Real-World Experience With TRBC1 Immunohistochemistry Across Cutaneous T-Cell Lymphoma Subtypes:A Large Cohort Study

T-cell receptor beta-chain constant region 1 (TRBC1) immunohistochemistry (IHC) identifies clonal αβ T-cell populations on tissue sections, but its real-world performance across cutaneous T-cell lymphoma (CTCL) and related infiltrates is uncharacterized. The analytic cohort comprised 665 biopsies (566 patients) with paired T-cell receptor (TCR) clonality testing, classified clinicopathologically as mycosis fungoides (MF-Patch, MF-Plaque, MF-Tumor, MF-Folliculotropic), MF/Sézary syndrome, primary cutaneous small/medium T-cell lymphoproliferative disorder, other CTCL-cutaneous lymphoproliferative disorder, or reactive. At the primary <15%/>85% threshold, TRBC1 IHC achieved 85.8% sensitivity (337/393), 79.8% specificity (217/272), 86.0% positive and 79.5% negative predictive value, and 83.3% accuracy, lowest in MF-Patch (84.2%). Three-reader agreement (Fleiss' κ = 0.943) fell to κ = 0.776 in 176 reflexed biopsies, with disagreement concentrated in MF-Patch and CD30-positive lymphoproliferative disorders. Monotypic TRBC1 predicted neoplasia, with odds rising with infiltrate density: MF-Patch (odds ratio 5.41), MF-Plaque (10.40), MF/Sézary syndrome with MF-Tumor (15.19), and CTCL-cutaneous lymphoproliferative disorder (18.16). Polytypic TRBC1 was associated with reactive disease (odds ratio 53.65), effectively excluded clonality (negative likelihood ratio 0.18); and was uniformly observed in an independent 270-biopsy reactive cohort. For observer-independent validation, digital image analysis-derived TRBC1 quantification (QuPath) was applied to a stratified random subset of 250 biopsies representative of the cohort's tumor-burden distribution. The digital read tracked molecular clonality (85.1% sensitivity, 80.1% specificity against TCR; area under the curve 0.842) and agreed with the dermatopathologist manual read in 87.6% of cases (κ = 0.752), with the data-derived cutoff matching the pre-specified <15%/>85% threshold. Discordance was directional for both manual scoring and digital quantification: in MF-Patch, 25/38 (65.8%) and 12/17 (70.6%) cases were polytypic with monoclonal TCR (false-negative-dominant); in reactive biopsies, 34/45 (75.6%) and 19/20 (95%) were monotypic with polyclonal TCR (false-positive-dominant). These findings support a TRBC1-first approach, reserving reflex TCR testing for borderline expression or clinicopathologic discordance, preserving diagnostic accuracy while reducing molecular testing and reimbursement-based costs.