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Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by a subset of patients who exhibit treatment resistance and poor prognoses. Genomic assays have been widely employed to identify high-risk individuals characterized by rearrangements in the MYC, BCL2 and BCL6 genes. These patients typically undergo more aggressive therapeutic treatments; however, there remains a significant variation in their treatment outcomes. This study introduces an MYC signature score (MYCSS) derived from gene expression profiles, specifically designed to evaluate MYC overactivation in DLBCL patients. MYCSS was validated across several independent cohorts to assess its ability to stratify patients based on MYC-related genetic and molecular aberrations, enhancing the accuracy of prognostic evaluations compared to conventional MYC biomarkers. Our results indicate that MYCSS significantly refines prognostic accuracy beyond that of conventional MYC biomarkers focused on genetic aberrations. More importantly, we found that nearly 50% of patients identified as high risk by traditional MYC metrics actually share similar survival prospects with those having no MYC aberrations. These patients may benefit from standard GCB-based therapies rather than more aggressive treatments. MYCSS provides a robust signature that identifies high-risk patients, aiding in the precision treatment of DLBCL, and minimizing the potential for overtreatment.
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INTRODUCTION: The definition of primary plasma cell leukemia (pPCL) has been revised from ≥20% to ≥5% circulating plasma cells (CPC). However, the precise prognosis associated with CPC remains controversial. This study aimed to investigate prognostic biomarkers for myeloma patients based on CPC presence. METHODS: A comprehensive analysis was conducted on 309 consecutive patients diagnosed with either multiple myeloma or pPCL, utilizing peripheral blood smears stained with Wright-Giemsa. RESULTS: Patients were grouped by CPC percentage: 0% (221, 71.5%), 1-4% (49, 15.9%), 5-19% (16, 5.2%), ≥20% (23, 7.4%). CPC >5% correlated with unfavorable characteristics, including anemia, renal dysfunction, and advanced International Staging System. Common cytogenetic abnormalities such as 1q21 amplification, 17p deletion, and Myc rearrangement were prevalent among CPC-positive patients. Median progression-free survival (PFS) and overall survival (OS) were shorter in patients with CPC ≥5% (29.47 vs. 10.03 months; 64.10 vs. 12.30 months). Additionally, PFS and OS were shorter in CPC-positive patients without autologous hematopoietic stem cell transplantation (ASCT) and those with response < partial remission to the first-line regimen. Furthermore, an association emerged between soft tissue-related extramedullary disease and inferior PFS, while Myc rearrangement correlated with abbreviated OS. CONCLUSION: Biological characteristics displayed greater aggressiveness in patients with positive CPC, leading to significantly shorter PFS and OS. The presence of CPC, ASCT, and overall response rate were independent prognostic factors. While no new threshold for pPCL with CPCs is proposed, Myc rearrangements and CPC positivity could serve as ultra-high-risk factors for multiple myeloma.
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B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) is a precursor B-cell neoplasm that often harbors specific cytogenetic/molecular abnormalities with distinctive clinical, phenotypic, and prognostic characteristics. Subcategorization of B-ALL/LBL therefore requires extensive cytogenetic and/or molecular testing to determine the appropriate classification and therapeutic interventions for these patients. Herein, we present a case of a 17-year-old young woman diagnosed with B-LBL harboring not only an IGH::MYC rearrangement but also BCL2 and BCL6 rearrangements (so-called "triple-hit") and somatic biallelic TP53 inactivation. MYC rearrangements are relatively rare in B-ALL/LBL, and the identification of a "triple-hit" elicited an initial diagnostic dilemma. However, a multimodal approach allowed for the classification of this complex case and helped guide selection of an appropriate therapeutic regimen.
