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Chronic myeloid leukemia (CML) is characterized by leukocytosis with left-shifted neutrophilia, basophilia, eosinophilia, and variable thrombocytosis. However, extremely rare cases of patients with CML without significant leukocytosis and thrombocytosis (aleukemic phase [ALP] CML, or CML-ALP) have been reported. Due to its rarity and limited awareness, there remains a significant knowledge gap concerning the pathologic diagnosis, disease progression, and optimal patient management and outcomes. In this multi-institutional study, we investigated 31 patients with CML-ALP. Over half (54.8%) of patients had a history of or concurrent hematopoietic or nonhematopoietic malignancies. At time of diagnosis of CML-ALP, approximately 26.7% of patients exhibited neutrophilia, 56.7% had basophilia, and 13.3% showed eosinophilia. The median number of metaphases positive for t(9;22)(q34;q11.2) was 15, with a median of 38.5% of interphase nuclei positive for BCR::ABL1 by fluorescence in situ hybridization. The median BCR::ABL1 level was 26.14%. Remarkably, 14 (45.2%) patients were initially misdiagnosed or not diagnosed before karyotype or fluorescence in situ hybridization information for BCR::ABL1 became available. Twenty-five patients received tyrosine kinase inhibitors (TKIs). One patient developed blast crisis while on TKI treatment 8 months after initial diagnosis. With a median follow-up time of 46.1 months, 20 of 22 patients who received TKI therapy and had detailed follow-up information achieved complete cytogenetic remission or deeper, 15 achieved major molecular remission or deeper, and 10 achieved molecularly undetectable leukemia. In conclusion, given the frequent occurrence of prior or concurrent malignancies, aleukemic presentation, and low level of t(9;22)(q34;q11.2)/BCR::ABL1, misdiagnosis or delayed diagnosis is common among these patients. While these patients generally respond well to TKIs, rare patients may develop blastic transformation. It is therefore important for pathologists and hematologists to be aware of this highly unusual presentation of CML to ensure timely diagnosis and appropriate management.
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Eosinofilia , Leucemia Mielógena Crónica BCR-ABL Positiva , Trombocitosis , Humanos , Hibridación Fluorescente in Situ , Leucocitosis , Proteínas de Fusión bcr-abl/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/diagnóstico , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Trombocitosis/genética , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
OBJECTIVES: This study assesses the clinical significance of additional cytogenetic abnormalities (ACAs) and/or the deletion of 3'CBFB (3'CBFBdel) resulting in unbalanced CBFB::MYH11 fusion in acute myeloid leukemia (AML) with inv (16)/t(16;16)/CBFB::MYH11. METHODS: We retrospectively evaluated the clinicopathologic features of 47 adult de novo AML with inv (16)/t(16;16)/CBFB::MYH11 fusion. There were 44 balanced and 3 unbalanced CBFB::MYH11 fusions. Given the low frequency of unbalanced cases, the latter group was combined with 19 published cases (N = 22) for statistic and meta-analysis. RESULTS: Both balanced and unbalanced cases were characterized by frequent ACAs (56.5% and 72.7%, respectively), with +8, +22, and del(7q) as the most frequent abnormalities. The unbalanced group tends to be younger individuals (p = .04) and is associated with a lower remission rate (p = .02), although the median overall survival (OS) was not statistically different (p = .2868). In the balanced group, "ACA" subgroup had higher mortality (p = .013) and shorter OS (p = .011), and patients with relapsed disease had a significantly shorter OS (p = .0011). Cox multivariate regression analysis confirmed that ACAs and history of disease relapse are independent risk factors, irrespective of disease relapse status. In the combined cohort, cases with ACAs had shorter OS than those with "Sole" abnormality (p = .0109). CONCLUSIONS: ACAs are independent high-risk factors in adult AML with inv (16)/t(16;16)/CBFB::MYH11 fusion and should be integrated for risk stratification in this disease. Larger studies are needed to assess the clinical significance of the unbalanced CBFB::MYH11 fusion resulting from the 3'CBFBdel.
