Childhood Cancer Genomics (PDQ®)–Health Professional Version
Mature B-cell Lymphoma
The mature B-cell lymphomas include Burkitt and Burkitt-like lymphoma, diffuse large B-cell lymphoma, and primary mediastinal B-cell lymphoma.
Burkitt and Burkitt-like lymphoma
The malignant cells show a mature B-cell phenotype and are negative for the enzyme terminal deoxynucleotidyl transferase. These malignant cells usually express surface immunoglobulin, most bearing a clonal surface immunoglobulin M with either kappa or lambda light chains. A variety of additional B-cell markers (e.g., CD19, CD20, CD22) are usually present, and most childhood Burkitt and Burkitt-like lymphomas/leukemias express CALLA (CD10).
Burkitt lymphoma/leukemia expresses a characteristic chromosomal translocation, usually t(8;14) and more rarely t(8;22) or t(2;8). Each of these translocations juxtaposes the MYC oncogene and immunoglobulin locus regulatory elements, resulting in the inappropriate expression of MYC, a gene involved in cellular proliferation.[2-4] The presence of one of the variant translocations t(2;8) or t(8;22) does not appear to affect response or outcome.
While MYC translocations are present in all Burkitt lymphoma, cooperating genomic alterations appear to be required for lymphoma development. Recurring mutations that have been identified in Burkitt lymphoma in pediatric and adult cases are listed below. The clinical significance of these mutations for pediatric Burkitt lymphoma remains to be elucidated.
Activating mutations in the transcription factor TCF3 and inactivating mutations in its negative regulator ID3 are observed in approximately 70% of Burkitt lymphoma cases.[6-9]
Mutations in TP53 are observed in one-third to one-half of cases.[6,8]
Mutations in cyclin D3 (CCND3) are commonly observed in sporadic Burkitt lymphoma (approximately 40% of cases) but are rare in endemic Burkitt lymphoma.[6,8]
Mutations in MYC itself are observed in approximately one-half of Burkitt lymphoma cases and appear to increase MYC stability.[6,10]
A study that compared the genomic landscape of endemic Burkitt lymphoma with the genomics of sporadic Burkitt lymphoma found the expected high rate of Epstein-Barr virus (EBV) positivity in endemic cases, with much lower rates in sporadic cases. There was general similarity between the patterns of mutations for endemic and sporadic cases and for EBV-positive and EBV-negative cases; however, EBV-positive cases showed significantly lower mutation rates for selected genes/pathways, including SMARCA4, apoptosis, CCND3, and TP53.
The distinction between Burkitt and Burkitt-like lymphoma/leukemia is controversial. Burkitt lymphoma/leukemia consists of uniform, small, noncleaved cells, whereas the diagnosis of Burkitt-like lymphoma/leukemia is highly disputed among pathologists because of features that are consistent with diffuse large B-cell lymphoma.
Cytogenetic evidence of MYC rearrangement is the gold standard for diagnosis of Burkitt lymphoma/leukemia. For cases in which cytogenetic analysis is not available, the World Health Organization (WHO) has recommended that the Burkitt-like diagnosis be reserved for lymphoma resembling Burkitt lymphoma/leukemia or with more pleomorphism, large cells, and a proliferation fraction (i.e., MIB-1 or Ki-67 immunostaining) of 99% or greater. BCL2 staining by immunohistochemistry is variable. The absence of a translocation involving the BCL2 gene does not preclude the diagnosis of Burkitt lymphoma/leukemia and has no clinical implications.
Studies have demonstrated that the vast majority of Burkitt-like or atypical Burkitt lymphoma/leukemia cases have a gene expression signature similar to Burkitt lymphoma/leukemia.[14,15] Additionally, as many as 30% of pediatric diffuse large B-cell lymphoma cases will have a gene signature similar to Burkitt lymphoma/leukemia.[14,16]
Burkitt-like lymphoma with 11q aberration was added as a provisional entity in the 2017 revised WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. In this entity, MYC rearrangement is absent, and the characteristic chromosome 11q finding (detected cytogenetically and/or with copy-number DNA arrays) is 11q23.2-q23.3 gain/amplification and 11q24.1-qter loss.[17,18] Most patients present in the adolescent and young adult age range with localized nodal disease, and outcomes appear favorable in the small number of cases identified. Cases show a very high proliferative index and can show a focal starry sky pattern. The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma; mutations commonly observed in Burkitt lymphoma (e.g., ID3, TCF3, and CCND3) are uncommon in Burkitt-like lymphoma with 11q aberration. Conversely, mutations in GNA13 appear to be common (up to 50%) in patients with Burkitt-like lymphoma with 11q aberration and are less common in patients with Burkitt lymphoma.
