Gastrointestinal Neuroendocrine Tumors

Etiology

The etiology of GI-NETs is multifactorial and involves a combination of genetic, molecular, and environmental factors. Most GI-NETs are sporadic. NETs of the foregut are associated with genetic syndromes, eg, Von Hippel Lindau and multiple endocrine neoplasia type 1 (MEN1) syndrome, but they are less likely to be responsible for midgut NETs.

Risk factors associated with GI-NETs include a positive family history of cancer, while lifestyle and metabolic factors may contribute to the development of these tumors. A high body mass index (BMI) and diabetes have been implicated as potential risk factors, possibly due to their association with chronic inflammation and metabolic dysregulation. Some evidence has also suggested that cigarette smoking and alcohol use may play a role in increasing the risk of GI-NETs.[3] However, the exact mechanisms remain unclear, and more recent data suggests that several germline mutations may be responsible, at least in part, for some NETs.[4] These risk factors, genetic predispositions, and environmental influences highlight the multifactorial nature of GI-NET pathogenesis.[3]

Epidemiology

GI-NETs are less common than adenocarcinomas, yet their incidence has steadily increased.[1] GI-NETs represent the most common subtype of neuroendocrine tumors, accounting for approximately 60% to 70% of cases, with the small intestine and appendix being the most frequently affected sites.[1] The annual incidence of GI-NETs is estimated to be 3 to 5 cases per 100,000 population, with a higher prevalence observed due to their typically indolent nature.[3] The incidence is also greater in more developed countries, attributable to greater availability of diagnostic testing and increased awareness. However, data suggests that the incidence is also increasing in less developed countries.[5] These tumors are most commonly diagnosed in individuals aged between 50 and 70 years and show a slight male predominance. Racial disparities have been noted, with African American populations exhibiting higher incidence rates compared to Caucasians, though the reasons for this disparity remain unclear. While the majority of GI-NETs occur sporadically, approximately 10% are associated with hereditary syndromes (eg, MEN1).[1]

Pathophysiology

GI-NETs arise from enterochromaffin and other neuroendocrine cells within the gastrointestinal tract, which regulate hormones and peptides. The pathophysiology involves a combination of genetic mutations, epigenetic alterations, and dysregulated signaling pathways that promote unchecked cellular proliferation, survival, and hormonal secretion. Key mutations in genes, eg, MEN1, DAXX, ATRX, and components of the mTOR pathway disrupt normal cell cycle control and apoptosis. These tumors can produce excessive amounts of bioactive substances like serotonin, gastrin, or vasoactive intestinal peptide, leading to clinical syndromes (eg, carcinoid syndrome) when functional.[6][4]

Nonfunctional GI-NETs, while not associated with overt hormonal symptoms, may still grow locally invasive or metastasize. Differentiation, histological grade, and the Ki-67 proliferation index determine tumor behavior, including growth rate and metastatic potential. The angiogenic and stromal microenvironment also plays a critical role in tumor progression, with vascular endothelial growth factor and other pro-angiogenic signals contributing to the formation of the rich blood supply typical of these tumors.[6][4]

Histopathology

GI-NETs are usually small, polyploid, solid, slow growing, often invading transmural, and spread to the lymphatics and adjacent mesentery. Jejunoileal NETs are frequently multifocal, with multiple lesions identified in up to 50% of cases.[6] NETs display monomorphic round cells with abundant eosinophilic cytoplasm and salt and pepper chromatin with rate mitotic figures. The internal structure may be solid, glandular, trabecular, or mixed, characterized by a highly vascular stroma with a low nuclear/cytoplasm ratio. Immunohistochemistry is positive for cytokeratins, chromogranin A, synaptophysin, somatostatin receptors, and various hormonal receptors in functional tumors.[6]

In contrast, neuroendocrine carcinoma (NEC) is characterized by polymorphic cells with frequent mitoses, necrosis, a high nuclear-to-cytoplasm ratio, and markedly aberrant cells. The degree of cytoplasm differentiates small and large cell types. The 2022 World Health Organization (WHO) classification of NETs based on tumor mitoses, Ki67 percent, and morphology is the most widely used (see Table. World Health Organization 2022 Classification of Neuroendocrine Tumors).[6]

