CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study

Abstract

CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ∼14% of DLBCL patients. Patients with CD30(+) DLBCL had superior 5-year overall survival (CD30(+), 79% vs CD30(-), 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor κB activation and lymphocyte survival, and downregulation of genes encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30(+) DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30(+) DLBCL as a distinct subgroup of DLBCL.

Figure 1

Morphology and immunophenotype of CD30⁺ de novo DLBCL. (A-D) A case of CD30⁺ DLBCL of the GCB subtype (panel A, H&E; panel B, CD30; panel C, CD10; and panel D, EBER in situ hybridization). (E-H) A case of CD30⁺ DLBCL of the ABC subtype (panel E, H&E; panel F, CD30; panel G, CD10; and panel H, MUM1). (I-L) A case of CD30⁺EBV⁺ DLBCL (panel I, H&E; panel J, CD30; panel K, CD10; and panel L, EBER in situ hybridization). Original magnification ×1000 (A,E,I) and ×500 (all others).

Figure 2

Prognostic impact of CD30 expression in de novo DLBCL. (A-B) OS (A) and PFS (B) of patients with CD30⁺ vs CD30^– DLBCL in the training set. (C) OS of patients with CD30⁺ vs CD30^– DLBCL in the validation set. These patients were part of an independent cohort of 442 patients with available survival information (supplementary Table 1). (D) OS of patients with CD30⁺ vs CD30^– DLBCL in combined training and validation sets.

Figure 3

Prognostic impact of CD30 expression in COO subtypes of DLBCL. (A-B) OS (A) and PFS (B) of patients with CD30⁺ DLBCL of the GCB subtype in the training set. (C) OS of patients with CD30⁺ DLBCL of the GCB subtype in the combined training and validation sets. (D-E) OS (D) and PFS (E) of patients with CD30⁺ DLBCL of the ABC subtype in the training set. (F) OS of patients with CD30⁺ DLBCL of the ABC subtype in the combined training and validation sets.

Figure 4

Gene expression profiles and GSEA analysis of CD30⁺ vs CD30^– DLBCL. (A) Comparison of gene expression profiles between CD30⁺ and CD30^– DLBCL. (B) GSEA for differentially expressed genes of cytokine and TNFR pathways was performed on Kyoto Encyclopedia of Genes and Genomes pathway gene sets using all the probe sets that are associated with a known gene. The gene sets with a false discovery rate q value <0.05 after performing 1000 permutations were considered to be significantly enriched.

Figure 5

Prognostic impact of concurrent EBV infection in CD30⁺ DLBCL. (A) OS of all CD30⁺EBER⁺ vs all CD30⁺EBER^– DLBCL patients. Age range, 52 to 91 for EBV⁺ group; 16 to 84 for EBV^– group. (B) OS of CD30⁺EBER⁺ vs CD30⁺EBER^– DLBCL patients in >60-year-old age group. Median age, 73 for EBV⁺ group; 70 for EBV^– group. (C) OS of CD30⁺EBV⁺ DLBCL patients in >50-year-old age group vs CD30⁺EBV^– DLBCL in >60-year-old age group. Median age, 70 for both groups.