Fig. 1: Study design, sample and patient characterization.

A Schematic overview of the frequency of NEN developing in the lung, liver, pancreas, duodenum, appendix, colorectum and skin. This overview was created in BioRender. Roessler, S. (2025) https://BioRender.com/yn6lb0a. B A total of 212 NEN, consisting of the discovery set (Heidelberg cohort, N = 197 tissues from 185 patients) and the independent validation set (Beaujon cohort, N = 15 tissues from 14 patients) were included in this study. All NEN included in the Beaujon cohort were hepatic NEN without a known primary. The NEN of the Heidelberg cohort detected in the liver included hepatic NEN without known primary tumor (N = 22) and hepatic metastases of known primary NEN (N = 22), of which 9 were paired samples with the respective non-hepatic primary. A total of 65 gastrointestinal NEN, which included gastric/duodenal NEN (N = 14), ileal NEN (N = 18), appendiceal NEN (N = 15) and colorectal NEN (N = 18), were analyzed. In addition, 49 NEN of the lung, including pulmonary NEC (N = 24) and pulmonary carcinoids (N = 25), pancreatic NEN (N = 25) and Merkel cell carcinomas (N = 14 tissues of 11 patients) were included. C–E Immunohistochemical analysis of three representative hepatic NEN cases without known primary tumor (total of N = 22). Shown are H&E, chromogranin A (CHGA), synaptophysin (SYP) and Ki67 immunohistochemical stainings of one case with low (C), intermediate (D) and high (E) proliferation each. In total, 3 cases exhibited low, 5 cases intermediate and 14 cases high proliferation based on Ki67 staining (Table 1).