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Aberraciones Cromosómicas , Inversión Cromosómica , Cromosomas Humanos Par 16 , Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/mortalidad , Leucemia Mieloide Aguda/diagnóstico , Adulto , Femenino , Masculino , Persona de Mediana Edad , Proteínas de Fusión Oncogénica/genética , Anciano , Cromosomas Humanos Par 16/genética , Pronóstico , Estudios Retrospectivos , Adulto Joven , Subunidad beta del Factor de Unión al Sitio Principal/genética , Adolescente , Anciano de 80 o más Años , Translocación Genética , Cadenas Pesadas de Miosina/genéticaRESUMEN
MECOM rearrangements are recurrent in myeloid neoplasms and associated with poor prognosis. However, only inv(3)(q21q26.2) and t(3;3)(q21;q26.2), the classic MECOM rearrangements resulting in RPN1-MECOM rearrangement with Mecom overexpression and GATA2 haploinsufficiency, define the distinct subtype of acute myeloid leukemia (AML), and serve as presumptive evidence for myelodysplastic syndrome based on the current World Health Organization classification. Myeloid neoplasms with nonclassic 3q26.2/MECOM rearrangements have been found to be clinically aggressive, but comparative analysis of clinicopathologic and genomic features is limited. We retrospectively studied cohorts of myeloid neoplasms with classic and nonclassic MECOM rearrangements. Cases with classic rearrangements consisted predominantly of AML, often with inv(3) or t(3;3) as the sole chromosome abnormality, whereas the group of nonclassic rearrangements included a variety of myeloid neoplasms, often with complex karyotype without TP53 mutations and similarly dismal overall survival. Immunohistochemistry revealed Mecom protein overexpression in both groups, but overexpression in cases with nonclassic rearrangements was mediated through a mechanism other than GATA2 distal enhancer involvement typical for classic rearrangement. Our results demonstrated that myeloid neoplasms with nonclassic 3q26.2/MECOM rearrangements encompass a diverse group of diseases with poor clinical outcome, overexpression of Mecom protein as a result of the nonclassic mechanism of MECOM activation.
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Reordenamiento Génico/genética , Leucemia Mieloide , Proteína del Locus del Complejo MDS1 y EV11 , Adulto , Anciano , Análisis Citogenético , Femenino , Genómica , Humanos , Leucemia Mieloide/diagnóstico , Leucemia Mieloide/genética , Leucemia Mieloide/patología , Proteína del Locus del Complejo MDS1 y EV11/genética , Proteína del Locus del Complejo MDS1 y EV11/metabolismo , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/patología , Estudios Retrospectivos , Adulto JovenRESUMEN
INTRODUCTION: Post-transplant lymphoproliferative disorders (PTLDs) comprise a heterogeneous group of Epstein-Barr virus (EBV)-positive or negative lymphoid or plasmacytic lesions in solid organ or hematopoietic stem cell (HSC) transplant recipients. Although PTLDs in adults have been extensively studied, the clinicopathologic features of monomorphic B-cell PTLD in children, particularly EBV-negative forms, are still poorly understood. METHODS: We retrospectively reviewed all our pediatric cases of monomorphic B-cell PTLDs diagnosed in the past 10 years. Clinical data were reviewed. Pathologic data including histologic types and EBV status were analyzed. Additional immunohistochemical stains, FISH studies, and TP53 gene mutational status were performed. RESULTS: 4 of 18 cases were EBV-negative. All 4 EBV-negative cases were strikingly confined to the gastrointestinal (GI) tract or abdominal lymph nodes, while tumors in EBV-positive cases were found at various anatomic sites; 2 of 4 EBV-negative cases carried mutations in TP53 gene. Our cohort also included 2 rare types of PTLD, one plasmablastic lymphoma and one high-grade B-cell lymphoma, not otherwise specified (HGBL, NOS). CONCLUSION: We report that monomorphic B-cell PTLDs in children have distinctive clinical and pathological features. More studies are needed to clarify whether and how much these pediatric PTLDs differ from their adult counterparts.
