The disease typically shows skin as well as frequent bone marrow and peripheral blood involvement. However, the pathogenesis of this disease is still not well understood. While somatic point mutations and genetic rearrangements have been described in BPDCN, the types and origins of these mutations and relationships to other cancer types is not well understood. MATERIALS AND METHODS: To probe the origins of BPDCN, we analyzed the exome sequence data of 9 tumor-normal pair cases of BPDCN. We utilized SignatureAnalyzer, SigProfiler and a custom microbial analysis pipeline to understand the relevance of endogenous and environmental mutagenic processes. RESULTS: Our results identified a significant tobacco exposure and aging genetic signature as well as signatures related to nucleotide excision repair deficiency, ultra violet (UV) exposure, and endogenous deamination in BPDCN. We also assessed the samples for microbial infectious disease organisms but did not find a link to a microbial etiology. CONCLUSION: The identification of a tobacco exposure and aging genetic signature in patients with BPDCN suggests that environmental and endogenous genetic changes may be central to the oncogenesis of BPDCN.
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Enfermedades Transmisibles , Neoplasias Hematológicas , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Neoplasias Hematológicas/genética , Mutación , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/patología , Trastornos Mieloproliferativos/metabolismo , Células DendríticasRESUMEN
Acute myeloid leukemia (AML) is an aggressive hematopoietic malignancy with several patient- and disease-associated variables known to impact prognosis. Tobacco smoking is an environmental factor associated with a greater incidence of AML, but there have been limited studies that evaluated smoking toward overall survival. We retrospectively searched for AML cases and collected clinical and diagnostic data for each case. We also used an independent next-generation sequencing (NGS) data set to assess for a distinct mutational signature associated with smoking. When stratified by smoking status, there was a greater number of males, patients aged ≥60 years, and patients with ≥2 comorbidities within the smoking category (P < .05). Survival analysis demonstrated decreased survival probability in the smokers, male smokers, smokers with 1 other comorbidity, and smokers without a prior history of nonhematopoietic malignancy (P < .05) as compared to nonsmokers. Smoking was associated with a decrease in survival within the World Health Organization categories of AML, not otherwise specified (AML NOS; P = .035) and AML with recurrent genetic abnormalities (AML RGA; P = .002). Multivariate analysis showed that patients who were smokers had a greater hazard ratio than nonsmokers after adjusting for the other covariates. Our findings demonstrated that smoking was independently associated with decreased overall survival after adjusting for other potentially confounding factors. In addition, our results suggest that a mutational signature can be recognized using NGS data in a subset of AML patients who smoke.
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Leucemia Mieloide Aguda , Humanos , Masculino , Estudios Retrospectivos , Leucemia Mieloide Aguda/genética , Aberraciones Cromosómicas , Pronóstico , Organización Mundial de la Salud , Fumar/efectos adversosRESUMEN
CONTEXT.: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with poor outcome. BPDCN diagnostically overlaps with entities such as acute myeloid leukemia, histiocytic/dendritic cell neoplasms, and natural killer/T-cell lymphomas. Unfortunately, large, patient-centered studies that comprehensively analyze clinical, pathologic, and other diagnostic features are lacking. As such, there is an incomplete understanding of this disease. OBJECTIVE.: To better characterize BPDCN, a multicenter working group consisting of hematopathologists and dermatopathologists gathered in person and remotely to review the current understanding of BPDCN, discuss specific issues regarding the diagnosis and differential diagnosis, and perform a retrospective analysis of the literature. DATA SOURCES.: The working group curated a database of published BPDCN patient cases (BPDCN Network literature database), and following careful discussion and review, 361 articles were identified, comprising a total of 1513 individually annotated patients. CONCLUSIONS.: By conducting an in-depth analysis, not only did we confirm known findings such as frequent skin involvement (84% of patients; 861 of 1028) and a male predominance among older patients (>60 years old; male to female ratio of 3.5:1; 617:177), but we also identified a number of underrecognized features, such as significant central nervous system involvement (38% of cases; 24 of 64), and a more equal male to female prevalence among patients younger than 40 years (male to female ratio of 1.25:1; 167:134). Furthermore, we were able to accurately summarize the immunophenotypic, cytogenetic, and molecular features of this disease. BPDCN is a complex disease with distinct morphologic, immunophenotypic, and molecular findings. Continual updates of the literature database generated here and further analysis can allow for prospective refinement of our understanding of this orphan disease.
