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1636 Refining Diagnostic Subtypes of Peripheral T-Cell Lymphoma Using a Multiparameter Approach

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational – Molecular and Genetic: Poster I
Hematology Disease Topics & Pathways:
Research, Translational Research, Lymphomas, T Cell lymphoma, Diseases, Lymphoid Malignancies
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Catalina Amador, MD1*, Dennis D Weisenburger, MD2*, Ana Gomez, MD3*, Alyssa Bouska, PhD4*, Francisco Vega, MD, PhD5, James R. Cook, MD, PhD6, Timothy C. Greiner, MS, MD2*, Andrew L. Feldman, MD7, Elaine S. Jaffe, MD8, Sarah L. Ondrejka, DO6, German Ott, MD9*, Neval Ozkaya, MD10*, Phil Raess, MD, PhD11*, Andreas Rosenwald, MD12*, Kerry J. Savage, MD, MSc, BSc13, Graham Slack, MD14*, Joo Y. Song, MD15, Lisa M. Rimsza, MD16, Wing C. Chan, MD17 and Javeed Iqbal, PhD, MSc2*

1Department of Pathology and Laboratory Medicine, University of Miami, Miami, FL
2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
3University of Miami, Miami, FL
4Department of Pathology and Microbiology, University of Nebraska Medical Center, OMAHA, NE
5Department of Hematopathology, MD Anderson Cancer Center , Houston, TX
6Department of Laboratory Medicine, Cleveland Clinic, Cleveland, OH
7Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN
8CCR Lab of Pathology, National Cancer Institute, Bethesda, MD
9Department of Clinical Pathology, Robert-Bosch-Krankenhaus, and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany
10Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, Bethesda, MD
11Department of Pathology and Laboratory Medicine, Oregon Health & Science University, Portland, OR
12Institute of Pathology, Julius-Maximilians-Universität Würzburg, Wuerzburg, Germany
13Division of Medical Oncology, BC Cancer, Vancouver, BC, Canada
14BC Cancer, Vancouver, BC, CAN
15Beckman Research Institute, City of Hope, Duarte, CA
16Mayo Clinic Scottsdale, Scottsdale, AZ
17Department of Pathology, City of Hope National Medical Center, Duarte, CA

Peripheral T-cell lymphoma (PTCL) encompasses a diverse group of post-thymic lymphomas, with ~40% of cases not further classifiable and designated as PTCL-not otherwise specified (PTCL-NOS). Two molecular prognostic subtypes of PTCL-NOS, PTCL-TBX21 and PTCL-GATA3, were identified through gene expression profiling (GEP). A subset of PTCL-NOS with T-follicular helper (TFH) differentiation was subsequently categorized as nodal PTCL with TFH phenotype (PTCL-TFH), also known in current classifications as nodal PTCL-TFH, NOS, or TFH lymphoma, NOS. However, the boundary between PTCL-NOS and PTCL-TFH remains poorly defined. To refine these subtypes, 101 PTCL-NOS with centralized pathology review and extensive immunophenotyping by immunohistochemistry (IHC) using 22 antibodies, digital GEP (nCounter, NanoString Inc) (n= 70), and RNA sequencing (n= 73) were included in this study. IHC was used to identify PTCL-TFH cases (those with strong expression of more than two TFH markers); the remaining patients were classified as PTCL-GATA3 and PTCL-TBX21 using pre-defined GEP signatures.

Cases were reclassified into PTCL-NOS (n= 63) and PTCL-TFH (n= 38), with PTCL-NOS subclassified into PTCL-GATA3 (n= 22; 34%) and PTCL-TBX21 (n= 41; 66%) and showing significant differences in OS (p<0.001). PTCL-GATA3 was characterized by medium to large transformed cells (average= 90%, 70-100%) and had minimal tumor microenvironment (TME) (TME-poor: 100%). In contrast, PTCL-TBX21 was more heterogeneous, associated with pleomorphic cells in a polymorphous background (TME-rich: 78%), including Lennert lymphoma-like cases (22%). mRNA and CIBERSORT analysis substantiated the findings and identified a subset enriched in cytotoxic features in the PTCL-TBX21 subtype.

IHC indicated that PTCL-GATA3 cases were CD4+/CD8- (83%) or CD4-/CD8- (17%) and lacked expression of CD8 or cytotoxic markers compared to PTCL-TBX21 (p<0.01). PTCL-GATA3 showed significantly higher expression of LEF1 (average= 80%), Ki67 (80%), and MYC (25%) than PTCL-TBX21 (25%, 30%, <5%, respectively, p<0.01). mRNA and protein expression of these biomarkers showed a significant positive correlation (r=0.5, p<0.001), and expectedly higher mRNA expression of LEF1 and MYC was observed in the PTCL-GATA3 versus PTCL-TBX21 (p<0.05). Strong expression of CD30 (>50% of cells) was only seen in PTCL-GATA3 cases. EBER positivity, found only in rare background cells, was not significantly different (18% of PTCL-GATA3 vs. 12% of PTCL-TBX21).

Within PTCL-TBX21, we identified cytotoxic and non-cytotoxic subsets with divergent morphological, phenotypic, and clinical findings. The cytotoxic PTCL-TBX21 exhibited an activated cytotoxic phenotype (23/25, 96%), denoted by TIA1 and granzyme-B and/or perforin expression. Extranodal involvement and single-cell apoptosis were observed in 17% and 45% of the cytotoxic cases, respectively, but absent in non-cytotoxic PTCL-TBX21 cases. A trend towards higher Ki67 expression (average= 40% vs. 20%, p= 0.08) was seen in the cytotoxic subgroup. In contrast, the non-cytotoxic PTCL-TBX21 was associated with a CD4+/CD8- phenotype and higher ICOS expression (average= 30%) and CCR4 (60%) compared to the cytotoxic PTCL-TBX21 (p= 0.001).

PTCL-TFH cases showed a CD4+/CD8- phenotype (90%) and rarely a CD4-/CD8- phenotype (10%). While a subset of PTCL-TFH cases had AITL-like features such as numerous clear cells and/or prominent vasculature (31% of cases), which were not seen in the other subgroups, the remaining cases exhibited morphology that was indistinguishable from other PTLC-NOS cases including sheets of transformed cells or pleomorphic cells in a polymorphous background. Morphologically, PTCL-TFH cases, like PTCL-TBX21 were associated with a rich TME (TME-rich: 75%). CIBERSORT analysis showed enrichment of plasma cells (p<0.01) in PTCL-TFH, compared to PTCL-TBX21, and validated by morphology (30% of cases vs. 5%). Expression of one TFH marker was frequent in some PTCL-NOS cases (PTCL-GATA3= 41% of cases, PTCL-TBX21-non cytotoxic= 47%, PTCL-TBX21-cytotoxic= 5%).

Conclusion: Our comprehensive evaluation underscores the importance of integrating morphology, immunophenotyping, and GEP in achieving an accurate diagnosis, potentially leading to more tailored treatment strategies for PTCL. Correlation with pending whole-exome sequencing studies will be provided at the time of presentation.

Disclosures: Vega: Allogene: Research Funding; Geron: Research Funding. Savage: Roche: Research Funding; Seagen: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding. Rimsza: Roche: Other: Consulting; NanoString: Other: Licensed intellectual property.

*signifies non-member of ASH