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Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.
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Doença de Erdheim-Chester , Mutação , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Doença de Erdheim-Chester/genética , Doença de Erdheim-Chester/tratamento farmacológico , Idoso , Adolescente , Terapia de Alvo Molecular , Adulto Jovem , Histiocitose de Células de Langerhans/genética , Histiocitose de Células de Langerhans/tratamento farmacológico , Criança , Histiocitose Sinusal/genética , Histiocitose Sinusal/tratamento farmacológico , Histiocitose Sinusal/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Inibidores de Proteínas Quinases/uso terapêutico , Pré-EscolarRESUMO
Genomic profiling of hematologic malignancies has augmented our understanding of variants that contribute to disease pathogenesis and supported development of prognostic models that inform disease management in the clinic. Tumor only sequencing assays are limited in their ability to identify definitive somatic variants, which can lead to ambiguity in clinical reporting and patient management. Here, we describe the MSK-IMPACT Heme cohort, a comprehensive data set of somatic alterations from paired tumor and normal DNA using a hybridization capture-based next generation sequencing platform. We highlight patterns of mutations, copy number alterations, and mutation signatures in a broad set of myeloid and lymphoid neoplasms. We also demonstrate the power of appropriate matching to make definitive somatic calls, including in patients who have undergone allogeneic stem cell transplant. We expect that this resource will further spur research into the pathobiology and clinical utility of clinical sequencing for patients with hematologic neoplasms.
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Neoplasias Hematológicas , Neoplasias , Humanos , Neoplasias/genética , Neoplasias Hematológicas/diagnóstico , Neoplasias Hematológicas/genética , Neoplasias Hematológicas/terapia , Mutação , Sequenciamento de Nucleotídeos em Larga Escala , DNARESUMO
ABSTRACT: Primary cutaneous gamma-delta T-cell lymphoma (PCGDTL) is a rare and diagnostically challenging primary skin lymphoma. We present a case of a 78-year-old otherwise healthy man who developed nonhealing nodules on his right posterior calf. Initial biopsy showed a dense, atypical, lymphoid infiltrate with gamma-delta and cytotoxic T-cell immunophenotypes. The diagnosis of PCGDTL was rendered; however, concurrent flow cytometry revealed expression of aberrant B-cell markers, including CD19 and cytoplasmic CD79a. Subsequent immunohistochemical studies corroborated this result. We report the extremely rare phenomenon of aberrant B-cell marker expression in PCGDTL, the first formally reported case to our knowledge.
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Linfoma Cutâneo de Células T , Linfoma de Células T , Neoplasias Cutâneas , Masculino , Humanos , Idoso , Neoplasias Cutâneas/patologia , Biópsia , Linfoma de Células T/patologia , Linfoma Cutâneo de Células T/patologia , Receptores de Antígenos de Linfócitos T gama-delta/metabolismoRESUMO
Langerhans cell histiocytosis (LCH) is an inflammatory myeloid neoplasm characterized by the accumulation of clonal mononuclear phagocyte system cells expressing CD1a and CD207. In the past decade, molecular profiling of LCH as well as other histiocytic neoplasms demonstrated that these diseases are driven by MAPK activating alterations, with somatic BRAFV600E mutations in >50% of patients with LCH, and clinical inhibition of MAPK signaling has demonstrated remarkable clinical efficacy. At the same time, activating alterations in kinase-encoding genes, such as PIK3CA, ALK, RET, and CSF1R, which can activate mitogenic pathways independent from the MAPK pathway, have been reported in a subset of histiocytic neoplasms with anecdotal evidence of successful targeted treatment of histiocytoses harboring driver alterations in RET, ALK, and CSF1R. However, evidence supporting the biological consequences of expression of PIK3CA mutations in hematopoietic cells has been lacking, and whether targeted inhibition of PI3K is clinically efficacious in histiocytic neoplasms is unknown. Here, we provide evidence that activating mutations in PIK3CA can drive histiocytic neoplasms in vivo using a conditional knockin mouse expressing mutant PIK3CAH1047R in monocyte/dendritic cell progenitors. In parallel, we demonstrate successful treatment of PIK3CA-mutated, multisystemic LCH using alpelisib, an inhibitor of the alpha catalytic subunit of PI3K. Alpelisib demonstrated a tolerable safety profile at a dose of 750 mg per week and clinical and metabolic complete remission in a patient with PIK3CA-mutated LCH. These data demonstrate PIK3CA as a targetable noncanonical driver of LCH and underscore the importance of mutational analysis-based personalized treatment in histiocytic neoplasms.