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Neoplasias Hematológicas , Leucemia Mieloide Aguda , Trastornos Mieloproliferativos , Neoplasias Cutáneas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Estudios Prospectivos , Células Dendríticas , Leucemia Mieloide Aguda/patología , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/patología , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patologíaRESUMEN
CONTEXT.: Evidence of T-cell clonality is often critical in supporting the diagnosis of a T-cell lymphoma. OBJECTIVES.: To retrospectively explore the significance of copy number losses at the 14q11.2 T-cell receptor α locus in relation to the presence of a T-cell neoplasm and proportion of T cells by targeted next-generation sequencing. DESIGN.: Targeted next-generation sequencing data from 139 tissue biopsies, including T-cell lymphomas, B-cell lymphomas, classic Hodgkin lymphomas, nonhematopoietic malignancies, and normal samples, were reviewed for copy number losses involving the T-cell receptor α gene segments at chr14q11.2. RESULTS.: We found that biallelic or homozygous deletion of 14q11.2 was found in most (28 of 33, 84.8%) T-cell lymphomas. The magnitude of 14q11.2 loss showed a statistically significant correlation with the proportion of T cells in lymphoma tissue samples. Copy number losses could also be detected in other lymphomas with high numbers of T cells (8 of 32, 25% of B-cell lymphomas, 4 of 4 classical Hodgkin lymphomas), though biallelic/homozygous deletion of 14q11.2 was not significantly observed outside of T-cell lymphomas. Most nonhematopoietic neoplasms and normal tissues (59 of 64, 92.2%) showed no significant copy number losses involving the T-cell receptor α locus at chr14q11.2. CONCLUSIONS.: Analysis of copy number losses at the T-cell receptor α locus chr14q11.2 with targeted next-generation sequencing can potentially be used to estimate the proportion of T cells and detect T-cell neoplasms.
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Enfermedad de Hodgkin , Linfoma de Células B , Linfoma de Células T Periférico , Linfoma de Células T , Humanos , Variaciones en el Número de Copia de ADN , Homocigoto , Estudios Retrospectivos , Linfocitos T , Eliminación de Secuencia , Linfoma de Células B/genética , Enfermedad de Hodgkin/diagnóstico , Enfermedad de Hodgkin/genética , Linfoma de Células T/diagnóstico , Linfoma de Células T/genética , Linfoma de Células T Periférico/genética , Biopsia , Cromosomas , Receptores de Antígenos de Linfocitos T/genéticaRESUMEN
INTRODUCTION: Pediatric-type follicular lymphoma (PTFL) is a rare and recently recognized subtype of nodal follicular B-cell lymphoma. While significant recent progress has been made in understanding the morphologic, immunophenotypic, and molecular findings, there are only rare case reports describing the cytomorphologic features of PTFL. MATERIALS AND METHODS: Four cases of PTFL initially evaluated on fine needle aspiration (FNA) biopsy were retrieved from our institutions' databases. The cytologic and subsequent surgical excision specimens were compared in terms of cytology, histology, immunophenotype, and molecular findings. RESULTS: A constellation of cytologic features for PTFL are able to distinguish it from other cytomorphologic entities in the differential including: 1) the presence of large blastoid cells with fine chromatin and irregular nuclear membranes, 2) small/intermediate-sized lymphocytes with subtle nuclear membrane irregularities, 3) near complete absence of cytoplasmic vacuoles in lymphoid cells, 4) tingible body macrophages, 5) mitotic figures, 6) absence of a diffuse large cell component, 7) and no significant plasma cell population. CONCLUSIONS: We present four cases of PTFL initially evaluated on FNA biopsy and define the cytomorphologic features of PTFL. FNA biopsy is presented as a practical tool for initial evaluation of this rare entity as part of a multimodal diagnostic approach, for which increased awareness among cytopathologists can ensure the appropriate triage of specimen studies necessary for the diagnosis. Additionally, we comprehensively review the current literature on PTFL and discuss the differential diagnosis on cytology, including potential pitfalls.