Table. World Health Organization 2022 Classification of Neuroendocrine Tumors

History and Physical

The history and physical examination for GI-NETs focuses on identifying symptoms associated with hormone hypersecretion, tumor mass effects, and potential complications. A history should encompass the evaluation of hallmark symptoms, including episodic flushing, watery diarrhea, and wheezing, which are characteristic of carcinoid syndrome, particularly in cases of metastatic disease associated with serotonin and other bioactive amine overproduction. Nonspecific manifestations include chronic abdominal pain, unintentional weight loss, early satiety, fatigue, and gastrointestinal bleeding, which may indicate tumor burden, local invasion, or secondary complications. The regional lymph nodes and the liver are the most common sites of metastasis, with the bone, lung, peritoneum, and other organs being less common. A comprehensive review of systems is critical to detect subtle clinical features and to assess for predisposing conditions, eg, MEN syndromes or von Hippel-Lindau syndrome.[7][8][9]

Physical examination findings often correlate with the tumor’s size, location, and extent of metastatic spread. Hepatomegaly, frequently indicative of metastatic liver involvement, should be carefully assessed through abdominal palpation. A palpable abdominal mass may suggest a primary tumor or significant regional lymphadenopathy. Signs of intestinal obstruction, such as abdominal distension, tenderness, or peritoneal irritation, may reflect tumor-related complications. Cutaneous findings, including telangiectasias, flushing, or pellagra-like dermatitis, may be observed in advanced disease due to niacin deficiency resulting from tryptophan diversion to serotonin synthesis. Furthermore, a thorough cardiovascular and respiratory evaluation is essential to identify features of carcinoid heart disease, eg, right-sided valvular dysfunction and associated murmurs.[7][8]

Evaluation

The diagnosis of GI-NETs is frequently delayed, often by 5 to 7 years for NETs, as patients are frequently asymptomatic or present with nonspecific symptoms. At the time of diagnosis, metastases are present in approximately 30% of NET patients, and this rate can reach as high as 70% in cases of midgut neuroendocrine tumors. NECs, due to their aggressive nature, often present with advanced disease at diagnosis.

Biochemical Testing

Comprehensive biochemical testing is critical for the diagnosis and management of NETs. Evaluation of all patients with chromogranin A (CgA), pancreastatin, and a 24-hour urine collection for 5-hydroxyindoleacetic acid (5-HIAA) is recommended.

Chromogranin A testing

CgA is a nonspecific biomarker for neuroendocrine tumors and is helpful for the screening and monitoring of functioning and non-functioning NETs. CgA levels should be tested with the patient fasting and avoiding physical exertion. CgA levels correlate with tumor burden and may have prognostic implications. However, small tumors may produce normal CgA levels, while false-positive elevations can occur in the presence of severe hypertension, chronic gastritis, proton pump inhibitor use, and renal insufficiency. Given this lack of sensitivity and specificity, its utility is limited.[10][11][12]

Twenty-four-hour urine collection

Measuring 5-HIAA with a 24-hour urine collection, a serotonin metabolite, is particularly useful for diagnosing and monitoring serotonin-secreting NETs, eg, midgut neuroendocrine tumors. Before and during urine collection, patients should avoid serotonin- and tryptophan-rich foods, as well as medications that can lead to false elevations. Serum serotonin measurements are not reliable due to variability related to daily activities. Although fasting plasma 5-HIAA testing offers convenience, additional validation is needed before it can replace the traditional 24-hour urine method. In NECs, specific biochemical markers depend on the functional status of the tumor.[13]

Genetic assays

Gene expression tests are increasingly used in many cancers, which also applies to NETs. An example is the NETest, a type of liquid biopsy that measures specific gene expression patterns in blood samples and generates a score indicating disease activity. Studies have shown that the NETest can achieve higher accuracy than standard biochemical tests (eg, chromogranin A), with reported sensitivities of around 93% and specificities of about 98%. However, further research is needed before these tools become widely adopted in routine clinical practice.[14][15]

Tumor circulation markers 

Markers of tumor circulation, including circulating tumor DNA and circulating tumor cells, are well-established in the management of malignancies such as colorectal and breast cancer. Emerging evidence indicates these markers may also have clinical utility in NETs.[16] 

Imaging Studies

Alongside biochemical testing, GI-NET diagnosis relies on imaging modalities, including computed tomography (CT), magnetic resonance imaging (MRI), and somatostatin receptor-based imaging.

