Despite common histopathological categories, important biological and clinical differences exist between children and adults with GEPNENs. These include differences in genetic predisposition, distribution of primary sites, functional status at presentation, patterns of metastatic spread, and long-term outcomes. In addition, while adult treatment algorithms are supported by randomized or prospective trials, pediatric treatment remains based on small series and extrapolation.

A structured comparative synthesis is therefore needed to: (i) delineate where pediatric biology and (Figure 1) clinical course diverge from adult disease; (ii) identify which elements of adult guideline recommendations can be safely translated to pediatrics; and (iii) highlight areas where pediatric-specific evidence is lacking and future collaborative studies are most urgently required.

A structured literature review was performed in PubMed/MEDLINE, Embase, and Web of Science for publications up to August 2025. Search terms included combinations of “neuroendocrine neoplasm”, “neuroendocrine tumor”, “pancreatic NET”, “gastrointestinal NET”, “hepatic NET”, “unknown primary”, “pediatric”, “adolescent”, and “child”. Reference lists of key studies and guidelines were screened manually to identify additional relevant reports.

Inclusion: Studies reporting original data on children and adolescents (<18 years) with histologically confirmed non-appendiceal GEPNENs, including pancreatic, gastric, duodenal, small-intestinal, colorectal, Meckel’s diverticulum, and NEN-CUP. Both registry-based and institutional series were eligible.

Exclusion: Appendiceal and bronchopulmonary NENs were excluded. Case reports were not systematically reviewed but used selectively to illustrate rare clinical scenarios.

For adult comparators, evidence was drawn primarily from current international guidelines: ENETS 2023–2024 site-specific recommendations for pancreatic, gastroduodenal, small intestinal, and colorectal NETs, and digestive NECs (5–8, 26). ESMO Clinical Practice Guidelines (latest available updates, 2020–2024) (9, 27). NANETS (2018–2023) guidelines on unresectable, metastatic, or high-grade GEPNEN (10, 11) ASCO 2023 guideline on systemic therapy for metastatic well-differentiated GEP-NETs (12).

Additional large-scale epidemiological analyses (e.g., SEER, European registries) and pivotal clinical trials were also included to contextualize treatment strategies and outcomes.

Given the rarity of pediatric GEPNENs and the absence of prospective trials, evidence synthesis relied heavily on: Registry data from the German Malignant Endocrine Tumor (MET) Registry (13, 14, 15, 28), the Italian TREP Project (16, 17), the French FRACTURE Registry (18), and North American SEER analyses (19, 20). retrospective series addressing pediatric pancreatic NENs, gastrointestinal NENs, and NEN-CUP (29–31), and narrative and systematic reviews, including those evaluating systemic therapy in pediatric NENs (21, 32–34).

Adult and pediatric data were then compared across the following domains: Epidemiology and clinical presentation, histological and molecular characteristics, treatment strategies (surgery, systemic therapy, liver-directed interventions, other approaches), and prognosis and long-term outcomes, and guideline recommendations and current clinical practice.

This framework was chosen to mirror the structure of existing adult guidelines and to facilitate direct comparison, highlighting both overlaps and divergences in disease biology, therapeutic approaches, and outcomes.

In adults, the incidence of GEPNENs has risen markedly over the past four decades. Population-based data from the SEER program and European registries document a 6- to 7-fold increase since the 1970s, with a current age-adjusted incidence of approximately 6–7 per 100,000 per year (22, 35–38). This rise is largely attributed to increased use of imaging, endoscopy, and histopathological recognition, resulting in a growing prevalence of indolent, localized NENs at diagnosis (38, 39). The median age at presentation in adults is typically in the fifth to sixth decade of life, with no consistent sex predominance across all sites, though pancreatic NENs show a slight male preponderance in some cohorts (37, 38).

In children and adolescents, GEPNENs are exceedingly rare, with an incidence estimated at <0.1 per million per year (23). Registry analyses from the German MET registry, the TREP Project, and FRACTURE confirm that pediatric cases represent <2% of all NENs (13, 14, 16–18, 40–43). The median age at diagnosis is mid-adolescence (14–16 years), with rare cases in younger children, the youngest published case being six years old (13). Unlike adults, where sporadic cases dominate (38), up to 20–30% of pediatric GEPNENs occur in the context of hereditary cancer predisposition syndromes, particularly multiple endocrine neoplasia type 1 (MEN1), von Hippel–Lindau (VHL), neurofibromatosis type 1 (NF1), and tuberous sclerosis complex (TSC) (14, 24).

