Reproducing the molecular subclassification of peripheral T-cell lymphoma–NOS by immunohistochemistry

open30siJ.I. and W.C.C. were supported by UH2/UH31UH2CA206127, STTR 1R41CA221466, and POI 1P01CA229100 from the National Institutes of Health National Cancer Institute, and National Cancer Institute Eppley Cancer Center Support grant P30CA036727. W.C.C. was supported by National Cancer Institute Specialized Program of Research Excellence (SPORE) 2P50CA107399-11A1, and City of Hope Cancer Center Support grant P30 CA033572. A.L.F. was supported in part by P50 CA97274 from the National Cancer Institute. S.T.L. and C.K.O. were supported by research funding from the Singapore Ministry of Health’s National Medical Research Council, the Tanoto Foundation, New Century Foundation Pte Ltd, the Ling Foundation, the Singapore National Cancer Centre Research Fund, and the Oncology Academic Clinical Program (ONCO ACP) Cancer Collaborative Scheme.Peripheral 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 5 .03). The IHC algorithm classification showed high interobserver reproducibility among pathologists and was validated in a second PTCL-NOS cohort (n 5 124), where a significant difference in OS between the PTCL-GATA3 and PTCL-TBX21 subtypes was confirmed (P 5 .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 5 .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 CD81 cytotoxic phenotype in the PTCL-TBX21 subtype (P 5 .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.openAmador C.; Greiner T.C.; Heavican T.B.; Smith L.M.; Galvis K.T.; Lone W.; Bouska A.; D'Amore F.; Pedersen M.B.; Pileri S.; Agostinelli C.; Feldman A.L.; Rosenwald A.; Ott G.; Mottok A.; Savage K.J.; de Leval L.; Gaulard P.; Lim S.T.; Ong C.K.; Ondrejka S.L.; Song J.; Campo E.; Jaffe E.S.; Staudt L.M.; Rimsza L.M.; Vose J.; Weisenburger D.D.; Chan W.C.; Iqbal J.Amador C.; Greiner T.C.; Heavican T.B.; Smith L.M.; Galvis K.T.; Lone W.; Bouska A.; D'Amore F.; Pedersen M.B.; Pileri S.; Agostinelli C.; Feldman A.L.; Rosenwald A.; Ott G.; Mottok A.; Savage K.J.; de Leval L.; Gaulard P.; Lim S.T.; Ong C.K.; Ondrejka S.L.; Song J.; Campo E.; Jaffe E.S.; Staudt L.M.; Rimsza L.M.; Vose J.; Weisenburger D.D.; Chan W.C.; Iqbal J