Computed tomography

CT constitutes a critical component of the initial diagnostic workup for patients presenting with suspected GI-NETs, partly due to its widespread availability and rapid image acquisition. Most NETs demonstrate hyperenhancement on contrast-enhanced CT, particularly during arterial and venous phases (see Image. Neuroendocrine Tumor Liver Metastases). This makes a triple-phase protocol (non-contrast, arterial, and venous imaging) advantageous for lesion detection and staging. Reported sensitivities for CT in diagnosing NETs vary by tumor site and size, with estimates ranging from 60% to 85% in detecting small primary lesions. While CT is an effective modality for identifying hepatic metastases—often revealing hypervascular lesions on the arterial phase—CT is generally less sensitive than MRI, particularly for smaller (<1 cm) liver metastases.[17][18]

Magnetic resonance imaging

Some studies indicate that MRI can detect up to 90% of liver metastases from NETs, underscoring the complementary role of MRI in diagnostic algorithms for patients with suspected metastatic disease.[17][18] MRI is often more sensitive than CT for identifying hepatic metastases, which characteristically appear hypervascular on arterial-phase images and may show rapid washout in later phases. T1-weighted, T2-weighted, and diffusion-weighted sequences complement contrast-enhanced imaging by highlighting tumor cellularity and vascularity, thereby refining lesion detection and characterization.[19][17]

Somatostatin receptor imaging

Somatostatin receptor scintigraphy (eg, Octreoscan) and positron emission tomography (PET) imaging with DOTATOC or similar radiolabeled somatostatin analogs are highly effective for identifying somatostatin receptor-expressing tumors and evaluating the extent of disease. Please see StatPearls' companion resource, "Octreotide Scan," for further information. In NECs, these modalities may have limited utility due to poor differentiation and variable receptor expression.[20][18]

Fluorodeoxyglucose positron emission tomography

Fluorodeoxyglucose positron emission tomography (FDG-PET) is generally an unsuitable modality for well-differentiated NETs due to their low proliferative activity. However, it is highly informative in NECs, where increased metabolic activity and proliferative rates correlate with FDG uptake.[21][22]

Endoscopy

Upper and lower gastrointestinal endoscopy allows for direct visualization and biopsy of accessible lesions. Enteroscopy or capsule endoscopy ("pill-cam") may be employed for small bowel lesions. However, routine use of capsule endoscopy is discouraged due to the risk of retention at the tumor site, which could lead to small bowel obstruction.

Enterography

CT and MR enterography can help identify small intestinal lesions not visualized by standard imaging techniques. This technique helps assess small bowel NETs beyond the reach of standard endoscopy. MR enterography can also aid the identification of subtle NET primaries and associated mesenteric fibrosis.[23] 

Echocardiography

An echocardiogram should be performed to assess for carcinoid heart disease, particularly in patients with serotonin-secreting tumors, before surgical intervention.[24]

Treatment / Management

The management of GI-NETs depends on the type, location, and stage of the tumor. Surgery is the mainstay of treatment for patients with localized disease and those with metastatic disease, which is amenable to cytoreduction. Somatostatin analogs, targeted agents, peptide receptor radioligand therapy, and chemotherapy are used in patients who are not candidates for surgery. 

