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Gastroenteropancreatic neuroendocrine tumors

What's new

The American Society of Clinical Oncology (ASCO) has published a new guideline for symptomatic management of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). For insulinoma, management includes patient education on hypoglycemia, dietary modifications with carbohydrate-rich meals and regular intake of simple carbohydrates, and somatostatin analogs (SSAs) if symptoms persist despite dietary changes. For gastrinoma, high-dose proton pump inhibitors and SSAs are suggested. For VIPoma, treatment includes IV fluids and electrolyte replacement for severe dehydration and SSAs and corticosteroids for diarrhea. For palliation in metastatic disease, suggested options include hepatic resection, thermal ablation, and intra-arterial therapies such as transarterial embolization, transarterial chemoembolization, and bland embolization. .

Background

Overview

Definition
Gastroenteropancreatic NETs are a heterogeneous group of epithelial neoplasms arising from neuroendocrine cells within the gastrointestinal tract and pancreas, characterized by variable hormonal activity and malignant potential.
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Pathophysiology
Gastroenteropancreatic NETs originate from neuroendocrine cells capable of hormone production and secretion. They are classified by primary site (e.g., pancreas, small intestine, rectum), functional status (hormone-secreting vs. nonfunctional), and histologic grade based on mitotic rate and Ki-67 proliferation index. The biological behavior varies widely, ranging from indolent, well-differentiated tumors to aggressive high-grade neuroendocrine carcinomas. Hormone-producing tumors may cause clinical syndromes such as carcinoid syndrome or insulinoma, while nonfunctional tumors often present late with mass effect or metastases.
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Epidemiology
The incidence of gastroenteropancreatic NETs has increased over recent decades. In the US, the estimated incidence is approximately 3.6 per 100,000 individuals per year, with a 20-year prevalence of 48 per 100,000. In Europe, incidence rates range from 1.3 to 2.3 per 100,000, though estimates vary due to heterogeneity in national and regional registry data.
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Risk factors
Most gastroenteropancreatic NETs are sporadic, but risk is increased in patients with inherited syndromes such as MEN1, von Hippel-Lindau disease, neurofibromatosis type 1, and tuberous sclerosis complex. Other risk factors may include chronic atrophic gastritis (for gastric NETs) and long-standing IBD.
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Disease course
The clinical presentation depends on tumor location, size, and functional status. Nonfunctional gastroenteropancreatic NETs are often indolent and asymptomatic until advanced stages, presenting with abdominal pain, mass effect, or metastases. Functional tumors present earlier due to hormone-related symptoms (e.g., flushing and diarrhea in carcinoid syndrome, hypoglycemia in insulinoma). Many tumors are diagnosed incidentally on imaging or endoscopy. Disease progression varies with tumor grade and site, and metastatic disease (most commonly to the liver) may occur even in low-grade tumors.
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Prognosis and risk of recurrence
Prognosis depends on tumor grade, stage, primary site, and functional status. Well-differentiated, low-grade gastroenteropancreatic NETs generally have a favorable prognosis with long survival, even in the presence of metastases. High-grade neuroendocrine carcinomas are aggressive and associated with poor outcomes. Early-stage tumors amenable to complete resection have the best prognosis. Ongoing surveillance is essential due to the potential for late recurrence or progression.
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Guidelines

Key sources

The following summarized guidelines for the evaluation and management of gastroenteropancreatic neuroendocrine tumors are prepared by our editorial team based on guidelines from the American Society of Clinical Oncology (ASCO 2025,2023), the European Society of Medical Oncology (ESMO 2020), and the Endocrine Society (ES 2012).
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Screening and diagnosis

Indications for screening
As per ES 2012 guidelines:
Obtain an annual plasma biochemical assessment of fasting gastrointestinal tract hormone profile, including measurement of gastrin, glucagon, vasointestinal polypeptide, pancreatic polypeptide, chromogranin A, and insulin with an associated fasting glucose level, as a minimum for screening of gastropancreatic NETs in patients with MEN1.
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Obtain an annual pancreatic and duodenal visualization with MRI, CT, or EUS as a minimum imaging in patients with MEN1.
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Classification and risk stratification

Staging: as per ESMO 2020 guidelines, use the TNM and the WHO classification systems for disease staging and prognostic assessment.
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Diagnostic investigations

Initial assessment
As per ESMO 2020 guidelines:
Make diagnostic and therapeutic decisions based on key features of neuroendocrine neoplasms, including proliferative activity, somatostatin receptor expression, tumor growth rate, and extent of the disease.
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Consider evaluating for a hereditary background in patients with neuroendocrine neoplasms, particularly in pancreatic NETs, as most are sporadic.
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  • Genetic testing

  • Somatostatin receptor imaging

  • Imaging for staging

Diagnostic procedures

Histopathology: as per ESMO 2020 guidelines, obtain and report morphology, grading, and immunohistochemical staining for chromogranin A and synaptophysin for appropriate pathological diagnosis. Consider obtaining somatostatin receptor staining or specific staining for peptide hormones and amines, as well as using molecular markers, based on clinical requirements.
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Medical management

General principles: as per ASCO 2025 guidelines, use a multidisciplinary approach for the treatment of patients with NET syndromes, involving an endocrinologist experienced in this area when possible.
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  • Watchful waiting

  • Chemotherapy

  • Somatostatin analogs

  • mTOR inhibitors

  • TKIs

  • Interferon alpha

  • Symptomatic management (general principles)

  • Symptomatic management (insulinoma)

  • Symptomatic management (gastrinoma)

  • Symptomatic management (glucagonoma)

  • Symptomatic management (VIPoma)

  • Palliative care

Therapeutic procedures

Radionuclide therapy
As per ASCO 2023 guidelines:
Offer peptide receptor radionuclide therapy in patients with somatostatin receptor-positive metastatic G1/G2 gastrointestinal NETs that have progressed following treatment with somatostatin analogs.
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Consider offering the same systemic options described above for G1/G2 NETs in patients with well-differentiated G3 gastroenteropancreatic NETs.
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  • Locoregional therapies

Surgical interventions

Indications for surgery, locoregional disease: as per ESMO 2020 guidelines, offer surgery as the treatment of choice for local or locoregional disease in NETs G1/G2. Initiate medical treatment before any intervention in functionally active tumors.
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  • Indications for surgery (metastatic disease)

  • Liver transplantation

Specific circumstances

Patients with MEN1: as per ESMO 2020 guidelines, offer a watch-and-wait management strategy for nonfunctioning pancreatic NETs ≤ 2 cm in the setting of MEN1 syndrome, as these tumors are often stable or slow growing.
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Follow-up and surveillance

Follow-up: as per ESMO 2020 guidelines, obtain follow-up investigations including clinical symptom monitoring, biochemical parameters, and conventional and somatostatin receptor imaging.
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