Genomics of diffuse large B-cell lymphoma

Most 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.[4,20-22] The age at which the favorable germinal center subtype changes to the less favorable nongerminal center subtype was shown to be a continuous variable.[23]

Pediatric diffuse large B-cell lymphoma rarely demonstrates the t(14;18) translocation involving the IGH gene and the BCL2 gene that is seen in adults.[20]

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.[24,25]

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 approximately one-half of the nonrearranged cases showing MYC gain or amplification.[25,26]

A large-scale retrospective study assessed the spectrum of MYC-rearranged B-cell lymphomas and the fluorescence in situ hybridization (FISH) results for MYC, BCL2, and BCL6 rearrangements and MYC immunoglobulin (IG) rearrangement partners in pediatric (n = 129) and young adult patients (n = 129). Most MYC-rearranged B-cell lymphomas in pediatrics (89%) and young adults (66%) were Burkitt lymphomas. Double-hit cytogenetics (MYC-rearranged with BCL2-rearranged or BCL6-rearranged high-grade B-cell lymphoma) was rare in the pediatric population (2%). Double-hit, high-grade B-cell lymphoma increased with age and was identified in 13% of young adult cases. Most double-hit, high-grade B-cell lymphomas had MYC and BCL6 rearrangements, while BCL2 rearrangements were rare in both groups (1%). MYC rearrangement without an IG partner was more common in the young adult group (12%) than in the pediatric group (2%; P = .001). The pediatric-to-young adult transition is characterized by decreasing frequency of Burkitt lymphoma and increasing genetic heterogeneity of MYC-rearranged B-cell lymphoma and the emergence of double-hit B-cell lymphoma with MYC and BCL6 rearrangements. The investigators concluded that FISH analysis to evaluate MYC, BCL2, and BCL6 rearrangements and MYC IG rearrangement partners is warranted in young adults with B-cell lymphoma.[27]

One report included 31 pediatric patients with diffuse large B-cell lymphoma, NOS. Most patients (n = 21) showed a germinal center phenotype, and the genomic alterations resembled those of adult germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) (e.g., SOCS1 and KMT2D variants). Among this group of patients, MYC rearrangements were detected in 3 patients, and 5 of 25 cases were EBV positive (4 with the activated B-cell phenotype).[22]

LBCL-IRF4 cases have a translocation that juxtaposes the IRF4 oncogene next to one of the IG loci.

In one report, diffuse large B-cell lymphoma cases with an IRF4 translocation were significantly more frequent in children than in adults with diffuse large B-cell lymphoma or follicular lymphoma (15% vs. 2%). One study of 32 pediatric cases of diffuse large B-cell lymphoma or follicular lymphoma found 2 (6%) with IRF4 translocations.[29] A second study of 34 cases of pediatric follicular lymphoma or diffuse large B-cell lymphoma found 7 cases (21%) with IRF translocations. Most of these cases occurred in the adolescent age range.[17]

LBCL-IRF4 cases are primarily germinal center–derived B-cell lymphomas. They commonly present with nodal involvement of the head and neck (particularly the Waldeyer ring) and less commonly in the gastrointestinal tract.[17,22,30-32]

LBCL-IRF4 shows strong IRF4 expression. In a study of 17 cases, the most frequently altered genes were CARD11 (35%) and CCND3 (24%).

LBCL-IRF4 appears to be a low stage at diagnosis and is associated with a favorable prognosis compared with diffuse large B-cell lymphoma cases lacking this abnormality.[17,22,30]

High-grade B-cell lymphoma, NOS, is a biologically heterogeneous disease. In a study of eight cases of pediatric high-grade B-cell lymphoma, NOS, four had variant profiles similar to that of Burkitt lymphoma (e.g., MYC rearrangements and variants in CCND3, ID3, and DDX3X).[22] The remaining cases lacked MYC rearrangements and had variant profiles closer to GCB-DLBCL (e.g., TNFRSF14, CARD11 and EZH2 variants), and lacked MYC translocations.