Differential Diagnosis

The differential diagnoses for GI-NETs include:

• Adhesive intestinal obstruction
• Adenocarcinoma 
• Lymphoma
• Sarcoma, especially gastrointestinal stromal tumor
• Nonmalignant polyps (hyperplastic, adenomas)
• Acute appendicitis

Surgical Oncology

Surgical Principles in Neuroendocrine Tumor Management

Preoperative care

All patients undergoing surgery for NETs should be evaluated for the presence of carcinoid syndrome. If carcinoid syndrome is identified, a preoperative transthoracic echocardiogram is essential to assess for carcinoid heart disease, including valvular dysfunction or heart failure. This evaluation is critical to optimizing the patient for surgery and reducing the risk of perioperative complications.[24]

Patients with carcinoid syndrome should receive preoperative treatment with a long-acting somatostatin analog (eg, octreotide or lanreotide) to prevent intraoperative or perioperative carcinoid crisis, characterized by severe flushing, diarrhea, bronchospasm, and hemodynamic instability. For patients undergoing abdominal surgery, particularly when long-term somatostatin analog therapy is planned, a prophylactic cholecystectomy should be considered. Prolonged somatostatin analog use increases the risk of biliary complications such as cholelithiasis or cholecystitis. Prophylactic cholecystectomy can mitigate these risks and prevent the need for subsequent surgical intervention.[25]

Jejunoileal neuroendocrine tumors surgical management

Complete surgical resection of the primary tumor with regional lymphadenectomy is the mainstay of managing jejunoileal NET. These tumors are often multifocal, necessitating meticulous intraoperative inspection of the small intestine via manual palpation. Many small lesions are detectable only through this technique, with the majority located in the ileum rather than the jejunum.[25]

Up to 70% of patients with jejunoileal NETs present with lymph node involvement at diagnosis, necessitating a regional lymphadenectomy. Mesenteric resection should be performed when significant mesenteric involvement is present. Cases requiring extensive mesenteric resection have a risk of short bowel syndrome. For these patients, conservative resection with preservation of bowel length may be considered, supplemented with adjunctive therapies. Preservation of the ileocecal valve, when feasible, is advised to minimize the risk of malabsorption and diarrhea. The characteristic desmoplastic reaction associated with NETs often results in mesenteric fibrosis, complicating dissection and increasing the technical challenges of surgery.[25]

For patients with metastatic disease confined to the liver, hepatic resection is indicated to improve symptom control, quality of life, and overall survival. Liver resection should aim to achieve at least 70% to 90% cytoreduction of the tumor burden. The feasibility of liver resection depends on the patient’s performance status, the presence of an adequate functional liver remnant, and the ability to achieve cytoreduction goals. Whenever possible, parenchyma-sparing techniques should be employed to maximize liver function postoperatively.[4][26] For patients with inoperable hepatic metastases, liver-directed therapies can reduce morbidity and improve quality of life. Options include percutaneous hepatic transarterial embolization, radioembolization with yttrium-90 microspheres, and ablation, which are discussed separately.[25]

Appendiceal neuroendocrine tumors surgical management

Appendiceal NETs are often diagnosed incidentally during an appendectomy performed for presumed appendicitis. Larger tumors may be identified preoperatively through imaging or other diagnostic evaluations. The surgical management of appendiceal NETs depends on several factors, including the tumor size, depth of invasion, and status of the tumor margins. The rationale for a right hemicolectomy in more advanced appendiceal NET is to perform an adequate lymphadenectomy. A right hemicolectomy is usually not beneficial for patients with low-risk tumors (eg, smaller size, well-differentiated, no transmural invasion).[25] The following management approaches are recommended based on tumor characteristics:

• Tumors sized <1 cm: No further treatment is required for completely resected tumors with negative margins. However, if the margins are positive, resection with a possible partial cecectomy is recommended.
• Tumors sized 1 to 2 cm: An appendectomy with negative margins is typically sufficient. However, if the tumor exhibits high-risk features, eg, a high Ki-67 index, invasion of the mesoappendix, or a higher histological grade, a completion right hemicolectomy is indicated.
• Tumors >2 cm in size: A right hemicolectomy is indicated to ensure complete resection and adequate lymphadenectomy.
• Metastatic disease: The indications for surgery in metastatic disease to the liver are the same as in jejunoileal NET.[4]

Colonic neuroendocrine tumors surgical management

Colonic NETs are most commonly identified incidentally during polypectomy specimens, although larger lesions may occasionally present symptomatically.[25] The following management approaches are recommended based on tumor characteristics:

• Lesions <2 cm: For tumors confined to the mucosa or submucosa without evidence of lymphadenopathy on imaging, endoscopic resection is the treatment of choice if technically feasible.
• Lesions >2 cm or unresectable endoscopically: Segmental colectomy with lymph node dissection is recommended. The procedure should follow oncologic principles similar to those for colorectal adenocarcinoma to ensure complete resection and proper staging.