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Linfocitos B/patología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trastornos Linfoproliferativos/patología , Trasplante de Órganos , Complicaciones Posoperatorias/patología , Adolescente , Niño , Preescolar , Infecciones por Virus de Epstein-Barr/diagnóstico , Infecciones por Virus de Epstein-Barr/etiología , Infecciones por Virus de Epstein-Barr/patología , Femenino , Humanos , Lactante , Recién Nacido , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/etiología , Masculino , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Estudios Retrospectivos , Adulto JovenRESUMEN
Aggressive morphologic variants of mantle cell lymphoma (MCL), including blastoid and pleomorphic (B/P-MCL), are rare and associated with poor clinical outcomes. The genomic landscape of these variants remains incompletely explored. In this multi-institutional study, we describe recurrent mutations and novel genomic copy number alterations (CNAs) in B/P-MCL, using next generation sequencing and SNP-array. Chromothripsis, a recently described phenomenon of massive chromosomal rearrangements, was identified in eight of 13 (62%) B/P MCL cases, and a high degree of genomic complexity with frequent copy number gains and losses was also seen. In contrast, a comparative cohort of nine cases of conventional MCL (C-MCL) showed no chromothripsis and less complexity. Twelve of 13 (92%) B/P-MCL cases showed loss of CDKN2A/B (6 biallelic and 6 monoallelic losses); while only one C-MCL showed monoallelic CDKN2A/B loss. In B/P-MCL, TP53 was the most commonly mutated gene, with mutations present in eight cases (62%), six of which showed concurrent loss of chromosome 17p. Of the eight cases with chromothripsis, six (85%) harbored TP53 mutations. Other recurrent mutations in B/P-MCL included ATM (7, 53%), CCND1 (5, 38%), NOTCH1 (2, 18%), NOTCH2, and BIRC3 (each in 3, 23%). Here, we describe high genomic instability associated with chromothripsis and a high frequency of CDKN2A/B and TP53 alterations in the aggressive variants of MCL. The nonrandom chromothripsis events observed in B/P-MCL may be an indicator of clinically aggressive MCL. In addition, frequent CDKN2A deletion and high genomic instability may provide potential targets for alternative treatment.
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Cromotripsis , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inestabilidad Genómica , Linfoma de Células del Manto/genética , Proteína p53 Supresora de Tumor/genética , Anciano , Cromosomas Humanos Par 17/genética , Femenino , Humanos , Linfoma de Células del Manto/patología , Masculino , Persona de Mediana Edad , MutaciónRESUMEN
Aggressive natural killer (NK)-cell leukemia/lymphoma is a systemic NK-cell neoplasm that preferentially affects Asians with a fulminant clinical course and is almost always associated with Epstein-Barr virus (EBV). The data on EBV-negative aggressive NK-cell leukemia/lymphoma are limited. Here we report a series of three patients (two Caucasians, one African-American) with EBV-negative aggressive NK-cell leukemia/lymphoma from a single institution, including a case diagnosed on post-mortem examination. Similar to EBV-positive aggressive NK-cell leukemia/lymphoma, our patients presented with constitutional symptoms and hepatosplenomegaly, and followed a highly aggressive clinical course. The disease involved peripheral blood, bone marrow, liver, spleen, and lymph node, and the neoplastic cells were pleomorphic with prominent azurophilic granules and demonstrated an atypical NK-cell phenotype. Lack of blood lymphocytosis (3 of 3), bone marrow interstitial infiltration (2 of 3), EBER negativity (3 of 3), and atypical phenotype including CD3 negativity by immunohistochemistry make an early recognition of the disease difficult. Ancillary studies revealed a complex karyotype (1 of 2), overexpression (3 of 3), and amplification (1 of 1) of c-MYC. The polycomb repressive complex 2 pathway-associated proteins EZH2 and H3K27me3 and immune checkpoint protein PD-L1 were overexpressed in three of three and two of three cases, respectively. Our findings indicate that the EBV-negative aggressive NK-cell leukemia/lymphoma shares similar clinicopathological features to the EBV-positive counterpart except for the high prevalence of Asian seen in EBV-positive cases. Overexpression of polycomb repressive complex 2 pathway-associated proteins and PD-L1 suggest potential therapeutic targets for this aggressive disease. Next-generation sequencing on two of three cases identified multiple genetic alterations but were negative for JAK-STAT pathway-associated gene mutations previously reported in EBV-positive NK/T-cell lymphoma, suggesting alternative molecular pathogenic mechanisms for EBV-negative aggressive NK-cell leukemia/lymphoma.