The World Health Organization (WHO) classification system does not recommend subclassification of diffuse large B-cell lymphoma on the basis of morphologic variants (e.g., immunoblastic, centroblastic).
Diffuse large B-cell lymphoma in children and adolescents differs biologically from diffuse large B-cell lymphoma in adults in the following ways:
The vast majority of pediatric diffuse large B-cell lymphoma cases have a germinal center B-cell phenotype, as assessed by immunohistochemical analysis of selected proteins found in normal germinal center B cells, such as the BCL6 gene product and CD10.[5,20,21] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.
Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the immunoglobulin heavy-chain gene and the BCL2 gene that is seen in adults.
As many as 30% of patients younger than 14 years with diffuse large B-cell lymphoma will have a gene signature similar to Burkitt lymphoma/leukemia.[14,16]
In contrast to adult diffuse large B-cell lymphoma, pediatric cases show a high frequency of abnormalities at the MYC locus (chromosome 8q24), with approximately one-third of pediatric cases showing MYC rearrangement and with approximately one-half of the nonrearranged cases showing MYC gain or amplification.[16,23]
A subset of pediatric diffuse large B-cell lymphoma cases was found to have a translocation that juxtaposes the IRF4 oncogene next to one of the immunoglobulin loci. Diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults (15% vs. 2%), were germinal center–derived B-cell lymphomas, and were associated with favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality. Large B-cell lymphoma with IRF4 rearrangement was added as a distinct entity in the 2016 revision of the WHO classification of lymphoid neoplasms.
Primary mediastinal B-cell lymphoma was previously considered a subtype of diffuse large B-cell lymphoma, but is now a separate entity in the most recent World Health Organization (WHO) classification. These tumors arise in the mediastinum from thymic B-cells and show a diffuse large cell proliferation with sclerosis that compartmentalizes neoplastic cells.
Primary mediastinal B-cell lymphoma can be very difficult to distinguish morphologically from the following types of lymphoma:
Diffuse large B-cell lymphoma: Cell surface markers are similar to the ones seen in diffuse large B-cell lymphoma, such as CD19, CD20, CD22, CD79a, and PAX-5. Primary mediastinal B-cell lymphoma often lacks cell surface immunoglobulin expression but may display cytoplasmic immunoglobulins. CD30 expression is commonly present.
Hodgkin lymphoma: Primary mediastinal B-cell lymphoma may be difficult to clinically and morphologically distinguish from Hodgkin lymphoma, especially with small mediastinal biopsies because of extensive sclerosis and necrosis.
Primary mediastinal B-cell lymphoma has a distinctive gene expression profile compared with diffuse large B-cell lymphoma; however, its gene expression profile has features similar to those seen in Hodgkin lymphoma.[27,28] Primary mediastinal B-cell lymphoma is also associated with a distinctive constellation of chromosomal aberrations compared with other NHL subtypes. Because primary mediastinal B-cell lymphoma is primarily a cancer of adolescents and young adults, the genomic findings are presented without regard to age.
Structural rearrangements and copy number gains at chromosome 9p24 are common in primary mediastinal B-cell lymphoma. This region encodes the immune checkpoint genes PD-L1 (PDL1) and PD-L2 (PDCD1LG2), and the genomic alterations lead to increased expression of these checkpoint proteins.[29-31]
Genomic alterations in CIITA, which is the master transcriptional regulator of major histocompatibility complex (MHC) class II expression, are common in primary mediastinal B-cell lymphoma and lead to loss of MHC class II expression. Loss of MHC class II expression provides another mechanism of immune escape for primary mediastinal B-cell lymphoma.
Genomic alterations involving JAK-STAT pathway genes are observed in most cases of primary mediastinal B-cell lymphoma.
