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Deficient (d) DNA mismatch repair (MMR) is a biomarker predictive of better response to PD-1 blockade immunotherapy in solid tumors. dMMR can be caused by mutations in MMR genes or by protein inactivation, which can be detected by sequencing and immunohistochemistry, respectively. To investigate the role of dMMR in diffuse large B-cell lymphoma (DLBCL), MMR gene mutations and expression of MSH6, MSH2, MLH1, and PMS2 proteins were evaluated by targeted next-generation sequencing and immunohistochemistry in a large cohort of DLBCL patients treated with standard chemoimmunotherapy, and correlated with the tumor immune microenvironment characteristics quantified by fluorescent multiplex immunohistochemistry and gene-expression profiling. The results showed that genetic dMMR was infrequent in DLBCL and was significantly associated with increased cancer gene mutations and favorable immune microenvironment, but not prognostic impact. Phenotypic dMMR was also infrequent, and MMR proteins were commonly expressed in DLBCL. However, intratumor heterogeneity existed, and increased DLBCL cells with phenotypic dMMR correlated with significantly increased T cells and PD-1+ T cells, higher average nearest neighbor distance between T cells and PAX5+ cells, upregulated immune gene signatures, LE4 and LE7 ecotypes and their underlying Ecotyper-defined cell states, suggesting the possibility that increased T cells targeted only tumor cell subsets with dMMR. Only in patients with MYC¯ DLBCL, high MSH6/PMS2 expression showed significant adverse prognostic effects. This study shows the immunologic and prognostic effects of genetic/phenotypic dMMR in DLBCL, and raises a question on whether DLBCL-infiltrating PD-1+ T cells target only tumor subclones, relevant for the efficacy of PD-1 blockade immunotherapy in DLBCL.
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Reparo de Erro de Pareamento de DNA , Linfoma Difuso de Grandes Células B , Microambiente Tumoral , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/imunologia , Linfoma Difuso de Grandes Células B/patologia , Reparo de Erro de Pareamento de DNA/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Masculino , Feminino , Mutação , Pessoa de Meia-Idade , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Prognóstico , Adulto , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismoRESUMO
Despite selective HDAC3 inhibition showing promise in a subset of lymphomas with CREBBP mutations, wild-type tumors generally exhibit resistance. Here, using unbiased genome-wide CRISPR screening, we identify GNAS knockout (KO) as a sensitizer of resistant lymphoma cells to HDAC3 inhibition. Mechanistically, GNAS KO-induced sensitization is independent of the canonical G-protein activities but unexpectedly mediated by viral mimicry-related interferon (IFN) responses, characterized by TBK1 and IRF3 activation, double-stranded RNA formation, and transposable element (TE) expression. GNAS KO additionally synergizes with HDAC3 inhibition to enhance CD8+ T cell-induced cytotoxicity. Moreover, we observe in human lymphoma patients that low GNAS expression is associated with high baseline TE expression and upregulated IFN signaling and shares common disrupted biological activities with GNAS KO in histone modification, mRNA processing, and transcriptional regulation. Collectively, our findings establish an unprecedented link between HDAC3 inhibition and viral mimicry in lymphoma. We suggest low GNAS expression as a potential biomarker that reflects viral mimicry priming for enhanced response to HDAC3 inhibition in the clinical treatment of lymphoma, especially the CREBBP wild-type cases.
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EBV-positive inflammatory follicular dendritic cell sarcoma (EBV+ IFDCS) is an uncommon disease primarily observed in Asia. It is characterized by the development of tumors believed to originate from follicular dendritic cells (FDC). The consistent association between this condition and clonal EBV infection suggests EBV's involvement as an etiological factor. However, diagnosing EBV+ IFDCS can be challenging due to its morphological variability and diverse immunohistochemical staining patterns. The genetic characteristics of EBV+ IFDCS remain insufficiently understood. To address this knowledge gap, we present a case study of a 47-year-old male patient diagnosed with EBV+ IFDCS. We utilized a Next-generation sequencing (NGS) platform to investigate the genetic profile of the tumor cells. We identified a single pathogenic mutation (G618R) in the STAT3 gene. This finding provides valuable insights into the genetic alterations associated with EBV+ IFDCS and potentially contributes to our understanding of the disease's pathogenesis.
