Characterizing Nodal Gamma-Delta T-Cell Lymphoma: Clinicopathological and Molecular Insights

Peripheral T-cell lymphomas with gamma-delta phenotype (GDTCL) are rare lymphoid malignancies. Beyond the well-recognized entities of extranodal lymphomas with gamma-delta phenotype as defined by the fifth edition of the World Health Organization Classification of Hematolymphoid Tumors and 2022 International Consensus Classification, there is a group of poorly defined gamma-delta T-cell lymphomas with predominantly nodal presentation, termed as nodal GDTCL (nGDTCL). In this study, we present a series of 12 cases of Epstein-Barr virus-negative nGDTCL, highlighting the clinical, histopathological, and molecular features of this rare entity. Seven cases reported in the literature were included in the analysis. Of the 12 cases, nGDTCL shows an increased incidence in elderly men, with a median age of 65.5 years. All cases presented primarily with enlarged lymph nodes, and 4 cases (4/12, 33.3%) showed involvement of extranodal sites, including skin, liver, spleen, and bone marrow. Histologically, 9 cases showed a diffuse and monomorphic proliferation of mostly medium-to-large lymphoid cells, whereas 3 cases demonstrated lymphoepithelioid morphology. All cases (12/12, 100%) were positive for CD3 and TCRγδ. CD4, CD8, and CD56 were positive in 66.7% (8/12), 25% (3/12), and 8.3% (1/11) of cases, respectively. Most cases (8/12, 66.7%) showed a noncytotoxic phenotype. Using immunohistochemistry, the majority of cases (6/8, 75.0%) belonged to the peripheral T-cell lymphoma-GATA3 subtype with GATA3 and/or CCR4 expression and a noncytotoxic CD4-positive phenotype. Two cases (2/8, 25%) belonged to the peripheral T-cell lymphoma-TBX21 subtype, of which 1 displayed a cytotoxic CD8-positive phenotype. Next-generation sequencing was performed in 9 cases, and TP53 mutation was detected in 66.7% (6/9) of the cases. Mutations of ATM and KSR2 were identified in 2 cases each. It remains uncertain whether nGDTCL represents a distinct entity, and further studies are needed for better characterization. Nonetheless, nodal-based GDTCL should be distinguished from secondary nodal involvement by other extranodal GDTCL and Epstein-Barr virus-positive T/NK-cell lymphoproliferative diseases.