The distribution of primary sites also differs: in adults, the small intestine and pancreas are the most common non-appendiceal GEPNEN sites (38, 39); in children, pancreatic NENs predominate among non-appendiceal primaries, followed by gastric, duodenal, and colorectal NENs, while primary hepatic NENs are extraordinarily rare (31–34, 44–46). Pediatric NEN -CUP is also reported, but accounts for <5% of all cases (14). A comparative overview on epidemiological features is presented in Table 1.

Adults most frequently present with non-specific abdominal pain, altered bowel habits, or incidental findings during imaging or endoscopy. Functioning tumors account for 10-30% of NENs, and when present, carcinoid syndrome (flushing, diarrhea, wheezing) is a hallmark of serotonin-producing midgut NENs with hepatic metastases. Functional pancreatic NETs (predominantly insulinoma, gastrinomas, more rarely glucagonomas, VIPomas and others) occur but account for a small proportion of adult cases (37–39).

In children, presentation differs significantly. Functional pancreatic NETs are relatively more frequent than in adults, with insulinomas being the single most common functional subtype (13, 16–18). These present with recurrent hypoglycemia, seizures, or neuroglycopenic symptoms. Gastrinomas are also reported in pediatric MEN1 cohorts, but VIPomas and glucagonomas remain exceptionally rare. Non-functional pancreatic NENs in children often manifest as abdominal pain, palpable mass, or incidental imaging findings (13, 17, 18).

Gastrointestinal NENs in children usually present with abdominal pain, vomiting, melena/hematochezia, or bowel obstruction (15, 17). Carcinoid syndrome is extremely rare in pediatric patients, reflecting the low incidence of serotonin-producing midgut NENs. Liver involvement generally represents metastasis from an occult gastrointestinal primary (14, 32, 33). Pediatric NEN-CUP presents with advanced disease, usually involving the liver, lymph nodes, or bone, and non-specific systemic symptoms (14).

The rise in adult GEPNEN incidence is closely linked to increased incidental detection during abdominal imaging or endoscopic evaluation for unrelated indications and surveillance (37–39). Consequently, a growing proportion of adults are diagnosed with small, localized, and indolent tumors before symptoms develop. Older SEER and population-based surveys reported ~50-60% advanced (regional/distant) disease at diagnosis, whereas more recent SEER analyses suggest this proportion has declined to roughly 40-45%, reflecting increased detection of localized cases (35, 47–49).

In children, early or incidental detection is less common. Most pediatric GEPNENs are identified when symptomatic or during work-up for hereditary syndromes (13, 14, 17, 18). Across recent multicenter and registry cohorts, roughly one-third of non-appendiceal pediatric NETs present with distant metastases at diagnosis, with variation by site and biology. Pediatric GEP-NECs—particularly of pancreatic origin—more frequently present with metastatic disease (13, 15, 17, 18).

The WHO 2019 classification defines GEPNENs based on differentiation (well vs poorly differentiated) and grade (G1–G3, determined by mitotic count and Ki-67 index). Within this framework: Well-differentiated NETs are subdivided into NET G1, G2, and G3, with increasing proliferative activity but preserved neuroendocrine morphology. Poorly differentiated NECs encompass small-cell and large-cell subtypes, which are biologically distinct from NET G3 and generally more aggressive.

In adults, the entire spectrum from NET G1 to NET is encountered, though distribution varies by site. NET G1 and G2 and NEC dominate small intestinal and gastric NETs, while pancreatic NETs more often include NET G2 and G3. NEC is relatively more frequent in adults, accounting for up to 10–15% of GEPNENs and carries a poor prognosis.

In children, available registry data demonstrate a predominance of well-differentiated NET G1 and G2, which account for the vast majority of cases. NET G3 is reported but rare, and NEC is exceptional, with only isolated cases in registry analyses. Importantly, the biological behavior of pediatric NETs often appears more indolent than in adults, even when proliferative indices approach those of NET G2 or low NET G3. This highlights potential differences in tumor biology across age groups.