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The blastoid (B) and pleomorphic (P) variants of mantle cell lymphoma (MCL) are associated with aggressive clinical behavior. In this study, we collected 102 cases of B-MCL and P-MCL from untreated patients. We reviewed clinical data, analyzed morphologic features using an image analysis tool (ImageJ) and we assessed mutational and gene expression profiles. The chromatin pattern of lymphoma cells was assessed quantitatively by the pixel value. Cases of B-MCL showed a greater median pixel value with lower variation compared with P-MCL, indicating a homogeneously euchromatin-rich pattern in B-MCL. In addition, the Feret diameter of the nuclei was significantly smaller (median 6.92 vs. 8.49 µm per nucleus, P <0.001) and had a lesser degree of variation in B-MCL compared with P-MCL, indicating that B-MCL cells have smaller cells with a more monomorphic appearance. B-MCL showed a significantly higher median Ki-67 proliferation rate (60% vs. 40%, P =0.003), and affected patients had poorer overall survival compared with those with P-MCL (median overall survival: 3.1 vs. 8.8 y, respectively, P =0.038). NOTCH1 mutation was significantly more frequent in B-MCL compared with P-MCL (33% and 0%, respectively, P =0.004). Gene expression profiling showed 14 genes overexpressed in B-MCL cases and gene set enrichment assay for the overexpressed genes showed significant enrichment in the cell cycle and mitotic transition pathways. We also report a subset of MCL cases that has blastoid chromatin but a higher degree of pleomorphism in nuclear size and shape, designated here as hybrid MCL. Hybrid MCL cases had a similar Ki-67 proliferation rate, mutation profile, and clinical outcome to B-MCL and distinct from P-MCL. In summary, these data suggest biological differences between B-MCL and P-MCL cases justifying their separate designation when possible.
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Linfoma de Célula do Manto , Adulto , Humanos , Cromatina , Antígeno Ki-67/análise , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/patologia , MutaçãoRESUMO
Crystal-storing histiocytosis (CSH) is a non-neoplastic histiocytic proliferation that results from the intra-lysosomal accumulation of immunoglobulins as crystals. CSH is frequently associated with various B-cell lymphomas or plasma cell neoplasms. CSH can potentially obscure underlying lymphoproliferative neoplasms. This association should always be considered and the tissue should be carefully evaluated.
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EZH2 coding mutation (EZH2MUT), resulting in loss-of-function, is an independent predictor of overall survival in MDS. EZH2 function can be altered by other mechanisms including copy number changes, and mutations in other genes and non-coding regions of EZH2. Assessment of EZH2 protein can identify alterations of EZH2 function missed by mutation assessment alone. Precise evaluation of EZH2 function and gene-protein correlation in clinical MDS cohorts is important in the context of upcoming targeted therapies aimed to restore EZH2 function. In this study, we evaluated the clinicopathologic characteristics of newly diagnosed MDS patients with EZH2MUT and correlated the findings with protein expression using immunohistochemistry. There were 40 (~6%) EZH2MUT MDS [33 men, seven women; median age 74 years (range, 55-90)]. EZH2 mutations spanned the entire coding region. Majority had dominant EZH2 clone [median VAF, 30% (1-92)], frequently co-occurring with co-dominant TET2 (38%) and sub-clonal ASXL1 (55%) and RUNX1 (43%) mutations. EZH2MUT MDS showed frequent loss-of-expression compared to EZH2WT (69% vs. 27%, p = 0.001). Interestingly, NINE (23%) EZH2WT MDS also showed loss-of-expression. EZH2MUT and loss-of-expression significantly associated with male predominance and chr(7) loss. Further, only EZH2 loss-of-expression patients showed significantly lower platelet counts, a trend for higher BM blast% and R-IPSS scores. Over a 14-month median follow-up, both EZH2MUT (p = 0.027) and loss-of-expression (p = 0.0063) correlated with poor survival, independent of R-IPSS, age and gender. When analyzed together, loss-of-expression showed a stronger correlation than mutation (p = 0.061 vs. p = 0.43). In conclusion, immunohistochemical assessment of EZH2 protein, alongside mutation, is important for prognostic workup of MDS.
