Abstract
AbstractPeripheral T-cell lymphoma (PTCL) is a heterogeneous group of mature T-cell malignancies; approximately one-third of cases are designated as PTCL–not otherwise specified (PTCL-NOS). Using gene-expression profiling (GEP), we have previously defined 2 major molecular subtypes of PTCL-NOS, PTCL-GATA3 and PTCL-TBX21, which have distinct biological differences in oncogenic pathways and prognosis. In the current study, we generated an immunohistochemistry (IHC) algorithm to identify the 2 subtypes in paraffin tissue using antibodies to key transcriptional factors (GATA3 and TBX21) and their target proteins (CCR4 and CXCR3). In a training cohort of 49 cases of PTCL-NOS with corresponding GEP data, the 2 subtypes identified by the IHC algorithm matched the GEP results with high sensitivity (85%) and showed a significant difference in overall survival (OS) (P = .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n = 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P = .003). In multivariate analysis, a high International Prognostic Index score (3-5) and the PTCL-GATA3 subtype identified by IHC were independent adverse predictors of OS (P = .0015). Additionally, the 2 IHC-defined subtypes were significantly associated with distinct morphological features (P < .001), and there was a significant enrichment of an activated CD8+ cytotoxic phenotype in the PTCL-TBX21 subtype (P = .03). The IHC algorithm will aid in identifying the 2 subtypes in clinical practice, which will aid the future clinical management of patients and facilitate risk stratification in clinical trials.
Highlights
Our geneexpression profiling (GEP) study suggested that PTCLTBX21 contains a subset with a high cytotoxic signature, which shows a worse clinical outcome than the rest of the PTCLTBX21.7,8 These studies suggest the cell of origin (TH1 or T-helper 2 (TH2)) of these subtypes, but these data need to be interpreted cautiously due to the plasticity associated with T-cell differentiation.[21]
Our additional studies have provided further evidence that these 2 groups are dependent on distinct genetic pathways and are characterized by enrichment of distinct oncogenic pathways, with peripheral T-cell lymphomas (PTCL)-GATA3 significantly associated with phosphatidylinositol 3-kinase (PI3K)–mammalian target of rapamycin activation and PTCL-TBX21 showing NF-kB activation.[7,8,22]
The training cohort included 49 cases that were used in previous GEP studies[7,8,9] and were molecularly classified as PTCL-GATA3 (n 5 14) and PTCL-TBX21 (n 5 26), and showed the expected difference in overall survival (OS)
Summary
Several studies have attempted to identify the clinical and pathologic features of prognostic importance in PTCL-NOS, but the findings have been inconsistent.[10,11,12,13,14,15] Through extensive geneexpression profiling (GEP) studies, we have defined robust molecular signatures for the major subtypes of PTCL.[7,8,9] These studies have led to the identification of 2 novel biological and prognostic subtypes within PTCL-NOS,[7,8] which are alluded to in the recent update of the WHO classification of lymphoid neoplasms.[1,16] One subtype, representing 33% of PTCL-NOS,[7] is characterized by high expression of GATA3 and its target genes. GATA3 is the master transcriptional regulator in T-helper 2 (TH2) cell differentiation and regulates interleukin-4 (IL-4), IL-5, and IL-13 expression.[17] The other subtype, representing 49% of PTCL-NOS,[7] is characterized by high expression of TBX21 and its target genes. Our additional studies have provided further evidence that these 2 groups are dependent on distinct genetic pathways and are characterized by enrichment of distinct oncogenic pathways, with PTCL-GATA3 significantly associated with phosphatidylinositol 3-kinase (PI3K)–mammalian target of rapamycin (mTOR) activation and PTCL-TBX21 showing NF-kB activation.[7,8,22]
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