T-cell/histiocyte-rich diffuse large B-cell lymphoma constitutes approximately 1-3% of all DLBCL cases, characterized by scattered large B-cells within an extensive reactive T-cell infiltrate. This rare variant demonstrates unique biological features including frequent immune evasion mechanisms and resistance to standard immunochemotherapy. CD20 antigen loss following rituximab-containing regimens represents a well-recognized but uncommon immune escape phenomenon, occurring in approximately 10-20% of relapsed/refractory DLBCL cases.

A 64-year-old female presented in late 2024 with abdominal pain, weight loss, and constitutional symptoms. Imaging studies revealed para-aortic lymphadenopathy, and trucut biopsy demonstrated T-cell/histiocyte-rich DLBCL with immunohistochemical profile showing CD20(+), PAX5(+), MUM1(+), CD3(+) reactive T-cells, and negative CD30. The diagnosis was confirmed by the presence of scattered large B-cells within an extensive CD3+ T-cell background.

The patient received in outer clinic standard R-CHOP chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) for 6 cycles at an external center. Post-treatment PET-CT in March 2025 demonstrated complete metabolic response with no residual FDG uptake in previously involved lymph nodes (Deauville score 1-2).

Unfortunately, the patient developed early relapse within 3 months, presenting in June 2025 with left cervical lymphadenopathy, constitutional symptoms, and weight loss. Restaging PET-CT revealed extensive disease with left cervical lymph nodes (22 × 15 mm, SUVmax: 7.96), massive para-aortic/iliac mass (87 × 42 × 212 mm, SUVmax: 7.96), left lung parenchymal involvement, and diffuse bone marrow activity.

Bone marrow biopsy performed in July 2025 confirmed lymphomatous infiltration with a striking finding: complete loss of CD20 expression while maintaining PAX5(+) and MUM1(+) positivity, with persistent extensive reactive CD3+ T-cell infiltrate. This represented clear evidence of CD20 antigen loss as an immune escape mechanism following rituximab exposure.

Given the patient's cardiac dysfunction precluding anthracycline-containing regimens, early relapse with CD20 negativity, and extensive disease burden and according to Turkish insurance systems low dose pralatrexate planned to targeting the T-cell-rich microenvironment in refractory settings.

This case illustrates several critical aspects of TCRLBCL management. The rapid relapse despite initial complete response highlights the aggressive nature of this DLBCL variant and its propensity for immune escape. The complete loss of CD20 antigen represents a well-documented resistance mechanism whereby malignant B-cells evade rituximab-mediated cytotoxicity through antigen downregulation or loss.

The extensive reactive T-cell infiltrate characteristic of TCRLBCL may contribute to both immune surveillance and paradoxically provide a protective microenvironment for malignant cells. This unique tumor microenvironment necessitates novel therapeutic approaches targeting both malignant B-cells and the surrounding immune milieu.

The importance of re-biopsy at relapse cannot be overstated, as demonstrated by the critical finding of CD20 loss that fundamentally altered treatment planning from CD20-targeting to alternative approaches.