Site-specific distribution also differs between children and adults. In adults, small intestinal NENs are the most frequent, followed by pancreatic and rectal NENs. In children, pancreatic NENs are the most frequent non-appendiceal subtype, followed by gastric/duodenal NENs. Midgut NENs are relatively rare in pediatrics, and carcinoid syndrome is exceptional. Primary hepatic NENs are extraordinarily rare in both groups, though in adults they have been described slightly more often; in children, nearly all hepatic NENs represent metastases from another primary.

Somatostatin receptor (SSTR) expression represents a clinically relevant biomarker across age groups. In adults, strong membranous expression of SSTR2 (and to a lesser extent SSTR5) is characteristic of well-differentiated NETs, underpinning the efficacy of both SSA and PRRT. Expression declines with increasing grade, and NECs mostly lack sufficient SSTR density for targeted imaging or therapy. In children, systematic data are limited, but registry cohorts and case series confirm a similarly high prevalence of SSTR2 expression in NET G1–2, enabling accurate detection with 68Ga-DOTA–labelled PET imaging and supporting the feasibility of SSA and PRRT in pediatric practice. As in adults, strong and homogenous expression is less common in NET G3 and is rarely present in NEC G3, thereby influencing treatment decisions. Nevertheless, the NETTER-2 trial demonstrated that a subset of well-differentiated NET G3—including adolescents aged 15 years and older—can exhibit strong and homogenous SSTR expression (50).

Molecular studies in adult GEPNENs have identified recurrent genetic alterations and pathway dysregulation. Pancreatic NETs frequently harbor mutations in MEN1, DAXX, ATRX, and genes of the mTOR pathway (e.g., TSC2, PTEN, PIK3CA). These molecular findings correlate with chromosomal instability and influence prognosis (51).

Small intestinal NETs typically lack recurrent oncogenic mutations (recurrent CDKN1B mutations present in 8-10%) but often show chromosomal copy-number changes, particularly loss of heterozygosity at chromosome 18 (52).

NECs exhibit a distinct genomic profile with frequent—but variably prevalent—TP53 and RB1 inactivation depending on cell type and primary site; overall rates are lower than those typically reported in small-cell lung carcinoma (53).

In children, the molecular landscape remains far less well characterized due to small cohort sizes and limited genomic studies. Key observations include: High prevalence of hereditary predisposition syndromes, particularly MEN1, VHL, NF1, and TSC, with germline variants often preceding tumor development (13, 14, 24). This stands in contrast to adults, where hereditary syndromes account for <10% of cases. Somatic mutation profiling of pediatric NENs remains sparse, though limited reports suggest overlap with adult patterns in pancreatic NETs (e.g., MEN1 alterations), but less consistent evidence for DAXX/ATRX involvement. Pediatric NECs are so rare that robust molecular profiling data are lacking; it remains uncertain whether their genomic landscape parallels adult NEC with TP53/RB1 alterations. A summary of the histological and molecular characteristics in adult and pediatric GEPNEN is presented in Table 2.

Emerging data suggest that epigenetic mechanisms and tumor microenvironment differences may contribute to distinct pediatric biology, though this remains speculative. Furthermore, comprehensive sequencing studies in children are lacking, underlining the need for systematic molecular profiling within prospective registries and international collaborative trials.

General principles: In both adults and children, complete macroscopic resection (R0) is the primary curative modality for well-differentiated GEPNENs. Adult guidelines emphasize early, anatomy- and grade-adapted resection with lymph-node assessment where indicated, followed by risk-adapted surveillance. ENETS 2023–2024 organ-site updates and ASCO 2023 systemic-therapy guidance frame surgery as the cornerstone for localized disease and as part of multimodal management in advanced cases.

Registry data confirm the prognostic importance of resection in children. In the German MET pancreatic NEN cohort (1997–2024), R0/R1 resection was significantly associated with improved event-free outcomes; metastatic status at diagnosis and surgical completeness were dominant determinants of prognosis (13). For pediatric GI-NENs (non-appendiceal), overall survival is high when tumors are resectable; relapse risk clusters in those with advanced stage and incomplete resection (15).

Systemic therapy is indicated for unresectable, metastatic, or progressive disease and for persistent symptoms in functioning tumors. Adult evidence (randomized/phase-III trials and consensus guidelines) defines the therapeutic backbone; pediatric use is largely extrapolative, with growing—but still limited—cohort-level experience.

A recent review has comprehensively summarized the cumulative experience with systemic therapies in pediatric GEPNENs, encompassing SSA, PRRT, targeted agents, and chemotherapy (21).

