Neuroendocrine tumors: what they are, how to recognize them, and how they are treated

“Neuroendocrine tumors, referred to as NETs or NENs, are rare neoplasms that arise from special cells with a hormonal function, present in numerous organs of the body. They are most commonly located in:

• the gastrointestinal tract;
• the pancreas;
• the lungs.

They can occur at any age but are more frequent between 40 and 70 years of age.

In recent years, a significant increase in the incidence and prevalence of these tumors has been observed. This increase does not necessarily reflect a real rise in cases, but is mainly attributable to the broader use of increasingly sophisticated imaging techniques, such as CT and MRI, which are able to detect very small and often asymptomatic lesions, even at early stages,” explains Prof. Partelli.

The classification of neuroendocrine tumors is complex and is based on several criteria useful for predicting their clinical behavior.

Biology of the neuroendocrine tumor

A first distinction concerns tumor biology:

• some NETs show slow growth and remain localized for many years;
• others show a more aggressive course and a greater tendency to metastasize.

Growth rate of the neuroendocrine tumor

A key parameter for assessing tumor growth rate is the Ki-67 proliferation index:

• low values identify grade 1 (G1) tumors, generally slow-growing;
• intermediate values define G2;
• high values characterize G3, associated with faster and more aggressive behavior.

This classification is crucial in guiding therapeutic decisions.

Functioning and non-functioning neuroendocrine tumors

From a functional perspective, NETs are divided into functioning and non-functioning tumors.

“Functioning NETs produce excess hormones and lead to specific clinical syndromes, as in the case of insulinomas, gastrinomas, or glucagonomas.

Non-functioning NETs, on the other hand, do not secrete biologically active hormones and therefore may remain asymptomatic for a long time. They are often diagnosed only when they reach a size sufficient to cause compressive symptoms or, more frequently, incidentally during imaging tests performed for other reasons.”

The exact causes underlying the development of neuroendocrine tumors are not yet fully understood.

“In most cases, onset is linked to sporadic mutations, meaning random genetic alterations that progressively modify cell behavior.

Only a minority of patients have a hereditary predisposition associated with well-defined genetic syndromes, such as:

• MEN1;
• MEN2;
• Von Hippel–Lindau syndrome;
• neurofibromatosis type 1;
• tuberous sclerosis.

These conditions increase the risk of developing endocrine tumors in different organs. It is important to emphasize that familial forms are extremely rare: the vast majority of NETs develop sporadically, without identifiable specific risk factors,” the specialist explains.

Neuroendocrine tumors are known for their ability to remain silent for long periods. Many patients have no symptoms for years, and diagnosis often occurs incidentally during tests such as CT or MRI performed for other reasons.

When symptoms do appear, they are often vague and non-specific:

• intermittent abdominal pain;
• unexplained weight loss;
• nausea;
• persistent feeling of fullness.

In some cases, tumor growth may lead to compression of the bile ducts or intestines, resulting in jaundice or episodes of intestinal obstruction.

Symptoms of functioning neuroendocrine tumors

The situation is different in functioning tumors, which produce excess hormones. In these cases, symptoms are more specific and depend on the substance secreted:

• insulinoma, for example, causes recurrent episodes of hypoglycemia with sweating, tremors, and confusion;
• gastrinoma causes gastric ulcers resistant to therapy and diarrhea;
• VIPoma presents with severe watery diarrhea;
• glucagonoma with weight loss and characteristic skin lesions.

Some tumors of the small intestine produce serotonin, responsible for carcinoid syndrome, characterized by:

• flushing;
• tachycardia;
• diarrhea.

“Diagnosis of neuroendocrine tumors requires an integrated approach combining laboratory tests, imaging, and histological confirmation when possible.

Laboratory tests

Blood tests may reveal the presence of specific hormones in functioning tumors. Among general markers, chromogranin A is the most widely used, although it has low specificity and may be elevated in non-tumor conditions,” Prof. Partelli continues.

Imaging

Imaging plays a central role. CT and MRI allow identification of the lesion, assessment of its characteristics, and evaluation of its extent. In the pancreas, endoscopic ultrasound is particularly useful both for detecting small tumors and for performing targeted biopsies.