The chromosome 9p region that shows gains and amplification in primary mediastinal B-cell lymphoma encodes Janus kinase 2 (JAK2), which activates the signal transducer and activator of transcription (STAT) pathway.[34,35]
SOCS1, a negative regulator of JAK-STAT signaling, is inactivated in approximately 50% of primary mediastinal B-cell lymphoma by either mutation or gene deletion.[36,37]
The interleukin-4 receptor gene (IL4R) shows activating mutations in approximately 20% of primary mediastinal B-cell lymphoma cases, and IL4R activation leads to increased JAK-STAT pathway activity.
Copy number gains and amplifications at 2p16.1, a region that encodes BCL11A and REL, also occur in primary mediastinal B-cell lymphoma.[34,35]
Lymphoblastic lymphomas are usually positive for terminal deoxynucleotidyl transferase, with more than 75% having a T-cell immunophenotype and the remainder having a precursor B-cell phenotype.[2,38]
As opposed to pediatric acute lymphoblastic leukemia, chromosomal abnormalities and the molecular biology of pediatric lymphoblastic lymphoma are not well characterized. The Berlin-Frankfurt-Münster group reported that loss of heterozygosity at chromosome 6q was observed in 12% of patients and NOTCH1 mutations were seen in 60% of patients, but NOTCH1 mutations are rarely seen in patients with loss of heterozygosity at 6q.[39,40]
While the predominant immunophenotype of anaplastic large cell lymphoma is mature T-cell, null-cell disease (i.e., no T-cell, B-cell, or natural killer-cell surface antigen expression) does occur. The World Health Organization (WHO) classifies anaplastic large cell lymphoma as a subtype of peripheral T-cell lymphoma.
All anaplastic large cell lymphoma cases are CD30-positive. More than 90% of pediatric anaplastic large cell lymphoma cases have a chromosomal rearrangement involving the ALK gene. About 85% of these chromosomal rearrangements will be t(2;5)(p23;q35), leading to the expression of the fusion protein NPM-ALK; the other 15% of cases are composed of variant ALK translocations. Anti-ALK immunohistochemical staining pattern is quite specific for the type of ALK translocation. Cytoplasm and nuclear ALK staining is associated with NPM-ALK fusion protein, whereas cytoplasmic staining only of ALK is associated with the variant ALK translocations, as shown in Table 4.
Table 4. Variant ALK Translocation and Associated Partner Chromosome Location and Frequencya
In adults, ALK-positive anaplastic large cell lymphoma is viewed differently from other peripheral T-cell lymphomas because prognosis tends to be superior. Also, adult ALK-negative anaplastic large cell lymphoma patients have an inferior outcome compared with patients who have ALK-positive disease. In children, however, this difference in outcome between ALK-positive and ALK-negative disease has not been demonstrated. In addition, no correlation has been found between outcome and the specific ALK-translocation type.[45-47]
In a European series of 375 children and adolescents with systemic ALK-positive anaplastic large cell lymphoma, the presence of a small cell or lymphohistiocytic component was observed in 32% of patients and was significantly associated with a high risk of failure in the multivariate analysis, controlling for clinical characteristics (hazard ratio, 2.0; P = .002). The prognostic implication of the small cell variant of anaplastic large cell lymphoma was also shown in the COG-ANHL0131 (NCT00059839) study, despite a different chemotherapy backbone.
Pediatric-type follicular lymphoma appears to be molecularly distinct from follicular lymphoma that is more commonly observed in adults. The pediatric type lacks BCL2 rearrangements; BCL6 and MYC rearrangements are also not present. The TNFSFR14 mutations are common in pediatric-type follicular lymphoma, and they appear to occur with similar frequency in adult follicular lymphoma.[48,49] However, MAP2K1 mutations, which are uncommon in adults, are observed in as many as 43% of pediatric-type follicular lymphomas. Other genes (e.g., MAPK1 and RRAS) have been found to be mutated in cases without MAP2K1 mutations, suggesting that the MAP kinase pathway is important in the pathogenesis of pediatric-type follicular lymphoma.[50,51] Translocations of the immunoglobulin locus and IRF4, mutations in IRF8, and abnormalities in chromosome 1p have also been observed in pediatric-type follicular lymphoma.[24,48,52]
Leoncini L, Raphael M, Stein H, et al.: Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. Lyon, France: International Agency for Research on Cancer, 2017, pp 330-4.
