RESUMEN
A 41-year-old woman with right shoulder pain was found to have multiple tumors with osteolysis and M-proteinemia. Abnormal plasma cells (CD38+, CD138+, Igλâ«κ) were detected in 1.4% of bone marrow nucleated cells, and G-banding analysis revealed a 46,XX,t (8;14), (q24;q32) karyotype in 4 of 20 cells analyzed. A biopsy specimen from an extramedullary lesion had a packed proliferation of aberrant plasmacytoid cells with positive IgH::MYC fusion signals on fluorescence in situ hybridization. The patient was diagnosed with symptomatic multiple myeloma and treated with the BLd regimen, which significantly reduced M protein levels. Extramedullary lesions were initially reduced, but increased again after four cycles. The lesions disappeared with subsequent EPOCH chemotherapy and radiation, and complete remission was confirmed. The patient was then treated with high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Complete remission was maintained for over one year with lenalidomide maintenance therapy. A solitary IgH::MYC chromosomal translocation is extremely rare in multiple myeloma and may be associated with high tumor proliferative capacity, multiple extramedullary lesions, and poor prognosis. Combined therapeutic modalities with novel and conventional chemotherapy and radiation might be a promising treatment strategy for patients with this type of multiple myeloma.
Asunto(s)
Mieloma Múltiple , Femenino , Humanos , Adulto , Mieloma Múltiple/terapia , Mieloma Múltiple/tratamiento farmacológico , Hibridación Fluorescente in Situ , Translocación Genética , Lenalidomida/uso terapéutico , CariotipificaciónRESUMEN
Chromosomal rearrangements leading to the relocation of proto-oncogenes into transcription-active regions are found in various types of tumors. In particular, the transfer of proto-oncogenes to the locus of heavy chains of immunoglobulins (IGH) is frequently observed in B-lymphomas. The increased expression of the MYC proto-oncogene due to IGH/MYC translocation is detected in approximately 85% of Burkitt lymphoma cases. The regulatory mechanisms affecting the oncogenes upon translocation include non-coding enhancer RNAs (eRNAs). We conducted a search for the eRNAs that may affect MYC transcription in the case of IGH/MYC translocation in Burkitt lymphoma, looking for potentially oncogenic eRNAs located at the IGH locus and predominantly expressed in B cells. Overexpression and knockdown of our primary candidate eRNA AL928768.3 led to the corresponding changes in the expression of MYC proto-oncogene in Burkitt lymphoma cells. Furthermore, we demonstrated that AL928768.3 knockdown decreased lymphoma cell proliferation and resistance to chemotherapy. Significant effects were observed only in cell lines bearing IGH/MYC abnormality but not in B-cell lines without this translocation nor primary B-cells. Our results indicate that AL928768.3 plays an important role in the development of Burkitt's lymphoma and suggest it and similar, yet undiscovered eRNAs as potential tissue-specific targets for cancer treatment.
Asunto(s)
Linfoma de Burkitt , Linfoma , Linfoma de Burkitt/tratamiento farmacológico , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Proliferación Celular , Resistencia a Antineoplásicos/genética , Humanos , Linfoma/genética , ARN , Translocación GenéticaRESUMEN
A 70-year-old man was admitted to our hospital due to fever, lymphadenopathy, and leukocytosis. White blood cell count was 22,700/µl with 92% blastoid cells. Bone marrow examination revealed abnormal lymphoid cell expansion. Abnormal cells expressed surface CD5 (dim), CD10, CD19, CD20, CD23 (dim) antigens, and kappa immunoglobulin light chains. Cytogenetic analysis of bone marrow cells at the time of diagnosis showed t (11:14) (q13;q32), t (14;18) (q32;q21), and t (8;14;18) (q24;q32;q21). Fluorescence in situ hybridization analyses of bone marrow identified translocations of IGH/MYC, IGH/BCL2, and IGH/CCND1. The patient was diagnosed with aggressive B-cell lymphoma with IGH/MYC, IGH/BCL2, and IGH/CCND1 translocation and was treated with various chemotherapies including R-CHOP, R-ESHAP, DA-EPOCH-R, R-hyper-CVAD, and radiotherapy. However, the lymphoma recurred after every chemotherapy session. Finally, he died after 6 months after first admission. Double-hit lymphoma/triple-hit lymphoma has previously been reported to present with an aggressive clinical course. In the present case, co-existence of IGH/CCND1, IGH/MYC, and IGH/BCL2 is very rare. Further clinical and biological investigations are necessary to establish an optimal treatment strategy.
Asunto(s)
Linfoma de Células B/genética , Translocación Genética , Anciano , Ciclina D1/genética , Resultado Fatal , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Hibridación Fluorescente in Situ , Linfoma de Células B/tratamiento farmacológico , Masculino , Recurrencia Local de Neoplasia , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genéticaRESUMEN
BACKGROUND: Burkitt lymphoma/leukemia (BL/L) is cytogenetically characterized by the t(8;14)(q24;q32) or its variants, t(2;8)(p11;q21), and t(8;22)(q24;q11.2), which juxtapose the MYC oncogene to one of the three immunoglobulin loci. The overall cure rate of BL/L in children is 70-90%, but patients diagnosed with advanced-stage disease have a less favorable prognosis. It is possible that secondary chromosomal abnormalities contribute to this unfavorable prognosis via chemotherapy resistance, but the results of genetic studies have been inconsistent. This study aimed to identify and characterize secondary chromosomal abnormalities associated with the t(8;14) and its variants in children with French-American-British-L3 leukemia or Burkitt lymphoma with bone marrow involvement at the time of diagnosis. PROCEDURE: Chromosome analysis was based on G-banding. Fluorescence in situ hybridization technique was applied using IGH/MYC/CEP8 dual-fusion and MYC break-apart probes. Multicolor chromosome banding was performed according to standard protocol. RESULTS: We describe a group of BL/L with extreme adverse clinical outcome, in which secondary chromosomal abnormalities, particularly those involving the long arms of chromosomes 1 and 13, were found in 71% of cases. The IGH/MYC fusion showed molecular heterogeneity in 14% of cases and two cases exhibited three IGH/MYC fusion signals. CONCLUSIONS: Secondary chromosomal abnormalities were found in a high proportion of patients. We observed an extent of IGH/MYC heterogeneity not previously reported in Burkitt lymphoma, including the novel finding of three fusion signals in two cases.