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Leucemia Linfocítica Granular Grande/patología , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The myelodysplastic syndromes (MDSs) include a spectrum of stem cell malignancies characterized by an increased risk of developing acute myeloid leukemia. Heterozygous loss of chromosome 5q (del[5q]) is the most common cytogenetic abnormality in MDS. DIAPH1 is localized to 5q31 and encodes one of the formin proteins, mDia1, which is involved in linear actin polymerization. Mice with mDia1 deficiency develop hematologic features with age mimicking human myeloid neoplasm, but its role in the pathogenesis of MDS is unclear. Here we report that mDia1 heterozygous and knockout mice develop MDS phenotypes with age. In these mice, CD14 was aberrantly overexpressed on granulocytes in a cell-autonomous manner, leading to a hypersensitive innate immune response to lipopolysaccharide (LPS) stimuli through CD14/Toll-like receptor 4 signaling. Chronic stimulation with LPS accelerated the development of MDS in mDia1 heterozygous and knockout mice that can be rescued by lenalidomide. Similar findings of CD14 overexpression were observed on the bone marrow granulocytes of del(5q) MDS patients. Mechanistically, mDia1 deficiency led to a downregulation of membrane-associated genes and a specific upregulation of CD14 messenger RNA in granulocytes, but not in other lineages. These results underscore the significance of mDia1 heterozygosity in deregulated innate immune responses in del(5q) MDS.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Portadoras/metabolismo , Deleción Cromosómica , Cromosomas Humanos Par 5 , Regulación de la Expresión Génica , Granulocitos/metabolismo , Heterocigoto , Inmunidad Innata , Receptores de Lipopolisacáridos/biosíntesis , Síndromes Mielodisplásicos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Animales , Células de la Médula Ósea/inmunología , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Proteínas Portadoras/genética , Proteínas Portadoras/inmunología , Femenino , Forminas , Granulocitos/inmunología , Granulocitos/patología , Humanos , Receptores de Lipopolisacáridos/genética , Receptores de Lipopolisacáridos/inmunología , Lipopolisacáridos/farmacología , Masculino , Ratones , Ratones Noqueados , Síndromes Mielodisplásicos/genética , Síndromes Mielodisplásicos/inmunología , Síndromes Mielodisplásicos/patología , ARN Mensajero/genética , ARN Mensajero/inmunología , ARN Mensajero/metabolismo , Receptor Toll-Like 4/agonistas , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 4/metabolismoRESUMEN
Subcutaneous panniculitis-like T-cell lymphoma is a rare subtype of cutaneous T-cell lymphoma. Virtually all cases are confined to the subcutaneous adipose tissue. In this report, we describe the first small series of subcutaneous panniculitis-like T-cell lymphoma (three patients) with bone marrow involvement. All patients presented with skin or soft tissue nodules, fever, and constitutional symptoms, and were diagnosed with subcutaneous panniculitis-like T-cell lymphoma based on the characteristic morphologic and immunophenotypic features of the subcutaneous lesions. Bone marrow core biopsies in these cases showed focal involvement by lymphoma with pathologic features similar to those seen in the diagnostic biopsies. Our observations suggest bone marrow involvement by subcutaneous panniculitis-like T-cell lymphoma does occur, and can be identified histologically and confirmed using standard immunohistochemistry. Our findings raise awareness of bone marrow involvement in this rare entity. However, the incidence and significance of bone marrow involvement in subcutaneous panniculitis-like T-cell lymphoma requires further evaluation.