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Linfoma de Células B , Leucemia-Linfoma Linfoblástico de Células Precursoras , Feminino , Humanos , Adolescente , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/uso terapêutico , Linfoma de Células B/diagnóstico , Linfoma de Células B/genética , Linfoma de Células B/tratamento farmacológico , Prognóstico , Rearranjo GênicoRESUMO
A small subset of high-grade B-cell lymphoma (HGBL) with blastoid morphology remains poorly understood. We assessed 55 cases of blastoid HGBL, not otherwise specified (NOS) and compared their clinicopathologic characteristics with those of 81 non-blastoid HGBL-NOS and 62 blastoid HGBL with MYC and BCL2, with or without BCL6 rearrangements (double/triple-hit lymphoma [D/THL]). Patients with blastoid HGBL-NOS showed similar clinicopathologic features to patients with blastoid D/THLs and non-blastoid HGBL-NOS, except more frequently with a history of low-grade B-cell lymphoma, bone marrow involvement, and BCL2 rearrangement (P < .05) compared to the latter. MYC rearrangement (MYC-R), detected in 40% of blastoid HGBL-NOS, was associated with aggressive clinicopathologic features and poorer overall survival, even worse than that of blastoid D/THL (P < .05). Transcriptome profiling revealed a distinct gene expression pattern with differentially expressed genes enriched in MYC and P53-targeted genes in MYC-R blastoid HGBL-NOS. Fifty-two percent of blastoid HGBL-NOS had a double hit-like signature, similar to non-blastoid HGBL-NOS (P = .73). The overall survival of the blastoid HGBL-NOS group was similar to that of the blastoid D/THL group but appeared poorer than that of its non-blastoid counterparts (P = .07). Taken together, blastoid HGBL-NOS is an aggressive B-cell lymphoma that shares overlapping clinicopathologic and genetic features with non-blastoid HGBL-NOS. MYC-R in patients with blastoid HGBL-NOS identifies a highly aggressive subgroup with distinct aggressive clinicopathologic features, unique molecular signatures, and a dismal clinical outcome.
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Linfoma de Células B , Linfoma Difuso de Grandes Células B , Humanos , Rearranjo Gênico , Linfoma de Células B/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Biomarcadores Tumorais/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Linfoma Difuso de Grandes Células B/patologia , Proteínas Proto-Oncogênicas c-bcl-6/genéticaRESUMO
AIMS: Subclassification of large B cell lymphoma (LBCL) is challenging due to the overlap in histopathological, immunophenotypical and genetic data. In particular, the criteria to separate diffuse large B cell lymphoma (DLBCL) and high-grade B cell lymphoma (HGBL) are difficult to apply in practice. The Lunenburg Lymphoma Biomarker Consortium previously reported a cohort of over 5000 LBCL that included fluorescence in-situ hybridisation (FISH) data. This cohort contained 209 cases with MYC rearrangement that were available for a validation study by a panel of eight expert haematopathologists of how various histopathological features are used. METHODS AND RESULTS: Digital whole slide images of haematoxylin and eosin-stained sections allowed the pathologists to visually score cases independently as well as participate in virtual joint review conferences. Standardised consensus guidelines were formulated for scoring histopathological features and included overall architecture/growth pattern, presence or absence of a starry-sky pattern, cell size, nuclear pleomorphism, nucleolar prominence and a range of cytological characteristics. Despite the use of consensus guidelines, the results show a high degree of discordance among the eight expert pathologists. Approximately 50% of the cases lacked a majority score, and this discordance spanned all six histopathological features. Moreover, none of the histological variables aided in prediction of MYC single versus double/triple-hit or immunoglobulin-partner FISH-based designations or clinical outcome measures. CONCLUSIONS: Our findings indicate that there are no specific conventional morphological parameters that help to subclassify MYC-rearranged LBCL or select cases for FISH analysis, and that incorporation of FISH data is essential for accurate classification and prognostication.
