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Non-Hodgkin Lymphoma
Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract
Ferrata Storti Foundation
Haematologica 2020 Volume 105(7):1895-1906
Craig R. Soderquist,1 Nupam Patel,1 Vundavalli V. Murty,1 Shane Betman,1 Nidhi Aggarwal,2 Ken H. Young,3 Luc Xerri,4 Rebecca Leeman-Neill,1 Suzanne K. Lewis,5 Peter H. Green,5 Susan Hsiao,1 Mahesh M. Mansukhani,1 Eric D. Hsi,6 Laurence de Leval,7 Bachir Alobeid1 and Govind Bhagat1
1Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA; 2Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; 3Department of Hematopathology, MD Anderson Cancer Center, Houston, TX, USA; 4Department of Bio-Pathology, Institut Paoli- Calmettes, Aix-Marseille University, Marseille, France; 5Department of Medicine, Celiac Disease Center, Columbia University Irving Medical Center, New York Presbyterian Hospital, New York, NY, USA; 6Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH, USA and 7Institute of Pathology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
ABSTRACT
Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic sub- sets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we per- formed targeted next-generation sequencing and comprehensive immunophenotypic analysis of ten indolent T-cell lymphoproliferative dis- orders of the gastrointestinal tract, which comprised CD4+ (n=4), CD8+ (n=4), CD4+/CD8+ (n=1) and CD4-/CD8- (n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) of these lymphoproliferative disorders. The CD4+, CD4+/CD8+, and CD4-/CD8- cases harbored frequent alterations of JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant muta- tions in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8+ cases exhibited structural alterations involving the 3’ untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case was a harbinger of disease transformation. The CD4+ and CD4+/CD8+ lymphoproliferative disorders displayed heterogeneous Th1 (T-bet+), Th2 (GATA3+) or hybrid Th1/Th2 (T-bet+/GATA3+) profiles, while the majority of CD8+ disorders and the CD4-/CD8- disease showed a type- 2 polarized (GATA3+) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8+ cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and confirm the heterogeneous nature of these dis- eases. Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanis- tic studies to determine whether therapeutic targeting of this signaling cas- cade is efficacious for a proportion of patients with these recalcitrant dis- eases.
Introduction
Non-Hodgkin lymphomas frequently occur in the gastrointestinal (GI) tract, with the majority representing B-cell neoplasms.1–3 T-cell lymphomas account for 10-20% of all primary GI lymphomas.1–3 Aggressive lymphomas, including
Correspondence:
CRAIG SODERQUIST
crs2130@cumc.columbia.edu
GOVIND BHAGAT gb96@cumc.columbia.edu
Received: July 8, 2019.
Accepted: September 25, 2019. Pre-published: September 26, 2019.
doi:10.3324/haematol.2019.230961
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