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Proteína Potenciadora do Homólogo 2 de Zeste , Síndromes Mielodisplásicas , Idoso , Idoso de 80 Anos ou mais , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Síndromes Mielodisplásicas/patologia , Prognóstico , Fatores de Transcrição/genéticaRESUMO
Guillain-Barré syndrome (GBS) is a rare condition caused by autoimmune damage of peripheral nerves. We describe a case where a man in his 80s presented with subacute, progressive fatigue and weakness. He had received an outpatient work-up for possible haematological malignancy, but eventually presented to the emergency department for worsening weakness. A physical exam and cerebrospinal fluid analysis suggested a diagnosis of GBS. Subsequently, a pathological diagnosis of angioimmunoblastic T-cell lymphoma was made. The patient underwent intravenous immunoglobulin treatment for GBS and was started on cyclophosphamide, doxorubicin, vincristine and prednisone therapy. Prior research has suggested that incident malignancy may be associated with GBS, which may be caused by a paraneoplastic-type phenomenon, malignancy-associated immune dysregulation or an autoimmune reaction triggered by a common exposure. Clinicians should be aware of the possible association between these two conditions and should remain open minded to the possibility of non-infectious triggers for GBS.
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Síndrome de Guillain-Barré , Linfoma de Células T , Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/etiologia , Humanos , Imunoglobulinas Intravenosas , Linfoma de Células T/complicações , Linfoma de Células T/diagnóstico , Linfoma de Células T/tratamento farmacológico , MasculinoRESUMO
The diagnosis of plasma cell neoplasms requires accurate, and ideally precise, percentages. This plasma cell percentage is often determined by visual estimation of CD138-stained bone marrow biopsies and clot sections. While not necessarily inaccurate, estimates are by definition imprecise. For this study, we hypothesized that deep learning can be used to improve precision. We trained a semantic segmentation-based convolutional neural network (CNN) using annotations of CD138+ and CD138- cells provided by one pathologist on small image patches of bone marrow and validated the CNN on an independent test set of image patches using annotations from two pathologists and a non-deep learning commercial software. On validation, we found that the intraclass correlation coefficients for plasma cell percentages between the CNN and pathologist #1, a non-deep learning commercial software and pathologist #1, and pathologists #1 and #2 were 0.975, 0.892, and 0.994, respectively. The overall results show that CNN labels were almost as accurate as pathologist labels at a cell-by-cell level. Once satisfied with performance, we scaled-up the CNN to evaluate whole slide images (WSIs), and deployed the system as a workflow friendly web application to measure plasma cell percentages using snapshots taken from microscope cameras.
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Enhancer of zeste homolog 2 (EZH2) is a catalytic component of the polycomb repressive complex 2 (PRC2) which reduces gene expression via trimethylation of a lysine residue of histone 3 (H3K27me3). Expression of EZH2 has not been assessed systematically in mantle cell lymphoma (MCL). Expression of EZH2 was assessed by immunohistochemistry in 166 patients with MCL. We also assessed other PRC2 components and H3K27me3. Fifty-seven (38%) of MCL patients were positive for EZH2 using 40% cutoff. EZH2 expression was associated with aggressive histologic variants (65% vs. 29%, p < 0.001), high Ki-67 proliferation rate (median, 72% vs. 19%, p < 0.001), and p53 overexpression (43% vs. 2%, p < 0.001). EZH2 expression did not correlate with expression of other PRC2 components (EED and SUZ12), H3K27me3, MHC-I, and MHC-II. Patients with EZH2 expression (EZH2+) had a poorer overall survival (OS) compared with patients without EZH2 expression (EZH2-) (median OS: 3.9 years versus 9.4 years, respectively, p < 0.001). EZH2 expression also predicted a poorer prognosis in MCL patients with classic histology (median OS, 4.6 years for EZH2+ and 9.6 years for EZH2-negative, respectively, p < 0.001) as well as aggressive histology (median OS, 3.7 years for EZH2+ and 7.9 years for EZH2-negative, respectively, p = 0.046). However, EZH2 expression did not independently correlate with overall survival in a multivariate analysis. Gene expression analysis and pathway enrichment analysis demonstrated a significant enrichment in cell cycle and mitotic transition pathways in MCL with EZH2 expression. EZH2 expression detected by immunohistochemistry is present in 38% of MCL cases and it is associated with high proliferation rate, p53 overexpression, aggressive histologic variants, and poorer OS. Based on gene expression profiling data, EZH2 expression could potentiate cell cycle machinery in MCL. These data suggest that assessment of EZH2 expression could be useful to stratify MCL patients into low- and high-risk groups.