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Neoplasias Hematológicas , Histiocitose de Células de Langerhans , Humanos , Animais , Camundongos , Proteínas Proto-Oncogênicas B-raf/genética , Histiocitose de Células de Langerhans/tratamento farmacológico , Receptores Proteína Tirosina Quinases , Fosfatidilinositol 3-Quinases/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
Little is known about outcomes following interruption of targeted therapy in adult patients with histiocytic neoplasms. This is an IRB-approved study of patients with histiocytic neoplasms whose BRAF and MEK inhibitors were interrupted after achieving complete or partial response by 18-fluorodeoxyglucose positron emission tomography (FDG-PET). 17/22 (77%) of patients experienced disease relapse following treatment interruption. Achieving a complete response prior to interruption, having a mutation other than BRAFV600E, and receiving MEK inhibition only were each associated with a statistically significant improvement in relapse-free survival. Relapse is common following treatment interruption however some patients may be suitable for limited-duration treatment.
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Neoplasias , Adulto , Humanos , Tomografia por Emissão de Pósitrons , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Quinases de Proteína Quinase Ativadas por Mitógeno , Recidiva , Fluordesoxiglucose F18 , Proteínas Proto-Oncogênicas B-raf/genéticaRESUMO
PURPOSE: To overcome barriers to genomic testing for patients with rare cancers, we initiated a program to offer free clinical tumor genomic testing worldwide to patients with select rare cancer subtypes. EXPERIMENTAL DESIGN: Patients were recruited through social media outreach and engagement with disease-specific advocacy groups, with a focus on patients with histiocytosis, germ cell tumors (GCT), and pediatric cancers. Tumors were analyzed using the MSK-IMPACT next-generation sequencing assay with the return of results to patients and their local physicians. Whole-exome recapture was performed for female patients with GCTs to define the genomic landscape of this rare cancer subtype. RESULTS: A total of 333 patients were enrolled, and tumor tissue was received for 288 (86.4%), with 250 (86.8%) having tumor DNA of sufficient quality for MSK-IMPACT testing. Eighteen patients with histiocytosis have received genomically guided therapy to date, of whom 17 (94%) have had clinical benefit with a mean treatment duration of 21.7 months (range, 6-40+). Whole-exome sequencing of ovarian GCTs identified a subset with haploid genotypes, a phenotype rarely observed in other cancer types. Actionable genomic alterations were rare in ovarian GCT (28%); however, 2 patients with ovarian GCTs with squamous transformation had high tumor mutational burden, one of whom had a complete response to pembrolizumab. CONCLUSIONS: Direct-to-patient outreach can facilitate the assembly of cohorts of rare cancers of sufficient size to define their genomic landscape. By profiling tumors in a clinical laboratory, results could be reported to patients and their local physicians to guide treatment. See related commentary by Desai and Subbiah, p. 2339.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Ovarianas , Humanos , Feminino , Mutação , Genômica , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , ExomaRESUMO
This report highlights the value of flow cytometry analysis, particularly in the setting of myeloproliferative neoplasms showing features of progression, as neoplastic plasmacytoid dendritic cell (PDC) proliferations may be present, representing either a clonal expansion of mature PDCs related to the underlying myeloproliferative neoplasm or transformation to blastic plasmacytoid dendritic cell neoplasm (BPDCN). BPDCN should always be considered in patients with myeloid neoplasms in progression and/or who develop new cutaneous findings, as it may prompt change of management.