When endoscopic resection is performed, the site should be marked (eg, with a tattoo) to facilitate close endoscopic surveillance. Unlike neuroendocrine tumors of the small intestine and appendix, cytoreductive surgery or liver-directed interventions are generally not indicated for colonic neuroendocrine tumors unless the tumor is hormonally active or causing significant symptoms.

Rectal neuroendocrine tumors surgical management

Rectal NETs are frequently identified incidentally during polypectomy or endoscopic evaluations. These lesions are often small and asymptomatic at the time of diagnosis.[25] The following management approaches are recommended based on tumor characteristics:

• Lesions <1 cm in size: Endoscopic resection is typically adequate for well-differentiated tumors confined to the mucosa or submucosa without evidence of lymphovascular invasion or lymphadenopathy.
• Lesions 1 to 2 cm in size: Lesions should be evaluated for high-risk features, eg, a high Ki-67 index, invasion into deeper layers, or positive margins after resection. If any high-risk features are present, transanal excision or proctectomy may be required.
• Lesions >2 cm or with high-risk features: Proctectomy with total mesorectal excision is recommended, following the same oncologic principles as rectal adenocarcinoma.

Close endoscopic follow-up is necessary for all patients undergoing resection of rectal NETs to monitor for recurrence or progression. Hormonal or cytoreductive interventions are generally not indicated unless the tumor is hormonally active or causing significant symptoms.

Radiation Oncology

Radiation therapy has a supportive role in the management of gastrointestinal NETs. Although these tumors have traditionally been considered relatively radioresistant, radiation therapy can be beneficial in certain clinical scenarios, particularly for palliation of symptoms and local control of metastases.[25] 

Conventional external beam radiation therapy (EBRT) is most commonly employed for symptomatic relief of localized metastatic lesions or for controlling tumor growth in sites where surgery is not feasible. For instance, EBRT can significantly reduce pain and stabilize skeletal lesions in bone metastases. It may also be considered for palliation of bulky disease in the liver or retroperitoneum, where tumor progression threatens organ function or causes significant morbidity (eg, obstruction, bleeding, or intractable pain).[25][27]

Stereotactic body radiation therapy (SBRT) has emerged as a more precise technique for delivering high-dose radiation to well-defined targets over fewer treatment sessions. This approach can be particularly effective for liver or lung metastases from well-differentiated NETs, achieving local control rates comparable to aggressive surgical interventions in select patients. While prospective data on SBRT in NETs remain limited, retrospective series have reported encouraging local control rates and durability of response, often with minimal toxicity.[25]

Selective internal radiation therapy (SIRT), or radioembolization, represents another modality for locoregional management of liver-dominant metastatic NETs. By infusing yttrium-90 microspheres into the hepatic artery, SIRT delivers targeted radiation to liver metastases while minimizing exposure to surrounding healthy tissue. Although randomized data are scarce, retrospective studies have observed meaningful tumor shrinkage, delayed disease progression, and symptomatic improvement in select patients with extensive liver involvement.[25][28]

Medical Oncology

Medical management is indicated in nonresectable, advanced, recurrent, or metastatic NEC. Key therapeutic modalities include somatostatin analogs, mTOR inhibitors, peptide receptor radionuclide therapy (PRRT), and chemotherapy.