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Biomarcadores Tumorais/análise , Proteína Potenciadora do Homólogo 2 de Zeste/análise , Linfoma de Célula do Manto/enzimologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Proliferação de Células , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Histonas/análise , Humanos , Imuno-Histoquímica , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/mortalidade , Linfoma de Célula do Manto/terapia , Masculino , Metilação , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Medição de Risco , Fatores de Risco , Fatores de Tempo , Transcriptoma , Resultado do TratamentoRESUMO
Myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U) is a poorly characterized entity among overlap myeloid syndromes. Recent studies have shown heterogeneous mutational profiles in this group being able to subclassify them into entities closely related to the more well-established disorders under the umbrella term of the MDS/MPN group. Recurrent cytogenetic alterations are, nonetheless, rare in MDS/MPN-U. Here, for the first time, we report a case of MDS/MPN-U with a t(X;17)(q28;q21) chromosomal rearrangement leading to the KANSL1-MTCP1 fusion gene.
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Cromossomos Humanos Par 17/genética , Cromossomos Humanos X/genética , Fusão Gênica/genética , Doenças Mieloproliferativas-Mielodisplásicas/genética , Proteínas Nucleares/genética , Translocação Genética/genética , Adulto , Citogenética , Humanos , Masculino , Proteínas Proto-Oncogênicas/genéticaRESUMO
A previously healthy 29-year-old man initially presented to the hospital with pleuritic chest pain and shortness of breath. Over the next 2 months he developed ongoing fevers and night sweats with recurrent exudative pleural effusions and ascites. He had an extensive infectious and autoimmune workup that was unremarkable. He had an initial lymph node biopsy that showed reactive changes only. He had an acute kidney injury and his renal biopsy revealed thrombotic microangiopathy. His liver biopsy showed non-specific inflammatory changes. His bone marrow biopsy showed megakaryocyte hyperplasia and fibrosis, which raised suspicion for the thrombocytopenia, ascites, reticulin fibrosis, renal dysfunction and organomegaly syndrome subtype of multicentric Castleman disease. This prompted a repeat lymph node biopsy, showing changes consistent with mixed type Castleman disease that fit with his clinical picture. He was initiated on steroids and siltuximab with significant clinical improvement.
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Biópsia/métodos , Células da Medula Óssea/patologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Rim/patologia , Fígado/patologia , Linfonodos/patologia , Adulto , Diagnóstico Diferencial , Humanos , Masculino , PescoçoRESUMO
Lymphoid enhancer binding factor 1 (LEF1) is consistently upregulated in chronic lymphocytic leukemia (CLL) and in a subset of large B cell lymphoma. Knowledge of LEF1 expression in Hodgkin lymphoma is limited. In this study, we used immunohistochemistry to survey LEF1 expression in various subsets of Hodgkin lymphoma, de novo classic Hodgkin lymphoma (CHL) (n = 43), Hodgkin lymphoma associated with Richter syndrome (HL-RS) (n = 20), and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) (n = 9). LEF1 expression was significantly higher in HL-RS compared with de novo CHL (12/20, 60% vs. 12/43, 28%; p = 0.0248). Only a single case (1/9; 11%) of NLPHL showed LEF1 expression. Epstein-Barr virus encoded RNA (EBER) was detected in 17 (40%) cases of de novo CHL and 14 (70%) HL-RS. Notably, we identified a correlation between LEF1 expression and EBER positivity (p = 0.0488). We concluded that LEF1 is commonly positive in CHL but not in NLPHL, and such a distinction may be helpful in this differential diagnosis. The higher frequency of LEF1 upregulation in HL-RS relative to de novo CHL suggests that these neoplasms might have different underlying pathogenic mechanisms and warrants further investigation.
