Extrapulmonary small cell neuroendocrine carcinoma (EP-SCNC) is a rare malignancy with a poor prognosis. Despite its morphological similarity to lung small cell carcinomas, its oncogenesis remains uncertain. One hundred and seventy-one EP-SCNC were enrolled in a multicenter study, and all tissue samples underwent an immunohistochemical p53 analysis. One hundred twenty-five samples were molecularly analyzed using next-generation sequencing (NGS), comprising DNA and RNA analysis. p53 normal/wild type expression was detected in 68 cases (39.8%), whereas aberrant expression was detected in 103 cases (60.2%). Molecular TP53 alteration was detected in 92 out of 125 tumors (73.6%). The TP53 mutation was shown to be prognostic and associated with shorter overall survival (p = 0.041). The multivariate analysis of p53 and TP53 mutational status found that it impacted overall survival relative to distinct sites of tumor locations (p = 0.004 and p = 0.001, respectively). Age did not influenced survival in the multivariate analysis of p53 and TP53 (p = 0.002; p < 0.001 resp.). Among tumors with paired immunohistochemical and molecular results, 108 exhibited concordance between the immunohistochemical and molecular analysis, whereas 17 were discordant. Accordingly, p53 aberrant expression was tightly associated with a TP53 mutation (p < 0.001). In discordant cases, molecular analysis revealed no alteration in three tumors with p53 overexpression. In contrast, in 14 tumors with wild-type p53 expression, TP53 genetic alteration was detected. Possible causes of discordance are discussed in this manuscript. Furthermore, the incidence of aberrant p53 expression / TP53 molecular alteration was noticeably lower in EP-SCNC than in small-cell lung carcinomas. Therefore, in EP-SCNC, other driver mutations should be sought since personalized therapy can improve patient prognosis.

Bioptická laboratoř S R O and Šikl's Department of Pathology Charles University Medical Faculty in Pilsen Pilsen Czech Republic

Department of Anaesthesia 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 in Prague Prague Czech Republic

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

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

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