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Mutations of TP53 are observed in 5-10% of patients in myelodysplastic syndrome (MDS) and are associated with adverse outcomes. Previous studies indicate that the TP53 allelic state and variant allele frequency of TP53 mutation impact patient outcomes, but there is significant heterogeneity within this MDS subgroup. We performed retrospective review of clinicopathologic and genomic information of 107 patients with TP53-mutated MDS. We assessed each mutation according to the phenotypic annotation of TP53 mutations (PHANTM) and analyzed the associations between predicted TP53 mutant function, represented by the PHANTM combined phenotype score, and overall survival (OS) using the log rank test and Cox regression. Our results indicated that patients with PHANTM combined phenotype score above the median (>1) had significantly shorter OS compared to those with scores below the median (median OS: 10.59 and 16.51 months, respectively, p = 0.025). This relationship remained significant in multivariable analysis (HR (95%CI): 1.62 (1.01-2.58), p = 0.044) and identified to have an independent prognostic influence, accounting for known risk such as IPSS-R and other standard risk variables. Our results suggest that the functional information of TP53 mutations, represented by PHANTM combined phenotype score, are associated with the clinical outcome of patients with TP53-mutated MDS.
RESUMO
Immunoglobulin light chain (AL) amyloidosis is characterized by the deposition of amyloid fibers derived from pathologic immunoglobulin light chains. Although systemic plasma cell neoplasms are the most common cause of AL amyloidosis, a subset of cases is caused by B-cell lymphoproliferative disorders such as lymphoplasmacytic lymphoma or extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Recently, SOX11-negative IGH hypermutated mantle cell lymphoma (MCL) is recognized to show frequent plasmacytic differentiation and indolent clinical course. Here, we report 3 cases of peritumoral AL amyloidosis associated with SOX11-negative MCL. All 3 cases showed cyclin D1 expression by immunohistochemistry and CCND1 translocation as detected by fluorescence in situ hybridization analysis. Peritumoral AL amyloidosis was observed at the biopsy sites in the gastrointestinal tract, a supraclavicular lymph node, and a cervical lymph node, and all presented with marked plasmacytic differentiation of lymphoma cells. None of the cases showed evidence of bone marrow involvement by morphology and immunophenotyping. None of the patients had distant organ involvement with systemic amyloidosis. All 3 patients had an indolent clinical course and are alive with disease at the time of the last follow-up (range: 48 to 74 mo). Our findings show that MCL with plasmacytic differentiation can cause amyloid deposition and CCND1 abnormalities should be performed in all cases of extramedullary AL amyloidosis. Recognition of indolent MCL as a cause of peritumoral AL amyloidosis may have important clinical management implications.
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Diferenciação Celular , Amiloidose de Cadeia Leve de Imunoglobulina/patologia , Linfoma de Célula do Manto/patologia , Plasmócitos/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Ciclina D1/genética , Feminino , Humanos , Amiloidose de Cadeia Leve de Imunoglobulina/tratamento farmacológico , Amiloidose de Cadeia Leve de Imunoglobulina/genética , Amiloidose de Cadeia Leve de Imunoglobulina/imunologia , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Linfoma de Célula do Manto/tratamento farmacológico , Linfoma de Célula do Manto/genética , Linfoma de Célula do Manto/imunologia , Pessoa de Meia-Idade , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Estudos Retrospectivos , Translocação Genética , Resultado do TratamentoRESUMO
t(6;9)(p22;q34.1)/DEK-NUP214 is a recurrent genetic abnormality that occurs in 1-2% of patients with acute myeloid leukemia (AML), and rarely in myelodysplastic syndrome (MDS). It has been suggested by others that all myeloid neoplasms with t(6;9)/DEK-NUP214 may be considered as AML, even when blast count is <20%. In this study, we compared the clinicopathologic features of 107 patients with myeloid neoplasms harboring t(6;9)/DEK-NUP214: 33 MDS and 74 AML. Compared with patients with AML, patients with MDS were older (p = 0.10), had a lower white blood cell count (p = 0.0017), a lower blast count in the peripheral blood (p < 0.0001) and bone marrow (p < 0.0001), a higher platelet count (p = 0.022), and a lower frequency of FLT3-ITD mutation (p = 0.01). In addition, basophilia was not a common feature in the patients of this cohort. Although there was no difference in overall survival between MDS and AML patients (p = 0.18) in the entire cohort, the survival curves did show a trend toward favorable survival in MDS patients. Multivariate analyses showed that initial diagnosis of MDS vs. AML and allogeneic hematopoietic stem cell transplantation were prognostic factors for survival of patients with t(6;9)/DEK-NUP214 (p = 0.008 and p < 0.0001, respectively). Our data suggest that MDS with t(6;9)/DEK-NUP214 is prognostically not equivalent to AML with t(6;9)/DEK-NUP214. These data also show that stem cell transplantation greatly improves the survival of MDS and AML patients with myeloid neoplasms associated with t(6;9)/DEK-NUP214.