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Linfoma Difuso de Grandes Células B , Humanos , Reprodutibilidade dos Testes , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Biomarcadores , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Rearranjo GênicoRESUMO
PURPOSE: MYC gene rearrangements in diffuse large B-cell lymphoma (DLBCL) patients are associated with poor prognosis. Our aim was to compare patterns of 2[18F]fluoro-2-deoxy-D-glucose positron emission tomography computed tomography (PET/CT) response in MYC + and MYC- DLBCL patients. METHODS: Interim PET/CT (I-PET) and end of treatment PET/CT (EoT-PET) scans of 81 MYC + and 129 MYC- DLBCL patients from 2 HOVON trials were reviewed using the Deauville 5-point scale (DS). DS1-3 was regarded as negative and DS4-5 as positive. Standardized uptake values (SUV) and metabolic tumor volume (MTV) were quantified at baseline, I-PET, and EoT-PET. Negative (NPV) and positive predictive values (PPV) were calculated using 2-year overall survival. RESULTS: MYC + DLBCL patients had significantly more positive EoT-PET scans than MYC- patients (32.5 vs 15.7%, p = 0.004). I-PET positivity rates were comparable (28.8 vs 23.8%). In MYC + patients 23.2% of the I-PET negative patients converted to positive at EoT-PET, vs only 2% for the MYC- patients (p = 0.002). Nine (34.6%) MYC + DLBCL showed initially uninvolved localizations at EoT-PET, compared to one (5.3%) MYC- patient. A total of 80.8% of EoT-PET positive MYC + patients showed both increased lesional SUV and MTV compared to I-PET. In MYC- patients, 31.6% showed increased SUV and 42.1% showed increased MTV. NPV of I-PET and EoT-PET was high for both MYC subgroups (81.8-94.1%). PPV was highest at EoT-PET for MYC + patients (61.5%). CONCLUSION: MYC + DLBCL patients demonstrate aberrant PET response patterns compared to MYC- patients with more frequent progression during treatment after I-PET negative assessment and new lesions at sites that were not initially involved. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: HOVON-84: EudraCT: 2006-005,174-42, retrospectively registered 01-08-2008. HOVON-130: EudraCT: 2014-002,654-39, registered 26-01-2015.
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Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18 , Rearranjo Gênico , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/terapia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tomografia por Emissão de Pósitrons , Prognóstico , Estudos RetrospectivosRESUMO
The prognosis of diffuse large B-cell lymphoma (DLBCL) having MYC rearrangement (MYC-R), including double hit lymphoma (DHL), is poor by standard immunochemotherapy. To evaluate the significance of hematopoietic stem cell transplantation (SCT) for DLBCL with MYC-R, we retrospectively analyzed Japanese SCT registry data. In total, 54 patients with DLBCL with MYC-R were identified from 4336 registered adult DLBCL patients. Detailed clinical and cytogenetic information was obtained for 48 patients. The median age at diagnosis of the 48 patients was 54.5 (range 21-67) years. Twenty-six (54%) patients had MYC-R only (single hit), and 22 (46%) had MYC-R and BCL2, and/or BCL6 rearrangement (double/triple hit). In 12 patients who received auto-SCT during the first complete response (CR), both the 2-year overall survival (OS) and progression-free survival (PFS) rates were 75.0% (95% confidence interval [CI], 40.8%-91.2%). In 20 patients who received auto-SCT after relapsed or refractory state, the 2-year OS and PFS rates were 68.2% (95% CI, 41.9%-84.5%) and 59.6% (95% CI, 35.1%-77.4%), respectively. In 17 patients who received allo-SCT, only 4 patients underwent SCT in CR. The 2-year OS and PFS rates were 29.4% (95% CI, 10.7%-51.1%) and 17.6% (95% CI, 4.3%-38.3%), respectively. The rate of non-relapse mortality at 1 year was 41.2% (95% CI, 17.1%-64.0%) in this group. The outcomes of single hit and double or triple hit were not different. These findings suggest that auto-SCT may be effective for MYC-R DLBCL, including DHL patients of chemosensitive relapsed or refractory state. Since most patients received allo-SCT not in CR, the outcome of allo-SCT was unsatisfactory due to high non-relapse mortality and early relapse. To clarify the role of allo-SCT for MYC-R DLBCL, further accumulation of patients is necessary.
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Aberrações Cromossômicas , Cromossomos Humanos Par 8/genética , Transplante de Células-Tronco Hematopoéticas , Linfoma Difuso de Grandes Células B , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Autoenxertos , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/terapia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
AIMS: MYC rearrangements are the main cytogenetic alterations in plasmablastic lymphoma (PBL). We aimed to investigate the relationship between MYC rearrangement and the clinicopathological features of PBL. METHODS AND RESULTS: MYC rearrangements assessed in 13 unpublished single-centre PBL cases, and an additional 85 cases from the literature, with reported MYC rearrangement information individualised by patient, were reviewed. In Asia, PBL was much less commonly diagnosed in human immunodeficiency virus (HIV)-positive patients (27% versus 84%, P = 0.000), with older age (median age at diagnosis: 52 years versus 44 years, P = 0.046) and a lower EBV infection rate (56.8% versus 81.8%, P = 0.049), than in non-Asian regions. Overall, MYC rearrangements were identified in 44 of 98 (44.9%) PBL cases, and IGH was the partner in almost all available cases (30/31, 96.8%), as confirmed with a MYC-IGH fusion probe. The MYC rearrangement rate in HIV-positive cases (33/55, 60.0%) was significantly higher than that in HIV-negative cases (11/38, 28.9%, P = 0.003). Patients with MYC rearrangement showed a trend towards an inferior median survival time (9.6 months versus 15.7 months, P = 0.122) and 2-year overall survival (17% versus 32%, P = 0.238). CONCLUSIONS: MYC rearrangement was frequently identified in PBL patients, and IGH was the partner gene in an overwhelming majority of MYC rearrangements. In addition, the MYC rearrangement rate was significantly higher in HIV-positive PBL patients than that in HIV-negative patients. MYC rearrangement may play an important role in the pathogenesis of HIV-positive PBL, but further studies are required to understand the underlying mechanisms.