Sandlund JT, Downing JR, Crist WM: Non-Hodgkin's lymphoma in childhood. N Engl J Med 334 (19): 1238-48, 1996. [PUBMED Abstract]
Perkins SL, Lones MA, Davenport V, et al.: B-Cell non-Hodgkin's lymphoma in children and adolescents: surface antigen expression and clinical implications for future targeted bioimmune therapy: a children's cancer group report. Clin Adv Hematol Oncol 1 (5): 314-7, 2003. [PUBMED Abstract]
Miles RR, Cairo MS, Satwani P, et al.: Immunophenotypic identification of possible therapeutic targets in paediatric non-Hodgkin lymphomas: a children's oncology group report. Br J Haematol 138 (4): 506-12, 2007. [PUBMED Abstract]
Gualco G, Weiss LM, Harrington WJ, et al.: Nodal diffuse large B-cell lymphomas in children and adolescents: immunohistochemical expression patterns and c-MYC translocation in relation to clinical outcome. Am J Surg Pathol 33 (12): 1815-22, 2009. [PUBMED Abstract]
Schmitz R, Young RM, Ceribelli M, et al.: Burkitt lymphoma pathogenesis and therapeutic targets from structural and functional genomics. Nature 490 (7418): 116-20, 2012. [PUBMED Abstract]
Richter J, Schlesner M, Hoffmann S, et al.: Recurrent mutation of the ID3 gene in Burkitt lymphoma identified by integrated genome, exome and transcriptome sequencing. Nat Genet 44 (12): 1316-20, 2012. [PUBMED Abstract]
Havelange V, Pepermans X, Ameye G, et al.: Genetic differences between paediatric and adult Burkitt lymphomas. Br J Haematol 173 (1): 137-44, 2016. [PUBMED Abstract]
Rohde M, Bonn BR, Zimmermann M, et al.: Relevance of ID3-TCF3-CCND3 pathway mutations in pediatric aggressive B-cell lymphoma treated according to the non-Hodgkin Lymphoma Berlin-Frankfurt-Münster protocols. Haematologica 102 (6): 1091-1098, 2017. [PUBMED Abstract]
Chakraborty AA, Scuoppo C, Dey S, et al.: A common functional consequence of tumor-derived mutations within c-MYC. Oncogene 34 (18): 2406-9, 2015. [PUBMED Abstract]
Grande BM, Gerhard DS, Jiang A, et al.: Genome-wide discovery of somatic coding and noncoding mutations in pediatric endemic and sporadic Burkitt lymphoma. Blood 133 (12): 1313-1324, 2019. [PUBMED Abstract]
Kluin PM, Harris NL, Stein H: B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. Lyon, France: International Agency for Research on Cancer, 2017, pp 314-6.
Masqué-Soler N, Szczepanowski M, Kohler CW, et al.: Clinical and pathological features of Burkitt lymphoma showing expression of BCL2--an analysis including gene expression in formalin-fixed paraffin-embedded tissue. Br J Haematol 171 (4): 501-8, 2015. [PUBMED Abstract]
Klapper W, Szczepanowski M, Burkhardt B, et al.: Molecular profiling of pediatric mature B-cell lymphoma treated in population-based prospective clinical trials. Blood 112 (4): 1374-81, 2008. [PUBMED Abstract]
Dave SS, Fu K, Wright GW, et al.: Molecular diagnosis of Burkitt's lymphoma. N Engl J Med 354 (23): 2431-42, 2006. [PUBMED Abstract]
Deffenbacher KE, Iqbal J, Sanger W, et al.: Molecular distinctions between pediatric and adult mature B-cell non-Hodgkin lymphomas identified through genomic profiling. Blood 119 (16): 3757-66, 2012. [PUBMED Abstract]
Wagener R, Seufert J, Raimondi F, et al.: The mutational landscape of Burkitt-like lymphoma with 11q aberration is distinct from that of Burkitt lymphoma. Blood 133 (9): 962-966, 2019. [PUBMED Abstract]
Gonzalez-Farre B, Ramis-Zaldivar JE, Salmeron-Villalobos J, et al.: Burkitt-like lymphoma with 11q aberration: a germinal center-derived lymphoma genetically unrelated to Burkitt lymphoma. Haematologica 104 (9): 1822-1829, 2019. [PUBMED Abstract]
Gascoyne RD, Campo E, Jaffe ES, et al.: Diffuse large B-cell lymphoma, NOS. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th rev. ed. Lyon, France: International Agency for Research on Cancer, 2017, pp 291-7.
