BACKGROUND: Extrapulmonary small cell neuroendocrine carcinoma (EP-SC) is a rare malignancy with a poor prognosis. In our study, one hundred and thirty-eight EP-SCNC tissue samples underwent a complex analysis. METHOD: Multicentric study included 138 high-grade small cell carcinomas exhibiting neuroendocrine morphology without known pulmonary involvement. Using TMA, we studied the possible benefit of TTF-1 (DAKO, clone 8G7G3/1, dilution 1:200), CDX-2 (DAKO, ready to use kit DAK-CDX2), PAX-8 (Cell Marque, polyclonal, dilution 1:50) and GATA-3 (Cell Marque, clone L50-823, 1:200) immunohistochemical analyses for determining the primary site of EP-SCNC origin. For statistical analyses, the Kaplan-Meier, the Cox regressions analyses, the Pearson chi-square test and the Fisher’s exact test were used. RESULTS: The median survival of our cohort was 11.5 months. Patients younger than 70 years had significantly better overall survival (p = 0.024). Across the full cohort, CDX-2 positivity was found in 19 tumors (13.9%), TTF-1 in 35 tumors (25.7%), PAX-8 in 63 tumors (46.3%) and GATA-3 in 8 tumors (6.5%), regardless of tumor origin. The expression of CDX-2, PAX-8 and GATA-3 did not differ significantly among different organ systems (p = 0.2; 0.3 and 0.12), respectively. The expression of TTF-1 differed significantly in tumors from various sites of origin (p = 0.009), expressed more often in breast, pancreatic, and genitourinary tumors. Interestingly, TTF-1 expression proved to have a negative prognostic impact relative to patient survival (age-adjusted Cox regression analysis, HR = 1.62, 95%CI:1.06–2.47, p = 0.021). CONCLUSION: As most patients with EP-SCNC had a metastatic presentation, finding the primary tumor origin, which is important for patient prognoses, is both challenging and important at the same time. Only TTF-1 immunohistochemical analysis proved to be helpful with this task. Moreover, a diagnosis of primary lung small cell carcinoma cannot be established based on TTF-1 positivity, since only 25.7% of EP-SCNC in our study displayed TTF-1 positivity. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13000-026-01753-3.

1st Institute of Pathologic Anatomy St Anne's University Hospital and Faculty of Medicine Masaryk University Brno Czech Republic

Bioptická laboratoř s r o and Šikl's Department of Pathology Charles University Medical Faculty in Pilsen Pilsen Czech Republic

Department of Anesthesia and Intensive Care 3rd Faculty of Medicine Charles University and University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Clinical and Molecular Pathology and Medical Genetics University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Oncological Pathology Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pathology and Molecular Medicine Thomayer University Hospital 3rd Faculty of Medicine Charles University Vídeňská 800 Prague 14059 Czech Republic

Department of Pathology University Hospital Kralovske Vinohrady 3rd Faculty of Medicine Charles University Prague Czech Republic

The Fingerland Department of Pathology Charles University Faculty of Medicine in Hradec Králové and University Hospital Hradec Kralove Hradec Králové Czech Republic

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