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Infecções por HIV/complicações , HIV/imunologia , Linfoma Plasmablástico/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adulto , Idoso , Feminino , Rearranjo Gênico , Infecções por HIV/virologia , Humanos , Imunofenotipagem , Hibridização in Situ Fluorescente , Masculino , Pessoa de Meia-Idade , Proteínas de Fusão Oncogênica , Linfoma Plasmablástico/complicações , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/patologia , Prognóstico , Adulto JovemRESUMO
OBJECTIVE: Diffuse large B-cell lymphoma (DLBCL) can be classified as germinal center B cell-like (GCB) or activated B cell-like (ABC)/non-GCB based on cell-of-origin (COO) classification. This study evaluated the prognostic significance of COO classification in 250 patients diagnosed with de novo DLBCL who received R-CHOP therapy. We also assessed whether the genomic status of MYC, BCL2, or MYC/BCL2 double expression (DE) could provide additional prognostic information for DLBCL patients. METHODS: The clinicopathologic features and outcome of patients with GCB DLBCL were compared to patients with non-GCB DLBCL using Fisher's exact test. The prognostic significance of COO, MYC-R, and MYC/BCL2 DE were studied using multivariate Cox proportional hazard analysis. RESULTS: There were 162 men and 88 women with a median age of 62 years (range, 18-86). Forty-five of 250 (18%) cases harbored MYC rearrangement (R). The frequency of MYC-R was much higher in GCB than in non-GCB tumors (40/165, 24% vs 5/85, 6%) (P = .0001). MYC/BCL2 DE was observed in 53 of 125 (42%) cases. COO classification failed to predict overall survival (OS) in DLBCL patients, either those patients with MYC-R were included (P = .10) or not (P = .27). In contrast, MYC-R and MYC/BCL2 DE significantly correlated with inferior OS (P = .0001 and P = .001, respectively). In multivariate analysis, MYC-R and MYC/BCL2 DE were still independent prognostic factors in DLBCL patients. CONCLUSIONS: MYC-R and MYC/BCL2 DE are independent prognostic factors for DLBCL patients treated with R-CHOP. In this cohort, COO classification failed to stratify patient outcome.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Genes bcl-2 , Genes myc , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Prednisona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Rituximab/uso terapêutico , Análise de Sobrevida , Vincristina/uso terapêutico , Adulto JovemRESUMO
BACKGROUND: Rearrangements of chromosome 8q24/MYC (8q24/MYC-r), resulting from t(8;14)(q24;q32), t(2;8)(p11;q24), or t(8;22)(q24;q11), are mainly associated with Burkitt lymphoma/leukemia (BL) and rarely observed in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The characteristics of BCP-ALL with 8q24/MYC-r are poorly understood. PROCEDURE: A retrospective nationwide study of data from patients with pediatric BCP-ALL with 8q24/MYC-r in Japan was conducted to clarify the clinical and biological characteristics associated with 8q24/MYC-r BCP-ALL. RESULTS: Ten patients with BCP-ALL with 8q24/MYC-r, including three with double-hit leukemia (DHL) (two with t(8;14)(q24;q32) and t(14;18)(q32;q21) and one with t(8;14) and t(3;22)(q27;q11)), were identified. Patients with BCP-ALL with 8q24/MYC-r had higher median age and uric acid and lactate dehydrogenase levels, than those without 8q24/MYC-r. All patients were initially treated with ALL-type chemotherapy; however, four, including one with DHL, were switched to BL-type chemotherapy, based on cytogenetic findings. One patient relapsed after standard-risk ALL-type chemotherapy, and two patients with DHL did not attain complete remission with chemotherapy; all three died within 11 months. The other seven patients treated with BL-type or high-risk ALL-type chemotherapy are alive without disease. CONCLUSIONS: The clinical and laboratory features of BL with IG-MYC rearrangement, displaying a BCP immunophenotype (Wagener et al. and Herbrueggen et al. termed it as pre-BLL), are similar to those of BCP-ALL with 8q24/MYC-r. Low-risk ALL-type chemotherapy may not be appropriate for them, and further studies are required to establish an adequate therapeutic strategy. Further studies of DHL to identify new treatment strategies are also needed.