Adults: In liver-dominant, unresectable, well-differentiated NET metastases, transarterial embolization (TAE), chemoembolization (TACE), and radioembolization (SIRT) are established options for cytoreduction and symptom control; no intra-arterial technique has proven superior in head-to-head RCTs, and selection is center- and patient-specific (62–64).

Pediatrics: Evidence is limited to isolated reports and very small series; decisions are highly individualized and should be confined to expert centers with pediatric interventional radiology and robust peri-procedural endocrine/nutritional support. Given growth considerations and late-effects risks, careful selection and multidisciplinary review are essential.

External-beam radiotherapy has a limited role for well-differentiated NETs in both adults and children, reserved for palliation of symptomatic bone/CNS metastases or select local control scenarios; it is more commonly considered for NEC. Thermal ablation (e.g., RFA/MWA) may be used as adjunctive therapy for small liver metastases in adults; pediatric experience is anecdotal.

Adults (guideline-based): For small-bowel NET with SSTR-positive, well-differentiated disease, the established sequence is somatostatin analogue followed by PRRT and everolimus (7). For pancreatic NET, sequencing typically follows SSA, PRRT or targeted therapy (everolimus or sunitinib), and chemotherapy; in high-volume or rapidly progressive disease—even at lower grade—cytotoxic chemotherapy may be used upfront (objective response ~40%), followed by targeted agents or PRRT (5, 6). Sequencing is tailored to grade, primary site, tumor burden, and symptoms, and decisions are individualized within multidisciplinary tumor boards, taking genetic background into account where applicable.

Pediatrics (evidence-adapted): For unresectable or metastatic disease, pediatric evidence is limited; thus, systemic management is generally adapted from adult protocols. In SSTR-positive, well-differentiated NET G1–G2, somatostatin analogues may be used; PRRT may be considered at experienced centers for progression or symptom control; targeted therapies may be options in progressive disease; chemotherapy is reserved for NET G3/NEC or rapidly progressive tumors. Given the paucity of pediatric data, no definitive sequencing can be recommended. All decisions should be individualized within pediatric tumor boards, with explicit attention to hereditary context and long-term toxicity (21).

Adults: Survival outcomes for adult GEPNENs are strongly influenced by primary site, stage, and grade. SEER and European registry analyses report 5-year overall survival (OS) of 60–90% for localized NETs, 40–70% for regionally advanced disease, and less than 30% for metastatic disease (65, 66). More recent U.S. data show ~90% 5-year OS for localized, ~85% for regional, and ~57% for distant stage, with marked site heterogeneity at distant stage—higher in small-intestinal NETs (~70%), intermediate for pancreatic NETs (~50%). and lower colorectal primaries (~30-35%) (47). For adult NEC, median OS rarely exceeds 12–18 months despite systemic therapy.

Children: Registry studies consistently demonstrate excellent survival in resected, localized pediatric GEPNENs, with 5-year OS rates exceeding 90% in pancreatic and GI NETs (15, 17, 18). Outcomes in metastatic disease are substantially worse: 40-60% in children with metastatic pancreatic NENs (13, 18, 67) Pediatric NECs remain anecdotal but, when present, have survival comparable to adult NECs (14, 18). Notably, even in advanced cases, prolonged survival has occasionally been reported after multimodal therapy including surgery, PRRT, and systemic agents, highlighting potential differences in tumor biology and treatment responsiveness between age groups.

Adults: Disease relapse after resection is common, particularly in pancreatic NETs, with recurrence rates of 30–60% depending on tumor size, grade, nodal status, and resection margins. Adult NETs often follow an indolent but chronic course, with long periods of stable disease interspersed with progression. In contrast, NECs are characterized by rapid progression and early recurrence.

Children: In pediatrics, recurrence rates appear lower in completely resected NET G1–G2, though robust data are scarce due to small numbers and limited follow-up. When recurrence occurs, it is usually distant rather than local, most often in the liver or lymph nodes. The overall disease course in children appears more indolent than in adults, even for higher Ki-67 indices, but late relapses have been reported, supporting the need for long-term surveillance. For pediatric NEN-CUP, relapse and progression are almost universal, reflecting the aggressive biology of this subgroup.

