TY - JOUR
T1 - Reproducing the molecular subclassification of peripheral T-cell lymphoma–NOS by immunohistochemistry
AU - on behalf of the Lymphoma/Leukemia Molecular Profiling Project
AU - Amador, Catalina
AU - Greiner, Timothy C.
AU - Heavican, Tayla B.
AU - Smith, Lynette M.
AU - Galvis, Karen Tatiana
AU - Lone, Waseem
AU - Bouska, Alyssa
AU - D’Amore, Francesco
AU - Pedersen, Martin Bjerregaard
AU - Pileri, Stefano
AU - Agostinelli, Claudio
AU - Feldman, Andrew L.
AU - Rosenwald, Andreas
AU - Ott, German
AU - Mottok, Anja
AU - Savage, Kerry J.
AU - de Leval, Laurence
AU - Gaulard, Philippe
AU - Lim, Soon Thye
AU - Ong, Choon Kiat
AU - Ondrejka, Sarah L.
AU - Song, Joo
AU - Campo, Elias
AU - Jaffe, Elaine S.
AU - Staudt, Louis M.
AU - Rimsza, Lisa M.
AU - Vose, Julie
AU - Weisenburger, Dennis D.
AU - Chan, Wing C.
AU - Iqbal, Javeed
N1 - Funding Information:
1Department of Pathology and Microbiology and 2Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE; 3Department of Pathology and Laboratory Medicine, Fundacion Santa Fe de Bogota University Hospital, Bogota, Colombia; 4Department of Hematology, Aarhus University Hospital, Aarhus, Denmark; 5European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Milan, Italy; 6Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy; 7Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic, Rochester, MN; 8Institute of Pathology and 9Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany; 10Department of Clinical Pathology and 11Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Robert-Bosch-Krankenhaus, Stuttgart, Germany; 12Center for Lymphoid Cancer, British Columbia Cancer Agency, Vancouver, BC, Canada; 13Institute of Human Genetics, Ulm University/University Medical Centre, Ulm, Germany; 14Institute of Pathology, Lausanne University Hospital, Lausanne, Switzerland; 15Département de Pathologie, Hôpital Henri-Mondor, Université Paris-Est, INSERM U955, Créteil, France; 16Division of Medical Oncology, National Cancer Centre Singapore/Duke–National University of Singapore (NUS) Medical School, Singapore; 17Department of Pathology, Cleveland Clinic, Cleveland, OH; 18Department of Pathology, City of Hope National Medical Center, Duarte, CA; 19Hematopathology Unit, Hospital Clinic, Barcelona, Spain; 20Institute of Biomedical Research August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; 21Laboratory of Pathology and 22Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; 23Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ; and 24Division of Hematology and Oncology, University of Nebraska Medical Center, Omaha, NE
Funding Information:
The authors thank Lijun Sun at University of Nebraska Medical Center (UNMC) and Aimin Li at City of Hope (COH) for optimization of the immunostains, the Tissue Science Facility of UNMC and Mayo Clinic for performance of the immunostains, and Maarja-Liisa Nairism?gi and Chee Leong Cheng for preparing the TMA and samples at Singapore General Hospital. J.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.
Funding Information:
J.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.
Publisher Copyright:
© 2019 American Society of Hematology. All rights reserved.
PY - 2019/12/12
Y1 - 2019/12/12
N2 - 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.
AB - 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.
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U2 - 10.1182/blood.2019000779
DO - 10.1182/blood.2019000779
M3 - Article
C2 - 31562134
AN - SCOPUS:85076253508
SN - 0006-4971
VL - 134
SP - 2159
EP - 2170
JO - Blood
JF - Blood
IS - 24
ER -