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Biomarcadores Tumorais/genética , Cromossomos Humanos Par 8/genética , Rearranjo Gênico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Proto-Oncogênicas c-myc/genética , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras B/epidemiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologia , Prognóstico , Estudos RetrospectivosRESUMO
The introduction of new lymphoma entities that are defined by chromosomal rearrangements has led to changes concerning the diagnostic algorithms in routine hematopathology, particularly for the large group of aggressive Bcell lymphomas. The new, genetically defined entity high-grade Bcell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double/triple hit lymphoma) is morphologically heterogenous and comprises lymphomas with the morphology of a diffuse large Bcell lymphoma (DLBCL), but also cases with blastoid appearance as well as intermediate/Burkitt-like morphology. This implies a cytogenetic analysis for the final classification of aggressive lymphomas with DLBCL morphology, which constitute the most common lymphomas in daily practice. This analysis is currently most efficiently performed via a sequential fluorescence in situ hybridization (FISH) approach, with an initial MYC-FISH, that is followed (if required, i.e., if a MYC rearrangement is detected) by an analysis regarding a BCL2- and BCL6-chromosomal rearrangement. In addition, the update of the fourth edition of the WHO classification for hematopoietic neoplasms introduced additional lymphoma subgroups that are defined by chromosomal rearrangements, such as Burkitt-like lymphoma with 11q aberration as well as large B cell lymphoma with IRF4 rearrangement. Therefore, FISH currently plays an important role in the diagnostic armamentarium in routine diagnostic hematopathology.
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Linfoma de Burkitt/diagnóstico , Hibridização in Situ Fluorescente , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma de Burkitt/genética , Aberrações Cromossômicas , Humanos , Fatores Reguladores de Interferon/genética , Linfoma Difuso de Grandes Células B/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-myc/genética , Translocação GenéticaRESUMO
Burkitt lymphoma (BL) and B-lymphoblastic lymphoma are subtypes of pediatric non-Hodgkin lymphoma with different presenting features, treatment, and outcomes. This case report documents a 5-year-old female who presented with B-cell lymphoma with lymphoblastic morphology, terminal deoxynucleotidyl transferase expression, MYC rearrangement, and features overlapping with BL. Genomic microarray analysis identified a gain on the long arm of chromosome 1 without other definitive changes. She was treated according to a BL protocol and remains in remission 16-months after initial diagnosis.
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Linfoma de Burkitt , Aberrações Cromossômicas , Cromossomos Humanos Par 1/genética , DNA Nucleotidilexotransferase/biossíntese , Rearranjo Gênico , Linfoma de Células B , Proteínas Proto-Oncogênicas c-myc/genética , Linfoma de Burkitt/tratamento farmacológico , Linfoma de Burkitt/enzimologia , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologia , Pré-Escolar , Cromossomos Humanos Par 1/metabolismo , DNA Nucleotidilexotransferase/genética , Feminino , Humanos , Linfoma de Células B/tratamento farmacológico , Linfoma de Células B/enzimologia , Linfoma de Células B/genética , Linfoma de Células B/patologia , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
Plasmablastic lymphoma (PBL) is recognized by the World Health Organization as a very aggressive subtype of non-Hodgkin lymphoma. It was initially described in the setting of human immunodeficiency virus (HIV) infection, but it has since been identified in immunocompetent patients, as well. PBL is characterized by CD20 negativity and is associated with Epstein-Barr virus infection. The outcome with available therapy is poor, with median survival of less than 1 year. Multiple adverse prognostic factors have been identified, including HIV-negativity, MYC gene rearrangement, high-risk international prognostic index, and not achieving complete remission after induction therapy. The role of intensification of induction chemotherapy is controversial. Novel agents have shown some activity in relapsed setting and may have a role in upfront line of treatment. The outcome for relapsed PBL is dismal. Autologous hematopoietic cell transplantation (AHCT) appears to be feasible and may produce better results than chemotherapy, but definitive data are sparse. Chemosensitivity before transplantation might be required to benefit from such therapy. Some data suggest a better outcome of PBL if consolidation with AHCT is used in first-line setting, particularly for those with high-risk disease.