Assuntos
Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Síndromes Mielodisplásicas/genética , Síndromes Mielodisplásicas/patologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Proteínas Cromossômicas não Histona/genética , Cromossomos Humanos Par 6/genética , Cromossomos Humanos Par 9/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complexo de Proteínas Formadoras de Poros Nucleares/genética , Fusão Oncogênica , Proteínas Oncogênicas/genética , Proteínas de Fusão Oncogênica , Proteínas de Ligação a Poli-ADP-Ribose/genética , Translocação Genética , Adulto JovemRESUMO
Stably acquired mutations in hematopoietic cells represent substrates of selection that may lead to clonal hematopoiesis (CH), a common state in cancer patients that is associated with a heightened risk of leukemia development. Owing to technical and sample size limitations, most CH studies have characterized gene mutations or mosaic chromosomal alterations (mCAs) individually. Here we leverage peripheral blood sequencing data from 32,442 cancer patients to jointly characterize gene mutations (n = 14,789) and mCAs (n = 383) in CH. Recurrent composite genotypes resembling known genetic interactions in leukemia genomes underlie 23% of all detected autosomal alterations, indicating that these selection mechanisms are operative early in clonal evolution. CH with composite genotypes defines a patient group at high risk of leukemia progression (3-year cumulative incidence 14.6%, CI: 7-22%). Multivariable analysis identifies mCA as an independent risk factor for leukemia development (HR = 14, 95% CI: 6-33, P < 0.001). Our results suggest that mCA should be considered in conjunction with gene mutations in the surveillance of patients at risk of hematologic neoplasms.
Assuntos
Aberrações Cromossômicas , Evolução Clonal/genética , Hematopoiese Clonal/genética , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Hematológicas/genética , Humanos , Pessoa de Meia-Idade , Mosaicismo , Neoplasias/genética , Medição de Risco , Seleção Genética , Adulto JovemAssuntos
Eosinofilia , Transtornos Mieloproliferativos , Neoplasias , Subunidade alfa 2 de Fator de Ligação ao Core , Eosinofilia/tratamento farmacológico , Proteínas de Fusão bcr-abl , Humanos , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/genética , Proteínas de Fusão Oncogênica/genética , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Tirosina Quinases/genéticaRESUMO
A 75-year-old man with no prior history of cytotoxic therapy presented with increasing fatigue and shortness of breath. He was found to have a new onset of pancytopenia, and chest X-ray showed severe pneumonia. Additional radiology exam revealed pan-lobar pneumonia, pleural effusion, generalized lymphadenopathy and mild splenomegaly. Bone marrow and mediastinal lymph node biopsy from the bilateral level 4 lymph nodes were performed to evaluate the cause of pancytopenia and generalized lymphadenopathy, respectively. Histologic sections of lymph nodes were consistent with angioimmunoblastic T-cell lymphoma (AITL), and bone marrow biopsy showed low level involvement by AITL. Background trilineage hematopoiesis showed features suggestive of myelodysplastic syndrome (MDS) with karyotyping showing deletion 20q; however, interpretation of dysplasia and exclusion of reactive process was difficult due to the presence of severe infection, administration of multiple medications and multiorgan failure. Therefore, to further evaluate the possibility of concomitant myeloid neoplasm, we performed flow cytometry sorting of bone marrow aspirate to isolate the myeloid cell population from the abnormal T-cell population, and comprehensive genomic profiling was performed in each population separately. Flow-sorted myeloid population showed three somatic mutations involving DNMT3A and BCORL1, supporting the diagnosis of MDS in conjunction with the presence of deletion 20q. Flow sorted abnormal T-cell population showed six somatic mutations consistent with AITL, involving Ras homolog gene family member A (RHOA), TET2, DNMT3A, NOTCH2 and XPO1. These two sorted populations shared the DNMT3A p.N612Rfs*26 mutation, and the variants unique to one sorted population were confirmed to be completely absent in another sorted population by manual review of the sample. These findings suggested that the two neoplasms were clonally related and were sharing a common hematopoietic progenitor precursor, but underwent clonal divergence over time, leading to the development of two distinct neoplastic processes of T and myeloid lineages. This illustrates a rare case of concurrent diagnosis of AITL and de novo MDS and reliable genomic assessment was performed at the time of diagnosis to detect mutations in each neoplastic process without contamination. Further studies are needed to assess hypomethylating agents as potential therapy options for these patients.
