RESUMEN
Follicular helper T-cell (TFH) lymphoma harbors recurrent mutations of RHOAG17V, IDH2R172, TET2, and DNMT3A. TET2 and DNMT3A mutations are the most frequently affected genes in clonal hematopoiesis (CH). The aim of our study was to investigate the frequency of CH in bone marrow biopsies (BMB) of TFH/angioimmunoblastic T-cell lymphoma (TFH-AITL) patients and its association with myeloid neoplasms. A total of 29 BMB from 22 patients with a diagnosis of TFH-AITL were analyzed by next-generation sequencing (NGS) with a custom panel. Morphologically, 5 BMB revealed that TFH-AITL infiltrates of >5% of bone marrow (BM) cellularity confirmed in 4 cases by NGS-based T-cell clonality. IDH2R172 was demonstrated only in 1 (3%) of 29, and RHOAG17V in 2 (7%) of 29 samples. TET2 and DNMT3A were identified in 24 (83%) of 29 and 17 (59%) of 29 BMB, respectively. In the parallel lymph node the frequencies of mutations were 27% (IDH2R172), 64% (RHOAG17V), 86% (TET2), and 50% (DNMT3A). TET2 and/or DNMT3A mutations identical in lymph node and BMB were present in 18 (82%) of 22 patients, regardless of BM infiltration. In 3 cases the CH mutations were detected 13, 41, and 145 months before TFH-AITL diagnosis. Cases with TET2/DNMT3A mutations and BM variant allele frequencies >40% (7/18, 39%) showed lower blood counts. However, only low platelet count was statistically significant (P = .024). Myeloid neoplasms and/or myelodysplastic syndrome-related mutations were identified in 4 cases (4/22; 18%); all with high TET2 variant allele frequencies (>40%; P = .0114). In conclusion, CH is present in 82% of TFH-AITL and can be demonstrated up to 145 months before TFH-AITL diagnosis. NGS T-cell clonality analysis is an excellent tool to confirm TFH-AITL BM infiltration. Concurrent myeloid neoplasms were identified in 18% of the cases and were associated with TET2 mutations with high allelic burden (>40%). We demonstrated that myeloid neoplasms might occur simultaneously or precede the diagnosis of TFH lymphoma.
Asunto(s)
Médula Ósea , Hematopoyesis Clonal , Mutación , Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Hematopoyesis Clonal/genética , Médula Ósea/patología , Anciano de 80 o más Años , Adulto , Linfadenopatía Inmunoblástica/genética , Linfadenopatía Inmunoblástica/patología , Linfadenopatía Inmunoblástica/inmunología , Linfoma Folicular/genética , Linfoma Folicular/patología , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Colaboradores-Inductores/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento , ADN Metiltransferasa 3A/genética , Proteínas de Unión al ADN , DioxigenasasRESUMEN
Recent studies have shown that follicular helper T-cell lymphoma of angioimmunoblastic type (AITL), the most common nodal peripheral T-cell lymphoma (PTCL), frequently arises in a background of clonal haematopoiesis (CH), a preneoplastic condition affecting up to 40% of elderly individuals. Data on a potential CH association are limited for other PTCL. We report a unique patient who sequentially developed both cytotoxic PTCL, not otherwise specified and AITL with distinct T-cell receptor rearrangements but shared somatic mutations originating from the same CH clone, thus providing convincing evidence that CH can give rise to T-cell neoplasms of different lineage.