Oschlies I, Klapper W, Zimmermann M, et al.: Diffuse large B-cell lymphoma in pediatric patients belongs predominantly to the germinal-center type B-cell lymphomas: a clinicopathologic analysis of cases included in the German BFM (Berlin-Frankfurt-Munster) Multicenter Trial. Blood 107 (10): 4047-52, 2006. [PUBMED Abstract]
Miles RR, Raphael M, McCarthy K, et al.: Pediatric diffuse large B-cell lymphoma demonstrates a high proliferation index, frequent c-Myc protein expression, and a high incidence of germinal center subtype: Report of the French-American-British (FAB) international study group. Pediatr Blood Cancer 51 (3): 369-74, 2008. [PUBMED Abstract]
Klapper W, Kreuz M, Kohler CW, et al.: Patient age at diagnosis is associated with the molecular characteristics of diffuse large B-cell lymphoma. Blood 119 (8): 1882-7, 2012. [PUBMED Abstract]
Poirel HA, Cairo MS, Heerema NA, et al.: Specific cytogenetic abnormalities are associated with a significantly inferior outcome in children and adolescents with mature B-cell non-Hodgkin's lymphoma: results of the FAB/LMB 96 international study. Leukemia 23 (2): 323-31, 2009. [PUBMED Abstract]
Salaverria I, Philipp C, Oschlies I, et al.: Translocations activating IRF4 identify a subtype of germinal center-derived B-cell lymphoma affecting predominantly children and young adults. Blood 118 (1): 139-47, 2011. [PUBMED Abstract]
Swerdlow SH, Campo E, Pileri SA, et al.: The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 127 (20): 2375-90, 2016. [PUBMED Abstract]
Jaffe ES, Harris NL, Stein H, et al.: Introduction and overview of the classification of the lymphoid neoplasms. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 157-66.
Rosenwald A, Wright G, Leroy K, et al.: Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med 198 (6): 851-62, 2003. [PUBMED Abstract]
Savage KJ, Monti S, Kutok JL, et al.: The molecular signature of mediastinal large B-cell lymphoma differs from that of other diffuse large B-cell lymphomas and shares features with classical Hodgkin lymphoma. Blood 102 (12): 3871-9, 2003. [PUBMED Abstract]
Green MR, Monti S, Rodig SJ, et al.: Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood 116 (17): 3268-77, 2010. [PUBMED Abstract]
Twa DD, Chan FC, Ben-Neriah S, et al.: Genomic rearrangements involving programmed death ligands are recurrent in primary mediastinal large B-cell lymphoma. Blood 123 (13): 2062-5, 2014. [PUBMED Abstract]
Chong LC, Twa DD, Mottok A, et al.: Comprehensive characterization of programmed death ligand structural rearrangements in B-cell non-Hodgkin lymphomas. Blood 128 (9): 1206-13, 2016. [PUBMED Abstract]
Mottok A, Woolcock B, Chan FC, et al.: Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression. Cell Rep 13 (7): 1418-1431, 2015. [PUBMED Abstract]
Viganò E, Gunawardana J, Mottok A, et al.: Somatic IL4R mutations in primary mediastinal large B-cell lymphoma lead to constitutive JAK-STAT signaling activation. Blood 131 (18): 2036-2046, 2018. [PUBMED Abstract]
Bea S, Zettl A, Wright G, et al.: Diffuse large B-cell lymphoma subgroups have distinct genetic profiles that influence tumor biology and improve gene-expression-based survival prediction. Blood 106 (9): 3183-90, 2005. [PUBMED Abstract]
Oschlies I, Burkhardt B, Salaverria I, et al.: Clinical, pathological and genetic features of primary mediastinal large B-cell lymphomas and mediastinal gray zone lymphomas in children. Haematologica 96 (2): 262-8, 2011. [PUBMED Abstract]
Melzner I, Bucur AJ, Brüderlein S, et al.: Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line. Blood 105 (6): 2535-42, 2005. [PUBMED Abstract]
Mestre C, Rubio-Moscardo F, Rosenwald A, et al.: Homozygous deletion of SOCS1 in primary mediastinal B-cell lymphoma detected by CGH to BAC microarrays. Leukemia 19 (6): 1082-4, 2005. [PUBMED Abstract]
