Prognostic Value of Tumor-Infiltrating TIA-1+ Cytotoxic T Cells (TIA1-CTCs) and FOXP3+ Regulatory T Cells (Tregs) in Post-Transplant Lymphoproliferative Disorder (PTLD) Following Solid Organ Transplant (SOT).

Background: PTLD is a rare, often fatal, complication of SOT. Several studies have identified clinical prognostic factors in PTLD. However, no published studies to our knowledge have yet correlated outcome with the number (#) or type of tumor infiltrating T-cells, which in other types of lymphoma may have prognostic value. We hypothesized that tumor infiltrating T-cells, including TIA1-CTCs and Tregs, would predict survival in SOT PTLD.

Methods: We searched the Cleveland Clinic pathology archives for SOT patients (pts), who were diagnosed with PTLD between 1987 and 2007; reviewed the medical records and extracted clinical information and outcomes; performed immunohistochemical (IHC) studies for CD3, TIA-1, and FOXP3; and analyzed the data by Cox proportional univariate and multivariate analyses.

Results: We identified 62 SOT pts (heart, 22; lung, 17; kidney 15; liver, 7; pancreas, 1), who were diagnosed with PTLD at median age of 51 years (range 7–73). The median time from SOT to PTLD was 1.8 years (range 0.2–20.9). 1^st therapeutic intervention (1^st TI) (usually >1) included “complete” resection (4), decreased immunosuppression (51), acyclovir or gancyclovir (32), rituximab (R) (18), “CHOP” chemotherapy (11), radiation therapy (7), and interferon (4). Response to 1^st TI was CR (34) or PR (10). The median follow-up among surviving pts is 3.6 years (range 0.1–11.7). 35 (including 4 CHOP and 9 R) pts have died; only 2 CHOP but all 9 R pts died from PTLD. IHC studies in 42 evaluable cases showed the following median # (and range) of cells /10 hpf: CD3 525 (8–2451), TIA1-CTCs 304 (6–1238) and FOXP3 13 (1–338). On univariate analysis, younger age, prior rejection episodes <2, PS <2, LDH normal, extranodal sites (ENS) <2, IPI <4, 1^st TI >1, 1^st TI with CHOP, # of CD3 cells >550/10 hpf, and # of TIA1-CTCs >300/10 hpf were associated with an improved overall survival (OS), PTLD-specific survival (PSS), and/or progression-free survival (PFS). On multivariate analyses, only PS <2, ENS <2, and 1^st TI with CHOP remained independent predictors of outcome. Among the subset of 47 pts with monomorphic B-cell (MMBC) PTLD, these same clinical factors were also independently statistically significant.

Conclusions: High #s of infiltrating T cells and TIA1-CTCs are associated with a favorable outcome and may reflect a relatively intact local anti-tumor response. Tregs, which may potentially antagonize such a response, are uniformly low and do not correlate with outcome in PTLD. In this analysis, a significant minority of SOT pts treated initially with single agent R still died from PTLD while pts treated initially with CHOP (with or without R) appeared to have a better outcome, arguing for its early use - at least in a subset of pts. Future studies should attempt to identify biological factors that predict which MMBC PTLD pts might benefit from the addition of CHOP to standard R as part of 1^st TI.