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Leucemia Mieloide Aguda/terapia , Síndromes Mielodisplásicas/terapia , Transplante de Células-Tronco , Doadores não Relacionados , HumanosAssuntos
Rearranjo Gênico , Genes myc , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/mortalidade , Derrame Pleural Maligno/patologia , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/terapia , Prognóstico , Análise de SobrevidaRESUMO
BACKGROUND: Myc rearrangement (Myc-R) is a controversial factor linked to adverse outcomes in newly diagnosed multiple myeloma (NDMM). AIMS: This study aimed to evaluate the impact of Myc-R on the prognosis of NDMM patients and its role in risk stratification compared with traditional high-risk cytogenetic abnormalities (HRCAs). MATERIALS & METHODS: A total of 417 NDMM patients enrolled from May 2009 to September 2022 were included. Fluorescence in situ hybridization (FISH) was used to detect Myc-R and other Myc abnormalities (Myc-OA). Median progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier methods and log-rank tests. Multivariate Cox regression analysis was used to identify independent risk factors. RESULTS: Myc-R was identified in 13.7% of patients, while 14.6% had Myc-OA. Patients with Myc-R had significantly shorter median PFS (15.9 months) and OS (25.1 months) compared with those with Myc-OA (24.5 months PFS; 29.8 months OS) and Myc-negative (Myc-N) status (29.8 months PFS, 29.8 months OS). Myc-R was independently associated with worse PFS and OS compared to Myc-OA. Patients with Myc-R alone had inferior median PFS (15.9 months vs. 28.1 months, p = 0.032) and OS (25.1 months vs. 61.2 months, p = 0.04) compared to those with traditional single HRCA. DISCUSSION: The study suggests that traditional single HRCA may not significantly impact survival in NDMM patients. However, incorporating Myc rearrangement or traditional double/triple-hit HRCAs into the risk stratification model improves its predictive value, highlighting the importance of Myc rearrangement in risk assessment. CONCLUSION: Myc rearrangement is an independent adverse prognostic factor in NDMM. The incorporation of Myc rearrangement or multiple HRCAs into risk stratification models improves their prognostic value, providing a novel perspective on high-risk factors in NDMM.
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Rearranjo Gênico , Mieloma Múltiplo , Proteínas Proto-Oncogênicas c-myc , Humanos , Mieloma Múltiplo/genética , Mieloma Múltiplo/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Proteínas Proto-Oncogênicas c-myc/genética , Prognóstico , Hibridização in Situ Fluorescente , Medição de Risco/métodos , Fatores de Risco , Adulto , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Estimativa de Kaplan-MeierRESUMO
Introduction: Fluorescence in situ hybridization (FISH) is an essential ancillary study used to identify clinically aggressive subsets of large B-cell lymphomas that have MYC, BCL2, or BCL6 rearrangements. Small-volume biopsies such as fine needle aspiration biopsy (FNAB) and core needle biopsy (CNB) are increasingly used to diagnose lymphoma and obtain material for ancillary studies such as FISH. However, the performance of FISH in small biopsies has not been thoroughly evaluated or compared to surgical biopsies. Methods: We describe the results of MYC, BCL2, and BCL6 FISH in a series of 222 biopsy specimens, including FNAB with cell blocks, CNBs, and surgical excisional or incisional biopsies from 208 unique patients aggregated from 6 academic medical centers. A subset of patients had FNAB followed by a surgical biopsy (either CNB or excisional biopsy) obtained from the same or contiguous anatomic site as part of the same clinical workup; FISH results were compared for these paired specimens. Results: FISH had a low hybridization failure rate of around 1% across all specimen types. FISH identified concurrent MYC and BCL2 rearrangements in 20 of 197 (10%) specimens and concurrent MYC and BCL6 rearrangements in 3 of 182 (1.6%) specimens. The paired FNAB and surgical biopsy specimens did not show any discrepancies for MYC or BCL2 FISH; of the 17 patients with 34 paired cytology and surgical specimens, only 2 of the 49 FISH probes compared (4% of all comparisons) showed any discrepancy and both were at the BCL6 locus. One discrepancy was due to necrosis of the CNB specimen causing a false negative BCL6 FISH result when compared to the FNAB cell block that demonstrated a BCL6 rearrangement. Discussion: FISH showed a similar hybridization failure rate in all biopsy types. Ultimately, MYC, BCL2, or BCL6 FISH showed 96% concordance when compared across paired cytology and surgical specimens, suggesting FNAB with cell block is equivalent to other biopsy alternatives for evaluation of DLBCL or HGBCL FISH testing.