Adults: Long-term surveillance in adults is guided by ENETS/ESMO, with imaging and biochemical follow-up intervals determined by grade, site, and stage. Survivorship challenges include hormone-related syndromes (functional tumors, carcinoid heart disease), treatment-related late effects (renal/hepatic from PRRT, metabolic from surgery), and psychosocial impact of chronic disease (26).

Children: In pediatric patients, lifelong follow-up is essential, even after complete resection, given the potential for late recurrence and the high prevalence of hereditary syndromes. Surveillance strategies are less standardized than in adults; expert consensus supports annual clinical review and imaging every 1–2 years for at least 10 years, with shorter intervals in higher-risk cases (large tumors, nodal or distant disease, higher grade).

Long-term survivorship issues are particularly relevant in children: Endocrine late effects from pancreatic resection (diabetes, exocrine insufficiency), hormonal sequelae in functional NETs, potential renal/gonadal toxicity from PRRT, psychosocial challenges related to chronic disease, hereditary risk, and transition to adult care.

Quality of life studies in pediatric GEPNENs are lacking; extrapolation from adult NET cohorts suggests that chronic treatment, surveillance burden, and anxiety about recurrence significantly impact well-being. The longer expected lifespan of pediatric patients amplifies the importance of minimizing late effects and integrating psycho-oncology into care.

In adults, care pathways for GEPNENs are codified by detailed, organ-site–specific recommendations that integrate histology/grade, stage, SSTR status, and patient factors. By contrast, pediatric guidance remains limited due to extreme rarity, a paucity of prospective data, and heterogeneous case-mix across centers. As a result, management in children largely adapts adult algorithms, with pediatric modifications for: (i) growth and developmental considerations, (ii) hereditary cancer predisposition syndromes (more frequent in childhood), and (iii) late-effects minimization (organ-sparing surgery, judicious use of radiation and alkylators).

Over the past decade, European collaborative structures—EXPeRT (European Cooperative Study Group for Paediatric Rare Tumours), ERN PaedCan, and EndoERN—have expanded the portfolio of European Standard Clinical Practice (ESCP) documents for very rare tumors (68). Within NENs, a first pediatric ESCP was completed for appendiceal NEN, while focused registry analyses and critical reviews have begun to outline pediatric-adapted recommendations. Together, these efforts form the substrate for a consolidated, site-spanning pediatric GEPNEN guidance.

Implication: The field now requires (i) a unified pediatric ESCP for non-appendiceal GEPNENs and (ii) integration of pediatric-feasible metrics (age-appropriate imaging, sedation needs, endocrine follow-up, fertility preservation) into decision pathways that were originally validated in adults.

Adult guideline ecosystems (ENETS, ESMO, ASCO, NANETS) offer granular, site-specific algorithms for diagnostic staging (including 68Ga-DOTA PET), histopathological work-up (grading per WHO 2019), and sequencing of surgery → SSA → PRRT/targeted agents → cytotoxic therapy, with selective use of liver-directed procedures. These frameworks are widely implemented in European NET centers (5–12).

Pediatric harmonization is advancing along three axes:

Adult algorithms stratify risk using WHO grade (Ki-67, mitotic index), TNM stage, tumor site, SSTR expression, and dynamic factors such as tumor growth rate and symptom burden. These variables remain relevant in children, but pediatric care benefits from additional, age-specific layers:

A pragmatic pediatric risk framework therefore layers WHO grade + SSTR status + stage on top of germline status and anticipated late-effects risk, to guide sequencing (e.g., SSA before PRRT/targeted agents in indolent SSTR-positive NET G1–G2; early escalation for NET G3; chemotherapy front-line for NEC).

Because pediatric GEPNENs often require lifelong surveillance, a structured transition to adult NET services is essential. Best practice includes:

Alignment: Core pillars—WHO grading, TNM staging, SSTR-guided imaging, early surgery for localized disease, SSA as first-line systemic therapy, PRRT/targeted agents for progression, and chemotherapy for high-grade tumors—are shared across adult and pediatric practice.

Pediatric adaptations: Higher prevalence of hereditary syndromes, organ-sparing imperatives, and long survivorship horizons necessitate tailored thresholds for intervention and long-term toxicity mitigation. Centralization and MDT review are especially critical given very low case volumes.

Harmonization agenda: Europe is well placed to formalize a pan-pediatric GEPNEN ESCP (non-appendiceal) that embeds adult evidence where appropriate, codifies pediatric-specific safeguards, and links seamlessly to the existing appendiceal NET ESCP.