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Doença de Hodgkin/metabolismo , Doença de Hodgkin/patologia , Fator 1 de Ligação ao Facilitador Linfoide/biossíntese , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Criança , Feminino , Humanos , Leucemia Linfocítica Crônica de Células B/complicações , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Adult T-cell acute lymphoblastic leukemia (T-ALL) is a heterogeneous group of acute leukemias that account for about one third of all cases of Philadelphia chromosome (Ph)-negative ALL. Recently, a molecular classifier using the mutational status of NOTCH1, FBXW7, RAS, and PTEN (NFRP) has been shown to distinguish low- vs high-risk groups in adult T-ALL patients treated using the Berlin-Frankfurt-Münster ALL protocol. However, it is unknown if this molecular classifier can stratify adult T-ALL patients treated with hyper-CVAD ± nelarabine. We identified a relatively small cohort of 27 adults with T-ALL who were uniformly treated with hyper-CVAD ± nelarabine with available mutational analysis at time of diagnosis. The most commonly mutated genes in this group were NOTCH1 (52%), NRAS (22%), DNMT3A (19%), KRAS (15%), and TP53 (7%). The NFRP molecular classifier failed to stratify overall survival (OS; P = .84) and relapse-free survival (RFS; P = .18) in this cohort. We developed a new stratification model combining K/NRAS and TP53 mutations as high-risk factors and showed that mutations in these genes predicted poorer OS (P = .03) and RFS (P = .04). While the current study is limited by cohort size, these data suggest that the NFRP molecular classifier might not be applicable to adult T-ALL patients treated with hyper-CVAD ± nelarabine. RAS/TP53 mutation status, however, was useful in risk stratification in adults with T-ALL.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , GTP Fosfo-Hidrolases/genética , Proteínas de Membrana/genética , Recidiva Local de Neoplasia/epidemiologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Adolescente , Adulto , Arabinonucleosídeos/uso terapêutico , Ciclofosfamida/uso terapêutico , Análise Mutacional de DNA/estatística & dados numéricos , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Registros Eletrônicos de Saúde/estatística & dados numéricos , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Recidiva Local de Neoplasia/prevenção & controle , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Prognóstico , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Vincristina/uso terapêuticoRESUMO
INTRODUCTION: Many pancreatic cystic lesions (PCL) are of neoplastic nature with potential to progress to pancreatic adenocarcinoma. Early stratification of patients to either clinical observation or surgical intervention can considerably increase the survival rate. Recent studies have shown the value of molecular analysis to current diagnostic modalities.The aim of this study is to evaluate the diagnostic improvement by utilizing multiple sequential cytologic and molecular cyst fluid analyses. MATERIALS AND METHODS: We prospectively evaluated 58 patients for whom multiple endoscopic ultrasound-guided fine-needle aspiration of cyst fluid specimens were available. Specimens were subjected to next generation sequencing to identify any recurrent gene mutations commonly found in PCL. The molecular findings were compared with cytologic and final diagnoses. RESULTS: Cytologic diagnoses were classified into 3 groups: non-diagnostic (first visit: 33.9%, cumulative: 15.8%, P = 0.03), negative (1st visit: 53.6%, cumulative: 56.1%, P = 0.85) and atypical/suspicious/positive (first visit: 12.5%, cumulative: 28.1%, P = 0.06). The mutational analyses were clustered into indeterminate/failure (first visit: 1.7%, cumulative: 0%), KRAS/GNAS/VHL group (first visit: 50.0%, cumulative: 53.4%) and any mutation (first visit: 50.0%, cumulative: 53.4%). Mutational analysis identifies up to 72% and 71% whereas cytologic analysis classified up to 46% and 63% of lesions correctly in first and multiple visits, respectively. CONCLUSIONS: The cytology and molecular analyses provide a complementary approach to patients with PCL. Power of molecular analysis in detection of a neoplastic lesion is significantly higher in one visit (P = 0.01) with comparable detection rates (P = 0.43) for both cytologic and molecular analyses after multiple visits.
