Subcutaneous panniculitis-like T-cell lymphoma in two unrelated individuals with BENTA disease

Abstract

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare primary cutaneous non-Hodgkin lymphoma involving CD8⁺ T cells, the genetic underpinnings of which remain incompletely understood. Here we report two unrelated patients with B cell Expansion with NF-κB and T cell Anergy (BENTA) disease and a novel presentation of SPTCL. Patient 1 presented early in life with recurrent infections and B cell lymphocytosis, linked to a novel gain-of-function (GOF) CARD11 mutation (p.Lys238del). He developed SPTCL-like lesions and membranoproliferative glomerulonephritis by age 2, treated successfully with cyclosporine. Patient 2 presented at 13 months with splenomegaly, lymphadenopathy, and SPTCL with evidence of hemophagocytic lymphohistiocytosis. Genetic analysis revealed two in cis germline GOF CARD11 variants (p.Glu121Asp/p.Gly126Ser). Autologous bone marrow transplant resulted in SPTCL remission despite persistent B cell lymphocytosis. These cases illuminate an unusual pathological manifestation for BENTA disease, suggesting that CARD11 GOF mutations can manifest in cutaneous CD4⁺and CD8⁺ T cell malignancies.

Keywords: B cell lymphocytosis; BENTA; CARD11; Lobular panniculitis; SPTCL.

Figure 1.

Clinical presentation of two unrelated children with SPTCL and B cell lymphocytosis, harboring novel heterozygous CARD11 GOF variants. (A) Subcutaneous nodules (black arrows) on back of Patient 1. (B) PET imaging of Patient 2 using fluoro-deoxyglucose (FDG, 555MBq) with CT demonstrating extensive areas of subcutaneous thickening and induration with abnormal moderate hypermetabolic activity before transplant (left), with complete resolution achieved post-HSCT (right). (C) Enhanced CT of Patient 2 demonstrating prominent soft tissue density and stranding within the subcutaneous fat pre-HSCT (top), which resolved post-HSCT (bottom). (D) Patient 1: Immunohistochemical staining of skin biopsy for CD3⁺ TIA1⁺ atypical neoplastic T cells (brown, 40x magnification), plus immunofluorescence of kidney biopsy showing IgG deposition in the glomerulus. (E) Patient 2: immunohistochemical staining of skin biopsy showing infiltration of neoplastic CD3⁺CD8⁺ granzyme B⁺ cytotoxic T cells (brown, 20x). (F) Absolute cell counts for peripheral blood lymphocyte subsets since initial diagnosis; gray zone delineates normal ranges for age-matched individuals (19). (G) Schematic of CARD11 protein: variants highlighted for each patient. (H-I) Top; Representative histograms depicting NF-κB-driven GFP MFI in JPM50.6 cells transfected with empty vector (EV), wild-type (WT) or mutant CARD11-FLAG expression constructs in the absence (H) or presence of WT CARD11-V5 (I), −/+ anti-CD3/CD28 stimulation. Numbers represent %GFP⁺ cells. Middle; Bar graphs of GFP MFI −/+ SEM (n=3); asterisks denote statistical significance vs. WT (H) or WT+WT (I) (p < 0.01). Bottom; Representative western blots showing comparable expression of CARD11-FLAG protein for each plasmid without (H) or with (I) WT CARD11-V5; β-actin serves as a loading control.