Small cell carcinomas (SMC) of the lung are now molecularly classified based on the expression of transcriptional regulators (NEUROD1, ASCL1, POU2F3, YAP1) and DLL3, which has emerged as an investigational therapeutic target. PLCG2 has been shown to identify a distinct subpopulation of lung SMC with stem cell-like and pro-metastasis features and poor prognosis. We analyzed the expression of these novel neuroendocrine markers and their association with traditional neuroendocrine markers and patient outcomes in a cohort of bladder neuroendocrine carcinoma (NEC) consisting of 103 SMC and 19 large cell neuroendocrine carcinomas (LCNEC) assembled in tissue microarrays. Co-expression patterns were assessed and integrated with detailed clinical annotation including overall (OS) and recurrence free survival (RFS) and response to neoadjuvant/adjuvant chemotherapy. We identified five distinct molecular subtypes in bladder SMC based on expression of ASCL1, NEUROD1 and POU2F3: ASCL1+/NEUROD1- (n=33; 34%), ASCL1-/NEUROD1+ (n=21; 21%), ASCL1+/NEUROD1+ (n=17; 17%), POU2F3+ (n=22, 22%), and ASCL1-/NEUROD1-/POU2F3- (n=5, 5%). POU2F3+ tumors were mutually exclusive with those expressing ASCL1 and NEUROD1 and exhibited lower expression of traditional neuroendocrine markers. PLCG2 expression was noted in 33 tumors (32%) and was highly correlated with POU2F3 expression (p < 0.001). DLL3 expression was high in both SMC (n=72, 82%) and LCNEC (n=11, 85%). YAP1 expression was enriched in non- neuroendocrine components and negatively correlated with all neuroendocrine markers. In patients without metastatic disease who underwent radical cystectomy, PLCG2+ or POU2F3+ tumors had shorter RFS and OS (p<0.05), but their expression was not associated with metastasis status or response to neoadjuvant/adjuvant chemotherapy. In conclusion, NEC of the bladder can be divided into distinct molecular subtypes based on the expression of ASCL1, NEUROD1 and POU2F3. POU2F3 expressing tumors represent an ASCL1/NEUROD1-negative subset of bladder NEC characterized by lower expression of traditional neuroendocrine markers. Marker expression patterns were similar in SMC and LCNEC. Expression of PLCG2 and POU2F3 was associated with shorter recurrence-free and overall survival. DLL3 was expressed at high levels in both SMC and LCNEC of the bladder, nominating it as a potential therapeutic target.
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2024 Jul 02 [Epub ahead of print]
Dilara Akbulut, Karissa Whiting, Min-Yuen Teo, Jacob E Tallman, Gamze Gokturk Ozcan, Merve Basar, Liwei Jia, Jie-Fu Chen, Judy Sarungbam, Ying-Bei Chen, Anuradha Gopalan, Samson W Fine, Satish K Tickoo, Rohit Mehra, Marina Baine, Bernard H Bochner, Eugene J Pietzak, Dean F Bajorin, Jonathan E Rosenberg, Gopa Iyer, David B Solit, Victor E Reuter, Natasha Rekhtman, Irina Ostrovnaya, Hikmat Al-Ahmadie
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD., Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY., Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Department of Surgery, Urology Service, Memorial Sloan Kettering Cancer Center, New York, NY., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pathology and Laboratory Medicine, Henry Ford Hospital, Detroit, MI., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY; Department of Pathology, UT Southwestern, Dallas, TX., Department of Pathology, University of Michigan, Ann Arbor, MI., Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. Electronic address: .