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Linfoma Folicular , Biopsia con Aguja Fina , Niño , Citodiagnóstico , Diagnóstico Diferencial , Humanos , InmunofenotipificaciónRESUMEN
Castleman disease (CD) is a rare lymphoproliferative disorder with distinct clinical subtypes. However, our understanding of the underlying pathogenesis of particular subtypes of CD remains unclear. While the characteristic morphologic changes within UCD, including occasional cases of overgrowth of spindled stromal and follicular dendritic cells have been described, the nature and origin of these spindle cells remain elusive. Few reports have suggested that underlying stromal cells in UCD are clonally neoplastic and may be of fibroblastic reticular cell (FRC) or follicular dendritic cell (FDC) origins given their close clonal relationship. Although certain histomorphologic features may aid diagnosis, there are no specific biomarkers that can differentiate a reactive process mimicking UCD from true UCD. Hence, we describe an index case with morphology consistent with the hyaline vascular subtype of UCD with concomitant atypical smooth muscle actin (SMA)-positive stromal spindle cell proliferation containing a recurrent PDGFRB N666S mutation and upregulation of p53 expression. Further analysis of 21 additional cases of UCD identified increased p53 expression by digital image analysis and SMA positive stromal cells predominantly within the paracortical and intrafollicular areas further strengthening the hypothesis of the stromal cellular derivation and origins of UCD.
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An indolent T-lymphoblastic proliferation (iT-LBP) is a rare benign disorder characterized by an abnormal expansion of immature T-cells, which morphologically can mimic malignancy. Since the first case was described in 1999, dozens more have been reported in the literature. However, the epidemiologic, clinical, pathologic, and biologic features of this disease have not been well described. Here, we retrospectively reviewed all known cases reported in the literature to better understand this entity. A PubMed search up to January 2022 highlighted 25 papers describing cases/case series of iT-LBP, one of which was a case presentation in a slide workshop. Except for 9 of the cases in one of the papers, where it was evident that the number of CD3+/TdT+ cells were too few to conform with a diagnosis of iT-LBP, all papers and all the cases reported were included in the study amounting to a total of 45 cases. Clinicopathologic characteristics were analyzed using descriptive statistics and frequencies. Our analysis highlighted the previously known association with Castleman disease and Castleman-like features and underlined its association with dendritic cell proliferations in general, as well as uncovering high frequency of concurrence with hepatocellular carcinoma and autoimmune diseases, most notably myasthenia gravis, paraneoplastic pemphigus and paraneoplastic autoimmune multiorgan syndrome. Furthermore, the co-expression of CD4 and CD8 and high prevalence of extranodal disease and recurrences were other less well described features that were revealed.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Trastornos Linfoproliferativos , Proliferación Celular , Humanos , Trastornos Linfoproliferativos/patología , Estudios RetrospectivosRESUMEN
Haemophagocytic lymphohistiocytosis (HLH) is a complex, often under-recognised hyperinflammatory immune dysregulation syndrome arising in a diverse range of clinical scenarios and conditions. The accurate and timely diagnosis of HLH is crucial for patient survival, and usually requires a high level of clinical suspicion. The histological corollary to clinical HLH-haemophagocytosis-is neither necessary nor sufficient for the diagnosis of HLH, as it may be seen in a variety of reactive conditions and may be absent in true HLH. Nevertheless, the finding of haemophagocytosis in specific clinical situations should prompt consideration of HLH and further testing to exclude the condition. Although haemophagocytosis is traditionally described in bone marrow, identification of it in other tissues, including lymphoid, splenic, liver or neural tissue, can contribute importantly to the overall recognition of HLH. In this review we discuss the underlying pathophysiology and aetiologies of HLH, and the morphological aspects of haemophagocytosis and its associated histological findings in different tissues, and give a brief overview of diagnostic criteria and clinical evaluation.
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Linfohistiocitosis Hemofagocítica/patología , HumanosRESUMEN
The basis for acquired resistance to JAK inhibition in patients with JAK2-driven hematologic malignancies is not well understood. We report a patient with a myeloproliferative neoplasm (MPN) with a BCR activator of RhoGEF and GTPase (BCR)-JAK2 fusion with initial hematologic response to ruxolitinib who rapidly developed B-lymphoid blast transformation. We analyzed pre-ruxolitinib and blast transformation samples using genome sequencing, DNA mate-pair sequencing (MPseq), RNA sequencing (RNA-seq), and chromosomal microarray to characterize possible mechanisms of resistance. No resistance mutations in the BCR-JAK2 fusion gene or transcript were identified, and fusion transcript expression levels remained stable. However, at the time of blast transformation, MPseq detected a new IKZF1 copy-number loss, which is predicted to result in loss of normal IKZF1 protein translation. RNA-seq revealed significant upregulation of genes negatively regulated by IKZF1, including IL7R and CRLF2. Disease progression was also characterized by adaptation to an activated B-cell receptor (BCR)-like signaling phenotype, with marked upregulation of genes such as CD79A, CD79B, IGLL1, VPREB1, BLNK, ZAP70, RAG1, and RAG2. In summary, IKZF1 deletion and a switch from cytokine dependence to activated BCR-like signaling phenotype represent putative mechanisms of ruxolitinib resistance in this case, recapitulating preclinical data on resistance to JAK inhibition in CRLF2-rearranged Philadelphia chromosome-like acute lymphoblastic leukemia.