Asunto(s)
Hematopoyesis Clonal , Linfadenopatía Inmunoblástica , Linfoma de Células T Periférico , Anciano , Humanos , Linfadenopatía Inmunoblástica/patología , Linfadenopatía Inmunoblástica/genética , Linfoma de Células T/patología , Linfoma de Células T/genética , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/patología , MutaciónRESUMEN
Approximately 15% of follicular lymphomas (FL) lack overexpression of BCL2 and the underlying translocation t(14;18). These cases can be diagnostically challenging, especially regarding follicular hyperplasia (FH). In a subset of FL, mutations in genes encoding for epigenetic modifiers, such as the histone-lysine N-methyltransferase EZH2 (enhancer of zeste homolog 2), were found, which might be used diagnostically. These molecular alterations can lead to an increased tri-methylation of histone H3 at position lysine 27 (H3K27m3) that, in turn, can be visualized immunohistochemically. The aim of this study was to analyze the expression of H3K27m3 in FL, primary cutaneous follicle center lymphomas (PCFCL), and pediatric-type FL (PTFL) in order to investigate its value in the differential diagnosis to FH and other B cell lymphomas and to correlate it to BCL2 expression and the presence of t(14;18). Additionally, the mutational profile of selected cases was considered to address H3K27m3's potential use as a surrogate parameter for mutations in genes encoding for epigenetic modifiers. Eighty-nine percent of FL and 100% of PCFCL cases overexpressed H3K27m3, independently of BCL2, EZH2, and the presence of mutations. In contrast, 95% of FH and 100% of PTFL cases lacked H3K27m3 overexpression. Other B cell lymphomas considered for differential diagnosis also showed overexpression of H3K27m3 in the majority of cases. In summary, overexpression of H3K27m3 can serve as a new, BCL2 independent marker in the differential diagnosis of FL and PCFCL, but not PTFL, to FH, while being not of help in the differential diagnosis of FL to other B cell lymphomas.
Asunto(s)
Linfoma de Células B , Linfoma Folicular , Niño , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Histonas/genética , Humanos , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/metabolismo , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Linfoma Folicular/patología , Lisina , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismoRESUMEN
Pediatric nodal marginal zone lymphoma (PNMZL) is an uncommon B-cell neoplasm affecting mainly male children and young adults. This indolent lymphoma has distinct characteristics that differ from those of conventional nodal marginal zone lymphoma (NMZL). Clinically, it exhibits overlapping features with pediatric-type follicular lymphoma (PTFL). To explore the differences between PNMZL and adult NMZL and its relationship to PTFL, a series of 45 PNMZL cases were characterized morphologically and genetically by using an integrated approach; this approach included whole-exome sequencing in a subset of cases, targeted next-generation sequencing, and copy number and DNA methylation arrays. Fourteen cases (31%) were diagnosed as PNMZL, and 31 cases (69%) showed overlapping histologic features between PNMZL and PTFL, including a minor component of residual serpiginous germinal centers reminiscent of PTFL and a dominant interfollicular B-cell component characteristic of PNMZL. All cases displayed low genomic complexity (1.2 alterations per case) with recurrent 1p36/TNFRSF14 copy number-neutral loss of heterozygosity alterations and copy number loss (11%). Similar to PTFL, the most frequently mutated genes in PNMZL were MAP2K1 (42%), TNFRSF14 (36%), and IRF8 (34%). DNA methylation analysis revealed no major differences between PTFL and PNMZL. Genetic alterations typically seen in conventional NMZL were absent in PNMZL. In summary, overlapping clinical, morphologic, and molecular findings (including low genetic complexity; recurrent alterations in MAP2K1, TNFRSF14, and IRF8; and similar methylation profiles) indicate that PNMZL and PTFL are likely part of a single disease with variation in the histologic spectrum. The term "pediatric-type follicular lymphoma with and without marginal zone differentiation" is suggested.
Asunto(s)
Linfoma de Células B de la Zona Marginal , Linfoma Folicular , Niño , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Factores Reguladores del Interferón/metabolismo , Linfoma de Células B de la Zona Marginal/diagnóstico , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Masculino , Mutación , Adulto JovenRESUMEN
Round robin testing is an important instrument for quality assurance. Increasingly, this also applies to the results of molecular diagnostics in pathology, which directly influence therapy decisions in precision oncology. In metastatic colorectal carcinoma (mCRC), the focus has been on detecting KRAS and NRAS mutations, whose absence allows therapy with EGFR blocking antibodies. Recently, BRAF has been added as another predictive marker, since mCRC patients with BRAF V600E mutation benefit significantly from treatment with encorafenib (a BRAF inhibitor) in combination with cetuximab (anti-EGFR antibody) after systemic therapy. Due to the approval of this treatment in 2020, it is a pre-requisite that BRAF V600E mutation detection in diagnostic pathologies is reliably performed. Therefore, this round robin test with BRAF V600E testing either by immunohistochemistry or molecular methods was performed. The round robin test results demonstrate that molecular BRAF V600E detection is currently clearly superior to immunohistochemical detection.
