The aims of the present exploratory investigation were to analyze: (I) the concordance between LSCC biopsies and paired surgical specimens in terms of characterization of TSR, stroma type, large cell nests and tumor budding; (II) the association between TSR, PD-L1 expression and other clinical–pathological features; (III) the prognostic and predictive role of TSR and PD-L1 in a consecutive series of LSCC. The gene discussed is CD274; the disease is neoplasm.