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Médula Ósea/patología , Linfoma de Células T/patología , Paniculitis/patología , Adulto , Femenino , Citometría de Flujo , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Adulto JovenRESUMEN
CSF3R activating mutation is a genetic hallmark of chronic neutrophilic leukemia (CNL), and is also present in a subset of atypical chronic myeloid leukemia (aCML), but infrequent in other myeloid neoplasms. However, the occurrence of CSF3R mutations in various myeloid neoplasms is not well studied. Here we evaluate the spectrum of CSF3R mutations and the clinicopathologic features of CSF3R mutated myeloid neoplasms. We retrospectively identified CSF3R mutations in a variety of myeloid neoplasms: two CNL, three atypical chronic myeloid leukemia (aCML), nine acute myeloid leukemia (AML), one chronic myelomonocytic leukemia, and one myeloproliferative neoplasm. The prototypic T618I mutation was found in 50% of cases: CNL (2/2), aCML (2/3) and AML (4/9). We observed a new recurrent CSF3R mutation Q776* in 25% of cases, and a potential-germline mutation in a 20-year-old patient. Co-occurring mutations were often in epigenetic modifier and spliceosome. IDH/RUNX1 and tumor suppressor mutations were frequent in AML but absent in CNL/aCML. All CNL/aCML patients succumbed within 2-years of diagnosis. We demonstrate that CSF3R mutations are not restricted to CNL. CNL and aCML show similar clinicopathologic and molecular features, suggesting that CNL may be best classified as myelodysplastic/myeloproliferative neoplasm rather than myeloproliferative neoplasm.
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Leucemia Neutrofílica Crónica , Mutación , Receptores del Factor Estimulante de Colonias , Humanos , Receptores del Factor Estimulante de Colonias/genética , Masculino , Persona de Mediana Edad , Femenino , Anciano , Leucemia Neutrofílica Crónica/genética , Leucemia Neutrofílica Crónica/patología , Estudios Retrospectivos , Adulto , Adulto Joven , Anciano de 80 o más Años , Trastornos Mieloproliferativos/genética , Trastornos Mieloproliferativos/patología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Análisis Mutacional de ADN , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/genética , Leucemia Mieloide Crónica Atípica BCR-ABL Negativa/patología , Predisposición Genética a la Enfermedad , Biomarcadores de Tumor/genética , FenotipoRESUMEN
Recent updates in the classification of myeloid neoplasms (MNs) recognize the poor prognostic impact of TP53 mutations, with particular emphasis on the TP53 allele status. Studies on the effect of TP53 allele status exclusively in therapy-related MNs (t-MNs) are lacking. We compared the clinicopathologic and survival characteristics of t-MNs with single-hit (SH) and multi-hit (MH) TP53 mutations. A total of 71 TP53-mutated t-MNs were included, including 56 (78.9%) MH and 15 (21.1%) SH. Both groups showed comparable genetic profiles with an excess of high-risk karyotypes and a paucity of other co-mutated genes. TP53 was the sole detectable mutation in 73.3% of SH and 75.0% of MH cases. The overall survival (OS) of SH TP53-mutated t-MNs was not significantly different from MH cases (median survival: 233 vs.273 days, p = 0.70). Our findings suggest that t-MNs with SH TP53 mutations share the poor prognostic and biologic profile of their MH counterparts.
RESUMEN
The MYC protooncogene plays a critical role in many cellular processes. MYC translocations are recurrent in large B-cell lymphomas (LBCLs) where they exhibit a negative effect on survival. Gain of MYC copies is also frequently identified; however, there is no consensus on the frequency and prognostic significance of MYC copy gains. We collected FISH data for MYC with reflex testing for BCL2 and BCL6 and IHC results at diagnosis for a cohort of 396 de novo and transformed LBCL cases and compared progression-free (PFS) and overall survival (OS) to determine the prognostic impact of extra MYC copies. The prevalence of cases with MYC copy number gain was 20.9%. PFS was shorter for patients with ≥5 MYC copies compared to controls (p = 0.0005, HR = 2.25). .MYC gain trended towards worse OS; patients with ≥7MYC copies had worse OS (p = 0.013), similar to patients with MYC translocations. We propose that MYC gain represents a dose-dependent prognostic factor for LBCLs.
