AIMS
Small cell carcinoma of the bladder (SmCCB) is a rare and aggressive malignancy that remains poorly defined. Using the transcriptional taxonomy established for small cell lung carcinoma (SCLC), we aimed to stratify SmCCB by dominant transcription factors and assess associations between IHC-defined phenotype, neuroendocrine differentiation and therapeutic biomarker expression.
METHODS AND RESULTS
A retrospective multi-institutional cohort of 88 SmCCBs was assembled. Of these, 79 cases underwent immunohistochemical characterization for ASCL1, NEUROD1, POU2F3, YAP1 and HNF4α, along with classical neuroendocrine markers, therapeutic biomarkers and antibody-drug conjugate targets. NECTIN4 amplification was also assessed by fluorescence in situ hybridization (FISH). Six IHC-defined subgroups were identified: ASCL1-driven (41.8%), NEUROD1-driven (25.3%), POU2F3-driven (20.3%), YAP1-driven (6.3%), mixed (5.1%) and full-negative (1.3%). ASCL1-driven, NEUROD1-driven and mixed tumours were classified as High-NE, with diffuse NE marker expression, whereas POU2F3-driven, YAP1-driven and full-negative tumours were classified as Low-NE, with weak or absent expression. Overall membranous Nectin-4 expression was low or absent but significantly higher in Low-NE tumours (P < 0.001). NECTIN4 amplification occurred in 21.9% (16/73), comparable to that reported in non-neuroendocrine urothelial carcinoma. Conversely, DLL3 and SLFN11 were significantly overexpressed in High-NE tumours, while expression of the remaining targets was almost entirely absent.
CONCLUSIONS
SmCCB may be stratified into two IHC-defined phenotypic groups with distinctive neuroendocrine differentiation and therapeutic biomarker profiles. Taken together, low membranous Nectin-4 expression and preferential DLL3 and SLFN11 expression in High-NE tumours support further investigation of alternative therapeutic strategies.
N. Tenace, M. Colecchia, A. Hartmann et al.· Histopathology· 0 citations
INTRODUCTION
Focal therapy (FT) in high-risk or very high-risk prostate cancer (CaP) is not guideline-recommended. However, it may be occasionally used, but its effect on cancer-specific mortality (CSM) relative to standard treatment options such as radical prostatectomy (RP) is unknown and was addressed in the present study.
METHODS
In the Surveillance, Epidemiology, and End Results (SEER) database (2010-2022), high-risk or very high-risk CaP patients according to the National Comprehensive Cancer Network (NCCN) guidelines, treated with either FT or RP, were identified. A multivariable logistic regression (MLR) model assessed the associations between sociodemographic characteristics and receipt of FT. Multivariable competing risks regression (CRR) models, after 1:1 propensity score matching (PSM), tested for CSM differences after adjustment for other cause mortality (OCM).
RESULTS
Overall, 20,192 high-risk or very high-risk CaP patients treated with FT or RP were identified. Of those, 416 (2.0%) underwent FT and 19,776 (98.0%) RP. In the MLR model, rural area of residence and unmarried status predicted a 2.4-fold (P < 0.001) and 1.8-fold (P < 0.001) higher likelihood of receiving FT, respectively. In PSM analysis, 416 FT patients could only be matched with one RP control from 19,776 RP patients. After 1:1 PSM, at 120 months of follow-up, CSM after RP was 9.2 vs. 16.0% after FT. The corresponding OCM rates were 19.5 after RP vs. 31.5% after FT. In multivariable CRR models adjusted for OCM, FT increased CSM in a 2.0-fold fashion (mHR: 1.98; 95% CI: 1.17-3.34; P = 0.011).
CONCLUSION
Despite lack of guidelines endorsement, occasional high-risk or very high-risk CaP patients may be treated with FT. Specifically, rural and unmarried patients with high-risk or very high-risk CaP are more likely to receive guideline-discordant FT. Such practice doubles the risk of CSM relative to RP, and its use should therefore be discouraged in this patient population.
L. Quarta, M. Petix, M. Filzmayer et al.· Urologic oncology· 0 citations
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