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Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
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Hematopoiese Clonal/genética , Segunda Neoplasia Primária/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/farmacologia , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/efeitos da radiação , Criança , Pré-Escolar , Evolução Clonal , Hematopoiese Clonal/efeitos dos fármacos , Estudos de Coortes , Feminino , Aptidão Genética , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide/genética , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Seleção Genética , Adulto JovemRESUMO
BACKGROUND: The role of imaging in the management of Rosai-Dorfman disease (RDD), a rare non-Langerhans cell histiocytosis, is not clearly defined. We present an analysis of FDG PET/CT findings obtained for initial disease characterization, follow-up evaluation, and treatment planning for this disease. METHODS: From an institutional pathology database (2001-2018), we identified RDD patients who underwent FDG PET/CT scans either as part of clinical care or when done as part of clinical trials. For all scans, sites of abnormal FDG uptake were assessed, and SUVmax was measured. Comparison of PET/CT findings was made with anatomic (CT/MRI-based) imaging, where available. Instances of changing treatment based on PET/CT were recorded. RESULTS: We reviewed 109 FDG PET/CT scans in 27 patients with RDD. Five of 27 patients had only nodal/cutaneous disease, whereas 22 patients had extranodal disease, most commonly in bone (n = 9) and central nervous system (n = 7). PET/CT identified sites of active disease in 24 of 27 patients. All identified bone and extraskeletal lesions, except for a brain lesion in 1 patient, were FDG-avid. In 6 of 20 patients (30%) with available prior CT or MRI, PET/CT demonstrated additional RDD lesions (bones: n = 5, pleura: n = 1) that were not apparent on anatomic imaging; 3 of these lesions were outside the CT field of view, and 3 were not recognized on CT. Overall, 13 of 109 PET/CT scans led to a change in management, affecting 41% (11/27) of patients. CONCLUSION: FDG PET/CT was valuable in defining disease extent and optimizing treatment strategy in patients with RDD.
Assuntos
Fluordesoxiglucose F18 , Histiocitose Sinusal/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Adulto , Feminino , Seguimentos , Histiocitose Sinusal/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
In patients with multiple myeloma, plasmablastic transformation in the bone marrow is rare and associated with poor outcomes. The significance of discordant extramedullary plasmablastic transformation in patients with small, mature clonal plasma cells in the bone marrow has not been well studied. Here, we report the clinicopathologic, cytogenetic, and molecular features of 10 such patients (male/female: 6/4, median age: 65 y, range: 48 to 76 y) with an established diagnosis of multiple myeloma in the bone marrow composed of small, mature plasma cells in parallel with a concurrent or subsequent extramedullary plasmablastic transformation. Eight patients with available survival data showed an overall aggressive clinical course with a median survival of 4.5 months after the diagnosis of extramedullary plasmablastic transformation, despite aggressive treatment and even in patients with low-level bone marrow involvement. Pathologically, the extramedullary plasmablastic myeloma were clonally related to the corresponding bone marrow plasma cells, showed high levels of CMYC and/or P53 expression with a high Ki-67 proliferation index by immunohistochemistry and harbored more complex genomic aberrations including frequent mutations in the RAS pathway and MYC rearrangements compared with their bone marrow counterparts. In summary, although genetic and immunohistochemical studies were not uniformly performed on all cases due to the retrospective nature of this study, our data suggest that discordant extramedullary plasmablastic transformation of multiple myeloma has an aggressive clinical course and is characterized by frequent mutations in the RAS pathway and more complex genomic abnormalities.