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Variaciones en el Número de Copia de ADN , Linfoma de Células B Grandes Difuso , Humanos , Pronóstico , Hibridación Fluorescente in Situ , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Translocación Genética , Proteínas Proto-Oncogénicas c-bcl-6/genéticaRESUMEN
Maintenance rituximab in mantle cell lymphoma (MCL) has improved survival and supports exploration of maintenance with novel agents. We evaluated the safety and efficacy of ibrutinib maintenance (I-M) after induction in patients with treatment-naive MCL. Patients with MCL with complete response (CR) or partial response to frontline chemoimmunotherapy ± autologous stem cell transplantation (auto-SCT) received I-M 560 mg daily for up to 4 years. Primary objective was 3-year progression-free survival (PFS) rate from initiation of I-M. Minimal residual disease (MRD) assessments by next-generation sequencing (NGS) on peripheral blood were measured before I-M initiation and at 1, 6, and 18 to 24 months after initiation. Among 36 patients, the median age was 60 years (range, 46-90). For frontline treatment, 18 patients (50%) had consolidation with auto-SCT in CR1 before I-M. At median follow-up of 55.7 months, 17 patients (47%) completed full course I-M (median, 37.5 cycles; range, 2-52). The 3-year PFS and overall survival (OS) rates were 94% and 97%, respectively. With prior auto-SCT, 3-year PFS and OS rates were both 100%. The most common treatment-related adverse event with I-M was infection (n = 31; 86%), typically low grade; the most common grade 3/4 toxicities were hematologic. In 22 patients with MRD assessments, all were MRD negative after induction. Six became MRD positive on I-M, with 2 reverting to MRD-negative status with continued I-M, and all maintain radiographic CR with the exception of 1 with disease progression. I-M is feasible in MCL after frontline chemoimmunotherapy with manageable toxicities although significant. Changes in NGS-MRD were noted in limited patients during maintenance with few progression and survival events. This trial was registered at www.clinicaltrials.gov as #NCT02242097.
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Trasplante de Células Madre Hematopoyéticas , Linfoma de Células del Manto , Humanos , Adulto , Persona de Mediana Edad , Linfoma de Células del Manto/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trasplante AutólogoRESUMEN
With the advent of next-generation sequencing (NGS), identifying and better understanding genetic mutations in cancer pathways has become more feasible. A mutation now commonly reported in NGS panels is the SETD2 gene (H3K36 trimethyltransferase). However, its contributions to colorectal cancer (CRC) are not well described. In this study, we describe the clinicopathologic characteristics of SETD2-mutated CRC, determine common mutation sites on the SETD2 gene, and correlate these mutations with the loss of H3K36 trimethylation and the aberrant expression of beta-catenin. By searching pathology reports at our institution which included the 161-gene NGS panel from 2019 to 2021, we identify 24 individuals with SETD2-mutated CRC. All samples were evaluated for microsatellite status, H3K36 trimethylation, and beta-catenin via immunohistochemistry. In this cohort of 24 SETD2-mutated CRC individuals (a median age of 62.4 years [interquartile range: 49.1-73.6]), 10 (41.7%) patients presented at American Joint Committee on Cancer (AJCC) tumor stage II, seven (29.2%) at stage III, six (25%) at stage IV, and one (4.2%) at stage I. Most tumors studied were adenocarcinomas with no further specification (22, 92%), and most tumors were microsatellite stable (18, 82.5%). Thirty-three mutation locations were represented by 24 patients, with one patient having six mutations in the SETD2 gene and two patients having three mutations. The dominant mutation type is missense mutations (N = 29, 87.9%), and no mutation hotspots were found. Only two samples lost trimethylation of histone H3K36, both from individuals with multiple SETD2 mutations and aberrant nuclear beta-catenin expression. SETD2-mutated CRC is similar in clinical and histologic presentation to other commonly reported CRC. SETD2 mutations were missense dominantand showed no hotspots, and multiple mutations are likely necessary for loss of H3K36 trimethylation. These results warrant further study on determining a role of SETD2-histone H3K36 pathway in CRC.
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Neoplasias Colorrectales , Histonas , Humanos , Persona de Mediana Edad , beta Catenina/genética , beta Catenina/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Histonas/genética , Histonas/metabolismo , Mutación , AncianoRESUMEN
OBJECTIVES: Acute myeloid leukemia (AML) with t(8;16)(p11;p13) abnormalities is a rare, aggressive, and diagnostically challenging subtype that results in KAT6A-CREBBP gene fusion. METHODS: To investigate their immunophenotype and genomic features, we identified 5 cases of AML with t(8;16) through a retrospective review of the databases at Northwestern Memorial Hospital in Chicago, IL, and Washington University Medical Center, in St Louis, MO. RESULTS: In all, 4 of 5 cases were therapy related and 1 was possibly therapy related. The leukemic blasts showed distinctive features, including bright CD45 expression and remarkably high side scatter that overlapped with maturing myeloid elements, making the blasts difficult to identify on initial examination. They were positive for CD13, CD33, and CD64 and negative for CD34 and CD117. Next-generation sequencing profiling of 4 cases revealed pathogenic ASXL1 (2 cases), FLT3-tyrosine kinase domain (TKD) mutations (2 cases), and other pathogenic mutations. In 3 patients, t(8;16) was the sole cytogenetic abnormality; additional aberrations were found in 2 patients. Single nucleotide polymorphism microarray revealed 1 case with 7q deletion as a secondary clone. CONCLUSIONS: Our data highlight the distinctive immunophenotypic profile of AML with t(8;16), which, along with its unique morphology, often presents a diagnostic challenge. We showed that mutations of either ASXL1 or FLT3-TKD are seen in most cases of this leukemia.