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Activación de Linfocitos , Trastornos Mieloproliferativos , Humanos , Janus Quinasa 2/genética , Nitrilos , Pirazoles/uso terapéutico , Pirimidinas , Receptores de Antígenos de Linfocitos BRESUMEN
Patients with core-binding factor (CBF) acute myeloid leukemia (AML), caused by either t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), have higher complete remission rates and longer survival than patients with other subtypes of AML. However, â¼40% of patients relapse, and the literature suggests that patients with inv(16) fare differently from those with t(8;21). We retrospectively analyzed 537 patients with CBF-AML, focusing on additional cytogenetic aberrations to examine their impact on clinical outcomes. Trisomies of chromosomes 8, 21, or 22 were significantly more common in patients with inv(16)/t(16;16): 16% vs 7%, 6% vs 0%, and 17% vs 0%, respectively. In contrast, del(9q) and loss of a sex chromosome were more frequent in patients with t(8;21): 15% vs 0.4% for del(9q), 37% vs 0% for loss of X in females, and 44% vs 5% for loss of Y in males. Hyperdiploidy was more frequent in patients with inv(16) (25% vs 9%, whereas hypodiploidy was more frequent in patients with t(8;21) (37% vs 3%. In multivariable analyses (adjusted for age, white blood counts at diagnosis, and KIT mutation status), trisomy 8 was associated with improved overall survival (OS) in inv(16), whereas the presence of other chromosomal abnormalities (not trisomy 8) was associated with decreased OS. In patients with t(8;21), hypodiploidy was associated with improved disease-free survival; hyperdiploidy and del(9q) were associated with improved OS. KIT mutation (either positive or not tested, compared with negative) conferred poor prognoses in univariate analysis only in patients with t(8;21).
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Leucemia Mieloide Aguda , Translocación Genética , Aberraciones Cromosómicas , Factores de Unión al Sitio Principal/genética , Femenino , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Estudios RetrospectivosRESUMEN
Vaccination and infection promote the formation, tissue distribution, and clonal evolution of B cells, which encode humoral immune memory. We evaluated pediatric and adult blood and deceased adult organ donor tissues to determine convergent antigen-specific antibody genes of similar sequences shared between individuals. B cell memory varied for different pathogens. Polysaccharide antigen-specific clones were not exclusive to the spleen. Adults had higher clone frequencies and greater class switching in lymphoid tissues than blood, while pediatric blood had abundant class-switched convergent clones. Consistent with reported serology, prepandemic children had class-switched convergent clones to severe acute respiratory syndrome coronavirus 2 with weak cross-reactivity to other coronaviruses, while adult blood or tissues showed few such clones. These results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.
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Anticuerpos Antivirales/inmunología , Linfocitos B/inmunología , Coronavirus/inmunología , Memoria Inmunológica , SARS-CoV-2/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Envejecimiento , Preescolar , Reacciones Cruzadas , Ebolavirus/inmunología , Femenino , Sangre Fetal/inmunología , Genes de Inmunoglobulinas , Humanos , Cambio de Clase de Inmunoglobulina , Inmunoglobulina D/genética , Inmunoglobulina D/inmunología , Cadenas Pesadas de Inmunoglobulina/inmunología , Inmunoglobulina M/genética , Inmunoglobulina M/inmunología , Lactante , Ganglios Linfáticos/inmunología , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos B/inmunología , Hipermutación Somática de Inmunoglobulina , Bazo/inmunología , Adulto JovenRESUMEN
B-cell and T-cell lymphomas and leukemias often have distinct genetic mutations that are diagnostically defining or prognostically significant. A subset of these mutations consists of specific point mutations, which can be evaluated using genetic sequencing approaches or point mutation specific antibodies. Here, we describe genes harboring point mutations relevant to B-cell and T-cell malignancies and discuss the current availability of these targeted point mutation specific antibodies. We also evaluate the possibility of generating novel antibodies against known point mutations by computationally assessing for chemical and structural features as well as epitope antigenicity of these targets. Our results not only summarize several genetic mutations and identify existing point mutation specific antibodies relevant to hematologic malignancies, but also reveal potential underdeveloped targets which merit further study.