Multicenter study comparing prognostic markers in primary pulmonary and extrapulmonary small cell neuroendocrine carcinoma

Small cell neuroendocrine carcinomas occur in both pulmonary (SCLC) and extrapulmonary sites (EP-SCNC). A multicenter retrospective study in the Czech Republik compared cohorts of SCLC (n=215) and EP-SCNC (n=184) with respect to molecular alterations and RNA and protein expression in tumor tissue. The median survival was 6.3 months for SCLC patients and 8.9 months for EP-SCNC patients (p<0.0001). Genetic alterations of TP53, RB1, and KMT2D were most common in both groups. TP53 mutation was associated with worse survival in EP-SCNC (HR 1.62; p=0.043), whereas KMT2D mutation was associated with worse survival in SCLC (HR 1.62; p=0.003). The tumor mutational burden was higher in SCLC (p<0.001). In RNA-Seq analyses, SCLC and EP-SCNC formed distinct RNA clusters; a total of 553 genes were expressed differentially. Immunohistochemistry revealed a higher expression of ASCL1 and NEUROD1 in SCLC than in EP-SCNC, while YAP1 and POU2F3 expressions were higher in EP-SCNC than in SCLC. The authors conclude that EP-SCNC compared with SCLC was associated with better survival, greater molecular heterogeneity, and distinct genetic, transcriptional, and immunohistochemical profiles, showing that the two tumor groups are biologically distinct.