B lymphocytes and tertiary lymphoid structures have a prognostic impact on penile squamous cell carcinoma

Several prognostic markers, including tumor-infiltrating lymphocytes, which have been recently identified in penile squamous cell carcinoma (pSCC), have focused mostly on T cells. The prognostic role of B cells and tertiary lymphoid structures (TLSs) has not yet been sufficiently described. We examined whole tissue sections histopathologically for TLSs and immunohistochemically for CD20 and CD138. The B-cell immunoscore (B-IS) divided the cohort into five categories based on the expression of these two B-cell/plasma cell markers (CD20 and CD138, respectively). Patients with fewer TLSs had worse overall survival (OS) [hazard ratio (HR) = 2.17; 95% CI: 0.94-5; p = 0.069]. A significant association was identified between a high TLS diameter and the presence of a lymphocytic infiltrate [odds ratio (OR) = 2.2442; 95% CI: 1.1022-4.55; p = 0.0208]. Patients with low B-IS (HR = 1.89, 95% CI: 1.18-3.03, p = 0.008), a low number of CD20⁺ cells in the tumor center (HR = 1.67, 95% CI: 1.04-2.7, p = 0.035), and a low number of CD20⁺ cells at the tumor invasion front (HR = 1.69, 95% CI: 1.06-2.78; p = 0.028) had significantly worse OS. High B-ISs were strongly associated with a mutated p53 profile detected by immunohistochemistry (OR = 4.76, 95% CI: 1.32-25, p = 0.011), low T-cell immunoscores (OR = 0.49; 95% CI: 0.23-1.03; p = 0.051), and brisk lymphocytic infiltration (OR = 2.0417, 95% CI: 1.01-4.76; p = 0.037). High CD20⁺ cell counts at the invasion front were associated with histological grade 3 disease (OR = 2.44, 95% CI 1.15-5.26, p = 0.015). An association was also observed between low B-IS and mutations in KMT2D (OR 0.31, 95% CI: 0.07-1.21, p = 0.057) and EGFR (OR = ∞, 95% CI: 0.86-∞, p = 0.053). In conclusion, high numbers of tumor-infiltrating B cells within TLSs represent a favorable prognostic marker in pSCC. These findings emphasize the need to identify novel microscopic prognostic markers during pathological assessment to guide early and appropriate therapeutic strategies.