Histological Evaluation of Tertiary Lymphoid Structures Predicts Prognosis in Upper Tract Urothelial Carcinoma: A...

Tertiary lymphoid structures (TLSs) are unencapsulated, ectopic lymphoid aggregates that arise in nonlymphoid tissues under chronic inflammation and reflect local antitumor immune responses. However, their prognostic significance in upper tract urothelial carcinoma (UTUC) remains largely unclear.

A retrospective cohort of 174 UTUC patients undergoing radical nephroureterectomy was studied. TLS was defined on hematoxylin and eosin staining as a discrete, dense, follicle-like lymphoid aggregate that lacked a surrounding capsule. TLS identification was further confirmed by immunohistochemistry, showing dense CD20⁺ B-cell aggregates with an adjacent CD3⁺ T-cell zone. TLS characteristics were then systematically assessed, including spatial location (intratumoral and peritumoral), TLS density, hotspot count, and maximal diameter. Cox proportional hazards models were used to evaluate associations between TLS metrics and 6 outcomes: overall survival (OS), cancer-specific survival (CSS), bladder recurrence-free survival (BRFS), contralateral recurrence-free survival (CRFS), metastasis-free survival (MFS), and disease-free survival (DFS). Nomograms for OS and BRFS were developed and internally validated using C-index, calibration, and decision curve analysis.

TLSs were identified in 80 of 174 patients (46.0%). The median follow-up duration was 76 months (range: 4-171 months). The numbers of events were 37/174 (21.3%) for OS, 47/174 (27.0%) for CSS, 77/174 (44.3%) for DFS, 39/174 (22.4%) for MFS, 37/174 (21.3%) for BRFS, and 7/174 (4.0%) for CRFS. TLS presence was independently associated with improved OS (hazard ratios [HR] = 0.367, 95% confidence interval [CI] 0.208-0.648) and CSS (HR = 0.327, 95% CI 0.169-0.631). Higher TLS hotspot counts were independently associated with prolonged BRFS (HR = 0.658, 95% CI 0.484-0.895). Kaplan-Meier analyses showed significantly better outcomes for TLS-positive versus TLS-negative patients for OS (P = .0056), CSS (P = .0095), and BRFS (P = .028). Internally validated nomograms were constructed for OS (optimism-corrected C-index = 0.742), outperforming the TNM staging (C-index = 0.662), and for BRFS (optimism-corrected C-index = 0.642), also exceeding TNM staging (C-index = 0.465).

TLSs serve as accessible prognostic indicators in UTUC. Incorporation of TLSs into nomogram models significantly improves survival prediction and helps postoperative risk stratification. As this study involved internal model development, prospective external validation in a larger cohort is warranted.