Asunto(s)
Neoplasias Colorrectales , Proteínas Proto-Oncogénicas B-raf , Anticuerpos Monoclonales , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Humanos , Mutación/genética , Medicina de Precisión , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
Plasmablastic lymphoma (PBL) represents a rare and aggressive lymphoma subtype frequently associated with immunosuppression. Clinically, patients with PBL are characterized by poor outcome. The current understanding of the molecular pathogenesis is limited. A hallmark of PBL represents its plasmacytic differentiation with loss of B-cell markers and, in 60% of cases, its association with Epstein-Barr virus (EBV). Roughly 50% of PBLs harbor a MYC translocation. Here, we provide a comprehensive integrated genomic analysis using whole exome sequencing (WES) and genome-wide copy number determination in a large cohort of 96 primary PBL samples. We identify alterations activating the RAS-RAF, JAK-STAT, and NOTCH pathways as well as frequent high-level amplifications in MCL1 and IRF4. The functional impact of these alterations is assessed using an unbiased shRNA screen in a PBL model. These analyses identify the IRF4 and JAK-STAT pathways as promising molecular targets to improve outcome of PBL patients.
Asunto(s)
Linfoma Plasmablástico/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Amplificación de Genes , Dosificación de Gen , Perfilación de la Expresión Génica , Humanos , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/metabolismo , Quinasas Janus/genética , Quinasas Janus/metabolismo , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Linfoma Plasmablástico/metabolismo , Linfoma Plasmablástico/mortalidad , Linfoma Plasmablástico/terapia , Factores de Transcripción STAT/genética , Factores de Transcripción STAT/metabolismo , Translocación Genética , Secuenciación del Exoma , Adulto JovenRESUMEN
SOX11 is a valuable marker to identify biologically and clinically relevant groups of mantle cell lymphoma such as cyclin D1 negative and leukemic non-nodal mantle cell lymphoma (MCL). We aimed to establish a sensitive in situ hybridization analysis of SOX11 mRNA allowing its quantification within the histopathological context and compare it with immunohistochemistry and real-time quantitative reverse transcription-PCR (RT-qPCR). Furthermore, TP53 status was correlated with SOX11 mRNA levels. Sixty-six cases were investigated; 58 conventional mantle cell lymphomas (cMCL), including six cyclin D1 negative (46 classic, 12 blas-toid) and eight leukemic non-nodal mantle cell lymphomas (nnMCL). RNAscope was used for the in situ hybridization and the results scored as 0 to 4. MCL cases with SOX11 positivity by immunohistochemistry (IHC) were positive by RNA in situ hybridization (RNAscope) but with different scores. RT-qPCR showed a good correlation with the median of the grouped scores but had a wide variation in individual cases. The SOX11 negative leukemic non-nodal mantle cell lymphomas were also negative by RNAscope. TP53 was mutated in 13/63 (21%) cases, including 5/7 (71%) leukemic non-nodal and 8/56 (14%) cMCL. Interestingly, of the TP53 mutated cases, nine were in the RNAscope negative/low SOX11 group (9/15; 60%) and four in the high SOX11 group (4/36; 11%) (P=0.0007). In conclusion, RNAscope is a reliable method to evaluate SOX11 mRNA levels. This study demonstrates the broad range of SOX11 mRNA levels in MCL. An important finding is the significant correlation of TP53 mutations with negative/low SOX11 mRNA level both in leukemic nnMCL and cMCL.