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Leucemia Mieloide Aguda , Aberraciones Cromosómicas , Citometría de Flujo/métodos , Humanos , Inmunofenotipificación , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Mutación , Translocación GenéticaRESUMEN
Splicing factor SF3B1 mutation occurs in 20-30% of myelodysplastic syndrome (MDS) and myelodysplasia/myeloproliferative neoplasm (MDS/MPN), particularly those with ring sideroblasts (RS), and rarely in acute myeloid leukemia (AML). In this study, we performed a comprehensive evaluation of 77 SF3B1-mutated myeloid neoplasms (45 MDS, 18 MDS/MPN, 13 AML, and 1 MPN), including their clinical presentations, morphologic features, cytogenetic studies, and targeted next-generation sequencing. Our study demonstrated that concurrent gene mutations were very different in SF3B1-mutated MDS, MDS/MPN, and AML. MDS cases were frequently characterized by either sole SF3B1 mutation or in combination with TET2 mutation. Acquiring additional mutations in transcription factors, such as RUNX1 and GATA2, were associated with increased blasts and progression to AML in patients with MDS or MDS/MPN. Our study also demonstrated that SF3B1-mutated MDS/MPN was not only associated with thrombocytosis (5/18, 27.7%), defined by the current WHO classification as MDS/MPN-RS-T, but also associated with neutrophilia (6/18, 33.3%), monocytosis (6/18, 33.3%), and mastocytosis (1/18, 5.6%). Our results indicate that although SF3B1-mutated myeloid neoplasms in general have a good prognosis, evaluation of the concurrent gene mutational profile is important for risk stratification. In addition, our study, in combination with other published data, suggests that the category of MDS/MPN-RS-T in the current WHO classification could be expanded to include SF3B1-mutated MDS/MPN-RS with peripheral leukocytosis such as neutrophilia and monocytosis.
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Leucemia Mieloide Aguda , Síndromes Mielodisplásicos , Enfermedades Mielodisplásicas-Mieloproliferativas , Trastornos Mieloproliferativos , Humanos , Enfermedades Mielodisplásicas-Mieloproliferativas/genética , Trastornos Mieloproliferativos/genética , Síndromes Mielodisplásicos/genética , Mutación , Leucemia Mieloide Aguda/genética , Fosfoproteínas/genética , Factores de Empalme de ARN/genéticaRESUMEN
Intrachromosomal amplification of chromosome 21 (iAMP21) defines a rare provisional entity of B-cell acute lymphoblastic leukemia (B-ALL) in the current WHO classification and has been described as specific for pediatric patients with a median age at diagnosis of 9-10 years. We report two adult cases of B-ALL with iAMP21, one 31-year-old woman and one 40-year-old man, identified by karyotyping and next generation sequencing (NGS), with fluorescence in situ hybridization (FISH) pattern meeting diagnostic criteria for iAMP21. Both patients were treated on high-risk chemotherapeutic regimen followed by stem cell transplant. In contrast to reported high relapse rate within the first three years in pediatric population, our adult patients are alive in remission, with the interval from diagnosis to last follow up of 2.95 and 3.96 years. Our cases illustrate the importance of screening for iAMP21 in adult population when ETV6-RUNX1 FISH testing is not routinely performed for adult patients.