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Adenocarcinoma/diagnóstico , Adenocarcinoma/genética , Cisto Pancreático/diagnóstico , Cisto Pancreático/genética , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Cístico/química , DNA/genética , DNA/isolamento & purificação , Análise Mutacional de DNA , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico/métodos , Feminino , Seguimentos , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase Multiplex , Mutação , Pâncreas/patologia , Cisto Pancreático/patologia , Neoplasias Pancreáticas/patologia , Estudos Prospectivos , Análise de Sequência de DNARESUMO
AML and MDS are most common myeloid neoplasms that affect mainly older patients. Overexpression of certain proto-oncogenes plays an indispensable role in tumorigenesis and overexpression can be a consequence of gene rearrangement, amplification and/or mutation. Rearrangement and amplification of KMT2A located at chromosome band 11q23 is a well-characterized genetic driver in a subset of AML/MDS cases and is associated with a poor prognosis. The presence of homogeneously staining regions (hsr) also has been correlated with amplification of specific proto-oncogenes. In this study, we correlated hsr(11)(q23) with KMT2A in a large cohort of AML/MDS (nâ¯=â¯54) patients. We identified 37 patients with hsr(11)(q23) in the setting of AML (nâ¯=â¯27) and MDS (nâ¯=â¯10). All patients showed a complex karyotype including 12 cases with monosomy 17. KMT2A FISH analysis was available for 35 patients which showed KMT2A amplification in all patients. Among control cases with hsr involving chromosomes other than 11q [non-11q hsr, nâ¯=â¯17], FISH analysis for KMT2A was available in 10 cases and none of these cases showed KMT2A amplification (pâ¯=â¯0.0001, Fisher's exact test, two-tailed). Mutational analysis was performed in 32 patients with hsr(11)(q23). The most common mutated gene was TP53 (nâ¯=â¯29), followed by DNMT3A (nâ¯=â¯4), NF1 (nâ¯=â¯4), and TET2 (nâ¯=â¯3). Thirty (83%) patients died over a median follow-up of 7.6 months (range, 0.4-33.4). In summary, hsr(11)(q23) in AML/MDS cases is associated with a complex karyotype, monosomy 17, KMT2A amplification, and TP53 mutation.
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Cromossomos Humanos Par 11 , Histona-Lisina N-Metiltransferase/genética , Leucemia Mieloide Aguda/genética , Síndromes Mielodisplásicas/genética , Proteína de Leucina Linfoide-Mieloide/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Genes p53 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Objective: Better tools are needed for early diagnosis and classification of pancreatic cystic lesions (PCL) to trigger intervention before neoplastic precursor lesions progress to adenocarcinoma. We evaluated the capacity of molecular analysis to improve the accuracy of cytologic diagnosis for PCL with an emphasis on non-diagnostic/negative specimens. Design: In a span of 7 years, at a tertiary care hospital, 318 PCL endoscopic ultrasound-guided fine needle aspirations (EUS-FNA) were evaluated by cytologic examination and molecular analysis. Mucinous PCL were identified based on a clinical algorithm and 46 surgical resections were used to verify this approach. The mutation allele frequency (MAF) of commonly altered genes (BRAF, CDKN2A, CTNNB1, GNAS, RAS, PIK3CA, PTEN, SMAD4, TP53 and VHL) was evaluated for their ability to identify and grade mucinous PCL. Results: Cytology showed a diagnostic sensitivity of 43.5% for mucinous PCL due in part to the impact of non-diagnostic (28.8%) and negative (50.5%) specimens. Incorporating an algorithmic approach or molecular analysis markedly increased the accuracy of cytologic evaluation. Detection of mucinous PCL by molecular analysis was 93.3% based on the detection of KRAS and/or GNAS gene mutations (p = 0.0001). Additional genes provided a marginal improvement in sensitivity but were associated with cyst type (e.g. VHL) and grade (e.g. SMAD4). In the surgical cohort, molecular analysis and the proposed algorithm showed comparable sensitivity (88.9% vs. 100%). Conclusions: Incorporating somatic molecular analysis in the cytologic evaluation of EUS-FNA increases diagnostic accuracy for detection, classification and grading of PCL. This approach has the potential to improve patient management.