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MYC-rearranged B-cell lymphoma (BCL) in the pediatric/young adult (YA) age group differs substantially in disease composition from adult cohorts. However, data regarding the partner genes, concurrent rearrangements, and ultimate diagnoses in these patients is scarce compared to that in adult cohorts. We aimed to characterize the spectrum of MYC-rearranged (MYC-R) mature, aggressive BCL in the pediatric/YA population. A retrospective study of morphologic, immunophenotypic, and fluorescence in situ hybridization (FISH) results of patients age ≤ 30 years with suspected Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL) or high-grade B-cell lymphoma (HGBCL), and a MYC-R by FISH between 2013-2022 was performed. Two-hundred fifty-eight cases (129 (50%) pediatric (< 18 years) and 129 (50%) YA (18-30 years)) were included. Most MYC-R BCL in pediatric (89%) and YA (66%) cases were BL. While double-hit (DH) cytogenetics (MYC with BCL2 and/or BCL6-R, HGBCL-DH) was rare in the pediatric population (2/129, 2%), HGBCL-DH increased with age and was identified in 17/129 (13%) of YA cases. Most HGBCL-DH had MYC and BCL6-R, while BCL2-R were rare in both groups (3/258, 1%). MYC-R without an IG partner was more common in the YA group (14/116 (12%) vs 2/128 (2%), p = 0.001). The pediatric to YA transition is characterized by decreasing frequency in BL and increasing genetic heterogeneity of MYC-R BCL, with emergence of DH-BCL with MYC and BCL6-R. FISH to evaluate for BCL2 and BCL6 rearrangements is likely not warranted in the pediatric population but should continue to be applied in YA BCL.
Assuntos
Rearranjo Gênico , Proteínas Proto-Oncogênicas c-myc , Humanos , Adolescente , Criança , Masculino , Adulto Jovem , Adulto , Feminino , Proteínas Proto-Oncogênicas c-myc/genética , Estudos Retrospectivos , Pré-Escolar , Hibridização in Situ Fluorescente , Linfoma de Células B/genética , Linfoma de Células B/patologia , Linfoma de Burkitt/genética , Linfoma de Burkitt/patologiaRESUMO
Background: Indiana University (IU) initiated fluorescence in situ hybridisation (FISH) methodology for Burkitt Lymphoma (BL) to advance the accuracy and speed of diagnosis in the AMPATH Reference Laboratory at Moi Teaching and Referral Hospital (MTRH) in Eldoret, Kenya. Standard diagnostic testing for BL at MTRH includes morphology of the biopsy specimen or aspirate and limited immunohistochemistry panels. Methods: Tumour specimens from 19 children enrolled from 2016 to 2018 in a prospective study to improve the diagnosis and staging of children with suspected BL were evaluated. Touch preps from biopsy specimens or smears from fine needle aspiration were collected, stained with Giemsa and/or H&E and reviewed by pathologists to render a provisional diagnosis. Unstained slides were stored and later processed for FISH. Duplicate slides were split between two laboratories for analysis. Flow cytometry results were available for all specimens. Results from the newly established FISH laboratory in Eldoret, Kenya were cross-validated in Indianapolis, Indiana. Results: Concordance studies found 18 of 19 (95%) of specimens studied yielded analysable FISH results for one or both probe sets (MYC and MYC/IGH) in both locations. There was 94% (17/18) concordance of results between the two FISH laboratories. FISH results were 100% concordant for the 16 specimens with a histopathological diagnosis of BL and two of three non-BL cases (one case no result in IU FISH lab). FISH was similarly concordant with flow cytometry for specimens with positive flow results with the exception of a nasopharyngeal tumour with positive flow results for CD10 and CD20 but was negative by FISH. The modal turn-around time for FISH testing on retrospective study specimens performed in Kenya ranged between 24 and 72 hours. Conclusion: FISH testing was established, and a pilot study performed, to assess the feasibility of FISH as a diagnostic tool for the determination of BL in a Kenyan paediatric population. This study supports FISH in limited resource settings to improve the accuracy and speed of diagnosis of BL in Africa.