One of the most sensitive tools is Gallium-68 PET, which exploits the expression of somatostatin receptors on neuroendocrine cells, allowing detection of even millimetric lesions and accurate assessment of disease spread.

In more aggressive tumors, which often lose these receptors, FDG-PET may be more appropriate, reflecting higher cellular metabolism.

Histological confirmation

Diagnostic confirmation is almost always based on histological examination, which is essential for determining tumor grade and guiding treatment. In some locations, such as the small intestine, preoperative biopsy may be difficult; in these cases, diagnosis is mainly based on clinical and radiological findings.

Depending on their characteristics, neuroendocrine tumors can be treated in different ways.

Treatment of pancreatic neuroendocrine tumors

Treatment of pancreatic NETs is highly personalized and depends on multiple factors, including tumor size, location, presence of symptoms, degree of aggressiveness, and the patient’s overall condition. When possible, surgery represents the main curative option.

“Surgical procedures may range from enucleation of small lesions to more extensive resections, such as distal pancreatectomy or pancreaticoduodenectomy. Minimally invasive techniques, such as laparoscopy and robotic surgery, are increasingly used and allow faster recovery with fewer complications,” the surgeon states.

In many cases, especially for pancreatic NETs smaller than 2 cm, a conservative approach can be chosen. These lesions, generally indolent, can be monitored over time with structured radiological follow-up, reserving surgery for cases of progression.

Treatment of gastric neuroendocrine tumors

For small gastric tumors, endoscopic removal represents an effective and minimally invasive option; for larger gastric NETs, with deep submucosal infiltration, high grading, or risk features (ulceration, positive margins, lymphovascular invasion), a surgical approach is indicated, which may range from local resection to partial gastrectomy with lymphadenectomy depending on stage and biological type.

Treatment of small intestine neuroendocrine tumors

For NETs of the small intestine, surgery is the treatment of choice even in the presence of limited metastatic disease, as it allows control of symptoms and disease progression. The standard procedure involves segmental intestinal resection with extensive mesenteric lymphadenectomy and careful evaluation of vascularization, given the frequent associated mesenteric fibrosis.

Treatment of colorectal neuroendocrine tumors

In colorectal NETs, the surgical strategy depends on location, size, and grading (i.e., tumor aggressiveness): rectal lesions equal to or larger than 1 cm, if well differentiated, can be treated locally (endoscopic or transanal resection).

Tumors larger than 2 cm, G2–G3, or with invasion of the muscular layer require formal oncological resection with lymphadenectomy, similar to colorectal adenocarcinomas.

Medical therapies for neuroendocrine tumors: when surgery is not indicated

“When surgery is not indicated or the disease is advanced, medical therapies are used. Somatostatin analogues, such as octreotide and lanreotide, are often the first choice in well-differentiated tumors, as they slow tumor growth and control hormonal symptoms.

In more complex cases, targeted therapies (everolimus, sunitinib) or chemotherapy regimens may be used, including temozolomide-capecitabine, streptozocin-5FU, or platinum and etoposide-based regimens in poorly differentiated forms.”

One of the most innovative treatments is PRRT (Peptide Receptor Radionuclide Therapy), also known as radioligand therapy. This technique uses radiopharmaceuticals that bind to somatostatin receptors, delivering radiation directly to tumor cells, with particular effectiveness in well-differentiated NETs.

Locoregional techniques may also be used, such as radiofrequency, percutaneous ablation, and embolization of liver metastases, as well as therapies aimed at symptom control.

The therapeutic pathway does not end with initial treatment. NETs are often chronic conditions with which many patients live for years, thanks to their generally slow progression and the availability of numerous treatment options.

In well-differentiated tumors, prognosis is often favorable: even in the presence of metastases, the disease may remain stable for long periods, allowing a good quality of life. In contrast, high-grade tumors tend to be more aggressive and require intensive treatment and close monitoring.

“Recurrences may occur even many years later, making follow-up an essential component. Monitoring includes:

• periodic visits;
• blood tests;
• imaging studies.

The frequency of follow-up is determined based on individual risk, but in most cases includes CT or MRI every 6–12 months, with Gallium-68 PET used when disease progression is suspected,” concludes Prof. Partelli.