Somatostatin Analogs

Somatostatin analogs (eg, octreotide long-acting release and lanreotide) are used for symptomatic control in functioning NETs and tumor growth inhibition in well-differentiated (ie, grade 1 or grade 2) tumors. They exert their effects by binding to somatostatin receptors on tumor cells, reducing hormone secretion and alleviating hormone-related symptoms, eg, flushing and diarrhea. Pivotal trials have documented their antiproliferative benefits in delaying tumor progression, most notably the PROMID study in patients with midgut NETs and the CLARINET study in a broader cohort of gastroenteropancreatic NETs. Adverse effects include gastrointestinal disturbances (eg, steatorrhea and abdominal bloating), biliary lithiasis resulting from reduced gallbladder contractility, and occasional dysglycemia.[25][29][30][25]

Targeted Therapies With mTOR Inhibitors

Everolimus, an mTOR inhibitor, has shown efficacy in progressive, well-differentiated pancreatic, gastrointestinal, or pulmonary NETs by blocking a key intracellular pathway responsible for cell growth and angiogenesis. The RADIANT-3 trial established its role in improving progression-free survival in patients with pancreatic NETs. The RADIANT-4 trial demonstrated similar benefits in non-functional lung or gastrointestinal NETs. Common adverse effects include stomatitis, hyperglycemia, dyslipidemia, fatigue, and immunosuppression, all of which necessitate vigilant metabolic and hematologic monitoring.[25][31]

Peptide Receptor Radionuclide Therapy

PRRT employs radiolabeled somatostatin analogs, eg, Lutetium-177 (¹⁷⁷Lu)-dotatate, to deliver targeted radiation to somatostatin receptor-expressing tumor cells. Please see StatPearls' companion resource, "Neuroendocrine Tumor Lu177Dotatate Therapy", for further information on ¹⁷⁷Lu-dotatate therapy. This strategy is effective in advanced, well-differentiated NETs that exhibit high somatostatin receptor density. The NETTER-1 trial significantly improved progression-free survival and quality of life with ¹⁷⁷Lu-dotatate compared to high-dose octreotide LAR in metastatic midgut NETs. Although generally well-tolerated, possible toxicities include mild to moderate bone marrow suppression, nephrotoxicity (requiring specific amino acid infusions for renal protection), and transient gastrointestinal adverse effects. Ongoing trials are looking to expand the indications for PRRT.[26][32][25]

Chemotherapy

Chemotherapy is integral in the management of poorly differentiated NECs (WHO grade 3) and certain high-grade NETs, which often display aggressive clinical behavior. Platinum-based regimens, such as cisplatin or carboplatin combined with etoposide, are the standard first-line therapy. Chemotherapy is less frequently utilized in well-differentiated NETs, although temozolomide-based regimens (sometimes combined with capecitabine) may be beneficial in select cases. Platinum agents can cause nephrotoxicity and ototoxicity, while temozolomide is associated with myelosuppression and gastrointestinal disturbances.[25]

Prognosis

GI-NETs exhibit a highly variable prognosis, influenced by tumor grade, Ki-67 index and mitotic count, stage at diagnosis, and histological differentiation. In general, well-differentiated, low- to intermediate-grade NETs tend to have a more indolent course, with 5-year survival rates exceeding 80% for small, localized lesions amenable to complete surgical resection. By contrast, poorly differentiated NECs, especially those presenting with advanced disease, carry a significantly worse outlook, with 5-year survival often falling below 20%. Functional status can also play a role in prognosis, as hormone-producing tumors may be detected earlier due to symptomatic hypersecretion syndromes, but aggressive biology can override any potential survival advantage.

Complications

GI-NETs can give rise to a wide range of complications that affect both quality of life and clinical outcomes. Hormone-related complications are seen with functional GI-NETs, causing carcinoid syndrome and, rarely, carcinoid crisis. Advanced or bulky GI-NETs can cause mechanical complications. Small bowel lesions, for instance, may lead to mesenteric fibrosis, obstruction, and ischemia, whereas colonic or rectal NETs can present with bleeding, altered bowel habits, or significant local mass effects. Metastatic spread, most commonly to the liver, may further compromise hepatic function and exacerbate systemic symptoms through increased hormone release directly into the systemic circulation. In addition, more extensive metastatic deposits can cause pain, organ dysfunction, or secondary complications such as biliary obstruction.