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BACKGROUND: Very little is currently known about molecular alteration of matrix-producing carcinoma of the breast. However, the morphological similarity with other neoplasm with a myxo-chondroid component is remarkable. In this pilot study we evaluated the molecular alterations involving PLAG1 and MYC genes in 12 cases of matrix producing carcinoma. METHODS: We evaluated PLAG1 rearrangements as Break-Apart and Gene Copy Gain, and MYC as amplification and polysomy in 12 cases of matrix producing carcinoma using a FISH method. RESULTS: Among the 12 cases of matrix producing carcinomas we found that the three cases harboring MYC amplification were all negative for PLAG1 break-apart; four cases with MYC polysomy were associated to PLAG1 break-apart and high Gene Copy Number; among four cases wild type for MYC, three showed a PLAG1- break-apart signal and of them two died with disease. One of the deceased patients showed an amplification of MYC with PLAG1- wild-type and the other showed a PLAG1 break-apart (6%) and a MYC wild-type. CONCLUSION: This is the first report to the best of our knowledge that shows a possible correlation between a matrix producing carcinoma with PLAG1 and MYC involvement in the development and progression of this kind of tumor. We can suppose that MYC amplification behaves in an aggressive way together with PLAG1- break-apart in the cases of matrix producing carcinoma presented here. The gene copy gain is a useful diagnostic tool in the case of difficult diagnosis because an increase was observed in more than 50% of cases.
Assuntos
Adenoma Pleomorfo , Carcinoma , Neoplasias das Glândulas Salivares , Humanos , Adenoma Pleomorfo/diagnóstico , Adenoma Pleomorfo/genética , Adenoma Pleomorfo/patologia , Carcinoma/genética , Proteínas de Ligação a DNA/genética , Imuno-Histoquímica , Projetos Piloto , Neoplasias das Glândulas Salivares/diagnóstico , Neoplasias das Glândulas Salivares/genética , Neoplasias das Glândulas Salivares/patologia , Fatores de Transcrição , Proteínas Proto-Oncogênicas c-myc/metabolismoRESUMO
OBJECTIVES: Malignant effusion is usually caused by metastatic carcinoma. Malignant lymphoma is often not included as a top differential diagnosis of malignant effusion. Here, we describe 3 cases of young female patients with no significant past medical history who presented with fluid overload and were diagnosed with high-grade B-cell lymphoma (HGBL). METHODS: We conducted histopathologic examination and immunophenotypic and cytogenetic analyses on three cases using immunohistochemistry, flow cytometry, fluorescence in situ hybridization (FISH), and karyotyping. We also included patients' clinical and radiological findings in our case reports. RESULTS: Histologic examination of the effusion samples showed numerous intermediate to large lymphoma cells with irregular nuclear contours and fine chromatin. The lymphoma cells were positive for CD10, CD20, BCL2, BCL6, and PAX5 and negative for CD34, cyclin D1, HHV-8, and TdT. In situ hybridization for Epstein-Barr virus (EBV)-encoded small RNAs was negative. The proliferation index by Ki-67 stain was more than 80%. Flow cytometry showed CD10-positive B cells with monotypic immunoglobulin light chain expression. Fluorescence in situ hybridization analysis demonstrated MYC, BCL2, or BCL6 rearrangements. These 3 patients were diagnosed as having HGBL with double-/triple-hit rearrangements. Despite receiving aggressive chemotherapy, all 3 patients had a dismal clinical course, with 2 patients dying less than 2 years after initial diagnosis. CONCLUSIONS: High-grade B-cell lymphoma should be considered in the differential diagnoses of malignant effusions. Flow cytometric and FISH analyses of the body fluid specimens are essential to reach an accurate and timely diagnosis.