Neth O, Seidemann K, Jansen P, et al.: Precursor B-cell lymphoblastic lymphoma in childhood and adolescence: clinical features, treatment, and results in trials NHL-BFM 86 and 90. Med Pediatr Oncol 35 (1): 20-7, 2000. [PUBMED Abstract]
Bonn BR, Rohde M, Zimmermann M, et al.: Incidence and prognostic relevance of genetic variations in T-cell lymphoblastic lymphoma in childhood and adolescence. Blood 121 (16): 3153-60, 2013. [PUBMED Abstract]
Burkhardt B, Moericke A, Klapper W, et al.: Pediatric precursor T lymphoblastic leukemia and lymphoblastic lymphoma: Differences in the common regions with loss of heterozygosity at chromosome 6q and their prognostic impact. Leuk Lymphoma 49 (3): 451-61, 2008. [PUBMED Abstract]
Tsuyama N, Sakamoto K, Sakata S, et al.: Anaplastic large cell lymphoma: pathology, genetics, and clinical aspects. J Clin Exp Hematop 57 (3): 120-142, 2017. [PUBMED Abstract]
Savage KJ, Harris NL, Vose JM, et al.: ALK- anaplastic large-cell lymphoma is clinically and immunophenotypically different from both ALK+ ALCL and peripheral T-cell lymphoma, not otherwise specified: report from the International Peripheral T-Cell Lymphoma Project. Blood 111 (12): 5496-504, 2008. [PUBMED Abstract]
Vose J, Armitage J, Weisenburger D, et al.: International peripheral T-cell and natural killer/T-cell lymphoma study: pathology findings and clinical outcomes. J Clin Oncol 26 (25): 4124-30, 2008. [PUBMED Abstract]
Stein H, Foss HD, Dürkop H, et al.: CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features. Blood 96 (12): 3681-95, 2000. [PUBMED Abstract]
Lamant L, McCarthy K, d'Amore E, et al.: Prognostic impact of morphologic and phenotypic features of childhood ALK-positive anaplastic large-cell lymphoma: results of the ALCL99 study. J Clin Oncol 29 (35): 4669-76, 2011. [PUBMED Abstract]
Alexander S, Kraveka JM, Weitzman S, et al.: Advanced stage anaplastic large cell lymphoma in children and adolescents: results of ANHL0131, a randomized phase III trial of APO versus a modified regimen with vinblastine: a report from the children's oncology group. Pediatr Blood Cancer 61 (12): 2236-42, 2014. [PUBMED Abstract]
Launay E, Pangault C, Bertrand P, et al.: High rate of TNFRSF14 gene alterations related to 1p36 region in de novo follicular lymphoma and impact on prognosis. Leukemia 26 (3): 559-62, 2012. [PUBMED Abstract]
Schmidt J, Gong S, Marafioti T, et al.: Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene. Blood 128 (8): 1101-11, 2016. [PUBMED Abstract]
Louissaint A, Schafernak KT, Geyer JT, et al.: Pediatric-type nodal follicular lymphoma: a biologically distinct lymphoma with frequent MAPK pathway mutations. Blood 128 (8): 1093-100, 2016. [PUBMED Abstract]
Schmidt J, Ramis-Zaldivar JE, Nadeu F, et al.: Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. Blood 130 (3): 323-327, 2017. [PUBMED Abstract]
Ozawa MG, Bhaduri A, Chisholm KM, et al.: A study of the mutational landscape of pediatric-type follicular lymphoma and pediatric nodal marginal zone lymphoma. Mod Pathol 29 (10): 1212-20, 2016. [PUBMED Abstract]
ver historia personal en: www.cerasale.com.ar [dado de baja por la Cancillería Argentina por temas políticos, propio de la censura que rige en nuestro medio]//
weblog.maimonides.edu/farmacia/archives/UM_Informe_Autoevaluacion_FyB.pdf - //
weblog.maimonides.edu/farmacia/archives/0216_Admin_FarmEcon.pdf - //
www.proz.com/kudoz/english_to_spanish/art_literary/523942-key_factors.html - 65k - // www.llave.connmed.com.ar/portalnoticias_vernoticia.php?codigonoticia=17715 // www.frusculleda.com.ar/homepage/espanol/activities_teaching.htm // http://www.on24.com.ar/nota.aspx?idNot=36331 ||