S100 expression and SDHB status define distinct biological subsets of bladder paraganglioma.

Bladder paraganglioma is an exceptionally rare neuroendocrine tumor with important diagnostic and prognostic implications. We retrospectively analyzed 110 bladder paragangliomas diagnosed between 2000 and 2025 to better characterize clinicopathologic features, immunophenotypic patterns, and clinical outcomes, with particular emphasis on S100, SOX10, and SDHB immunohistochemistry. The cohort showed a slight female predominance (F:M = 1.34) and a mean age at diagnosis of 62.7 years. Most tumors involved the muscularis propria, supporting a bladder wall origin. Among cases with available S100 staining, nearly half (48.5%) demonstrated diffuse, strong S100 expression in both chromaffin and sustentacular cells, an unusual pattern that frequently caused diagnostic confusion and was the reason for consultation. In contrast, SOX10 expression remained restricted to sustentacular cells in all tested tumors, underscoring its reliability as a Schwannian marker. Loss of SDHB expression was identified in 14.5% of tumors and was significantly associated with younger age, male sex, absence of diffuse S100 expression, and metastatic disease. All S100-positive tumors retained SDHB expression. Among patients with available follow-up, 20% developed metastatic disease, with a 5-year metastatic rate of 38.5%; most metastatic tumors showed SDHB loss and were S100-negative. No paraganglioma-related deaths were documented. These findings demonstrate that diffuse S100 positivity in bladder paraganglioma is relatively common and represents a significant diagnostic pitfall. Importantly, S100-positive tumors appear to be associated with intact SDHB expression and a potentially less aggressive phenotype, whereas SDHB loss identifies a higher-risk subset with increased metastatic potential.