Asunto(s)
Médula Ósea/patología , Linfoma de Burkitt , Cromosomas Humanos/genética , Proteínas de Fusión Oncogénica/genética , Translocación Genética , Adolescente , Brasil , Linfoma de Burkitt/genética , Linfoma de Burkitt/patología , Niño , Preescolar , Pintura Cromosómica , Citogenética , Femenino , Humanos , MasculinoRESUMEN
Classification of DLBCL relies on clinical, immunohistochemical, and genetic information. We report a case of primary testicular diffuse large B-cell lymphoma (PT-DLBCL) with a hitherto unreported constellation of pathologic findings to illustrate the challenges of DLBCL classification. A standard hematopathology workup was followed by gene expression profiling (GEP) to determine the DLBCL cell of origin (COO). A 75-year-old man presented with a unilateral testicular mass that had developed over the course of 1 month. Pathologic examination demonstrated involvement by DLBCL. Clinical staging revealed no systemic disease. Genetic testing showed an MYD88 mutation, as well as IGH::MYC and IRF4- and BCL6-rearrangements. Gene expression profiling demonstrated an activated B-cell expression profile. This case highlights the genetic complexity of DLBCL arising in the testis and questions the clinical significance of the identified genetic abnormalities.
Asunto(s)
Linfoma de Células B Grandes Difuso , Neoplasias Testiculares , Anciano , Humanos , Masculino , Pruebas Genéticas , Linfoma de Células B Grandes Difuso/diagnóstico , Mutación , Factor 88 de Diferenciación Mieloide/genética , Proteínas Proto-Oncogénicas c-bcl-6 , Neoplasias Testiculares/genéticaRESUMEN
BACKGROUND: An atypical form of Burkitt leukemia/lymphoma (BL), BL with a phenotype of precursor B-cells (preBLL), is listed in the WHO Classification. Recent reports suggested that preBLL and classical BL could be distinguished by the differences in IG-MYC translocation architecture and an additional mutated genes profile. The characteristics of classical BL are IG-MYC by aberrant somatic hypermutation or class switch recombination, and BL-specific gene mutations such as MYC, ID3, and CCND3. Meanwhile, preBLL is characterized by IG-MYC due to aberrant VDJ recombination and mutations in NRAS and KRAS. However, it is not clear whether all preBLL cases can be differentiated. This report investigated the molecular characteristics of an infant preBLL case, with a more advanced stage of maturity than typical preBLL. CASE: The patient showed BL-like morphology with IGH-MYC rearrangement. In the immunophenotyping, CD20 and surface immunoglobulin were negative, whereas other markers were consistent with BL. To evaluate the genetic contribution, we performed whole-exome sequencing. The breakpoint analysis revealed the IG-MYC occurred due to an aberrant VDJ recombination. Meanwhile, additional somatic mutations were detected in FBXO11, one of the mutant genes specific to BL. In the analysis of the specimen in complete remission, mutation in KRAS, frequently mutated in preBLL, was detected with low frequency, suggesting somatic mosaicism. CONCLUSION: The present case showed the characteristics of both typical preBLL and classical BL. Because preBLL includes atypical cases such as the present case, further studies are required to elucidate preBLL features.
Asunto(s)
Linfoma de Burkitt , Proteínas F-Box , Linfoma de Burkitt/genética , Proteínas F-Box/genética , Humanos , Fenotipo , Células Precursoras de Linfocitos B/patología , Proteína-Arginina N-Metiltransferasas/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Translocación GenéticaAsunto(s)
Cadenas Pesadas de Inmunoglobulina/genética , Leucemia de Células Plasmáticas/genética , Proteínas de Fusión Oncogénica/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-myc/genética , Translocación Genética/genética , Adulto , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Resultado Fatal , Femenino , Citometría de Flujo , Humanos , Hibridación Fluorescente in Situ , Leucemia de Células Plasmáticas/metabolismo , Leucemia de Células Plasmáticas/patologíaRESUMEN
OBJECTIVES: Rare cases of clonally related histiocytic sarcoma (HS) following B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) have been reported to date. METHODS: We present a patient with HS, which appeared as a breast mass 12 months after the initial diagnosis of B-ALL. RESULTS: Both HS and the B-ALL shared IGH-MYC and IGK gene rearrangements. Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAF D594G. The patient achieved complete remission of B-ALL, but HS failed to respond to many cycles of intensive chemotherapy regimens. A partial response was achieved with sorafenib, a BRAF-targeted therapy. CONCLUSIONS: To our knowledge, this is the first study to demonstrate by WES that clonally related B-ALL and HS arise through divergent evolution from a common precursor. We present our findings together with a discussion of the previously reported cases of HS in patients with B-ALL.