Open Access

Michaela Kuhlen, Katharina Karges, Marina Kunstreich, Michael Abele, Jörg Fuchs, Christian Vokuhl, Constantin Lapa, Rainer Claus, Antje Redlich

• Background Neuroendocrine neoplasms of unknown primary (NEN-CUP) are rare in adults but remain virtually uncharacterized in children. The distinction between true CUP and undetected primaries is diagnostically and clinically significant yet poorly defined in children. Methods We retrospectively analysed patients aged <18 years with histologically confirmed NEN-CUP enrolled in the German Malignant Endocrine Tumour (MET) Registry between 1997 and 2024. All patients had metastatic disease with no identifiable primary despite comprehensive diagnostic work-up. Complementary population-level data were obtained from the SEER database using neuroendocrine histology and unknown primary topography codes. Results Eight paediatric NEN-CUP patients were identified in the MET Registry. The median age at diagnosis was 14.6 years (range, 12.2–18.6), and six were male. Presenting symptoms were non-specific and all tumours were non-functional. Somatostatin receptor imaging was positive in 5/7Background Neuroendocrine neoplasms of unknown primary (NEN-CUP) are rare in adults but remain virtually uncharacterized in children. The distinction between true CUP and undetected primaries is diagnostically and clinically significant yet poorly defined in children. Methods We retrospectively analysed patients aged <18 years with histologically confirmed NEN-CUP enrolled in the German Malignant Endocrine Tumour (MET) Registry between 1997 and 2024. All patients had metastatic disease with no identifiable primary despite comprehensive diagnostic work-up. Complementary population-level data were obtained from the SEER database using neuroendocrine histology and unknown primary topography codes. Results Eight paediatric NEN-CUP patients were identified in the MET Registry. The median age at diagnosis was 14.6 years (range, 12.2–18.6), and six were male. Presenting symptoms were non-specific and all tumours were non-functional. Somatostatin receptor imaging was positive in 5/7 cases. Tumour grading revealed five poorly differentiated NECs, two well-differentiated grade 2 NETs, and one grade 1 NET. Complete resection was not achieved in any patient. The 1-year and 2-year overall survival rates were 83.3% and 33.3%, respectively. The SEER analysis identified an additional 12 paediatric NEN-CUP cases over several decades, underscoring the extreme rarity of this disease entity. Conclusions Paediatric NEN-CUP is an exceptionally rare and clinically heterogenous group of tumours. Diagnostic ambiguity persists despite modern imaging and pathology. Our findings suggest both truly occult primaries and rare, under-recognized sites may contribute to this phenotype. Paediatric-specific diagnostic criteria and collaborative frameworks are urgently needed to better define and manage children and adolescents with NEN-CUP. Keywords cancer of unknown primary neuroendocrine neoplasms children and adolescents…