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Leucemia de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras B , Niño , Humanos , Hibridación Fluorescente in Situ , Cromosomas Humanos Par 21/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/terapia , Aberraciones CromosómicasRESUMEN
Background: The impact of gene mutations typically associated with myelodysplastic syndrome (MDS) in acute myeloid leukemia (AML) with NPM1 mutation is unclear. Methods: Using a cohort of 107 patients with NPM1-mutated AML treated with risk-adapted therapy, we compared survival outcomes of patients without MDS-related gene mutations (group A) with those carrying concurrent FLT3-ITD (group B) or with MDS-related gene mutations (group C). Minimal measurable disease (MMD) status assessed by multiparameter flow cytometry (MFC), polymerase chain reaction (PCR), and/or next-generation sequencing (NGS) were reviewed. Results: Among the 69 patients treated intensively, group C showed significantly inferior progression-free survival (PFS, p < 0.0001) but not overall survival (OS, p = 0.055) compared to group A. Though groups A and C had a similar MMD rate, group C patients had a higher relapse rate (p = 0.016). Relapse correlated with MMD status at the end of cycle 2 induction (p = 0.023). Survival of group C patients was similar to that of group B. Conclusion: MDS-related gene mutations are associated with an inferior survival in NPM1-mutated AML.
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Although mRNA vaccines against SARS-CoV-2 were highly efficacious against severe illness and hospitalization, they seem to be less effective in preventing infection months after vaccination, especially with the Delta variant. Breakthrough infections might be due to higher infectivity of the variants, relaxed protective measures by the general public in "COVID-19 fatigue", and/or waning immunity post-vaccination. Determining the neutralizing antibody levels in a longitudinal manner may address this issue, but technical complexity of classic assays precludes easy detection and quick answers. We developed a lateral flow immunoassay NeutraXpress™ (commercial name of the test kit by Antagen Diagnostics, Inc.) and tested fingertip blood samples of subjects receiving either Moderna or Pfizer vaccines at various time points. With this device, we confirmed the reported clinical findings that mRNA vaccine-induced neutralizing antibodies quickly wane after 3-6 months. Thus, using rapid tests to monitor neutralizing antibody status could help identify individuals at risk, prevent breakthrough infections, and guide social behavior to curtail the spread of COVID-19.
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Lymphoid-enhancer-binding factor 1 (LEF1), coupling with ß-catenin, functions as a key nuclear mediator of WNT/ß-catenin signaling, which regulates cell proliferation and survival. LEF1 has an important role in lymphopoiesis, and is normally expressed in T and pro-B cells but not mature B cells. However, gene expression profiling demonstrates overexpression of LEF1 in chronic lymphocytic leukemia, and knockdown of LEF1 decreases the survival of the leukemic cells. So far, the data on LEF1 expression in B-cell lymphomas are limited. This study represents the first attempt to assess LEF1 by immunohistochemistry in a large series (290 cases) of B-cell lymphomas. Strong nuclear staining of LEF1 was observed in virtually all neoplastic cells in 92 of 92 (100%) chronic lymphocytic leukemia/small lymphocytic lymphomas including two CD5- cases, with strongest staining in cells with Richter's transformation. LEF1 also highlighted the morphologically inconspicuous small lymphocytic lymphoma component in three composite lymphomas. All 53 mantle cell lymphomas, 31 low-grade follicular lymphomas and 31 marginal zone lymphomas, including 3 CD5+ cases, were negative. In 12 grade 3 follicular lymphomas, LEF1 was positive in a small subset (5-15%) of cells. Diffuse large B-cell lymphoma, however, demonstrated significant variability in LEF1 expression with overall positivity in 27 of 71 (38%) cases. Our results demonstrate that nuclear overexpression of LEF1 is highly associated with chronic lymphocytic leukemia/small lymphocytic lymphoma, and may serve as a convenient marker for differential diagnosis of small B-cell lymphomas. The expression of ß-catenin, the coactivator of LEF1 in WNT signaling, was examined in 50 chronic lymphocytic leukemia/small lymphocytic lymphomas, of which 44 (88%) showed negative nuclear staining. The findings of universal nuclear overexpression of LEF1 but lack of nuclear ß-catenin in the majority of chronic lymphocytic leukemia/small lymphocytic lymphoma suggest that the pro-survival function of LEF1 in this disease may be independent of WNT/ß-catenin signaling.