Epidemiology: How Common Are NENs?

As mentioned earlier, NETs are rare diseases. However, their exact prevalence is difficult to determine because they are often diagnosed late and were not always accurately recorded in the past. An increase in diagnoses has been observed in recent decades. This is mainly due to improved diagnostic methods and increased awareness of these tumors. It is estimated that approximately 5 to 10 people per 100,000 population are newly diagnosed with NENs each year. 

Causes: Why Do NENs Develop?

The exact causes of NENs are not yet fully understood. It is believed that a combination of genetic and environmental factors plays a role.

Genetic factors:

• Sporadic NENs: Most NENs arise spontaneously (sporadically) and without any identifiable hereditary cause. These are random changes (mutations) in the genetic material of individual cells that occur over the course of a person’s life. These mutations can cause cells to grow and divide uncontrollably.

• Familial NEN syndromes: A small proportion of NENs are hereditary and occur as part of specific syndromes. Among the best known are: 

  • Multiple Endocrine Neoplasia Type 1 (MEN1): This syndrome is associated with changes in the MEN1 gene and predisposes individuals to NENs of the pancreas, parathyroid glands, and pituitary gland.

  • Neurofibromatosis Type 1 (NF1): In this condition, NENs can develop, particularly in the intestine.

  • Von Hippel-Lindau syndrome (VHL): This increases the risk of NENs of the pancreas.

Environmental and risk factors:

Unlike other types of cancer, there are no clearly defined risk factors for NENs—such as smoking or excessive alcohol consumption—that are unequivocally linked to their development. 

In summary, NETs are a diverse group of tumors that usually arise sporadically, but in a small proportion of cases are genetically determined. Researchers continue to work toward a better understanding of the exact causes in order to develop more precise diagnostic and treatment options in the future.

Pathology:

NENs are divided into two main categories: neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs). The fundamental difference lies in their growth behavior and aggressiveness, which is crucial for treatment and prognosis. An important pathological criterion for differentiation is the Ki-67 index, which indicates how many tumor cells are actively growing:

• Neuroendocrine tumors (NETs) generally grow more slowly and typically have a Ki-67 index of less than 20%. Specifically, Grade 1 NETs have an index of up to 3%, Grade 2 NETs have an index of 3% to 20%, and, rarely, Grade 3 NETs (G3) have a Ki-67 index above 20%. They retain many characteristics of the original neuroendocrine cells and have a comparatively good prognosis.

• Neuroendocrine carcinomas (NECs), also known as small-cell or large-cell neuroendocrine carcinomas, are highly aggressive and rapidly growing tumors. Their Ki-67 index is typically above 20%, often even exceeding 55%. These high values reflect their aggressive behavior.

This distinction, based on the Ki-67 index as well as morphological characteristics, is of great importance to pathologists in order to correctly classify the tumor and plan the best possible treatment.

Diagnosis of Neuroendocrine Neoplasms

The diagnosis of neuroendocrine neoplasms (NENs) is often complex and requires a combination of various investigative methods to locate the tumor, determine its characteristics, and assess the extent of the disease.

1. Laboratory parameters and tumor markers:

• General laboratory values: Blood tests provide information about overall health and any changes in organ function.

• Hormonal markers: Since NETs can produce hormones, specific hormone analyses are important. These include, for example: 

  • Chromogranin A (CgA): This is a commonly used general tumor marker for NETs; its levels may be elevated in the blood, but they can also rise in other conditions.

  • 5-Hydroxyindoleacetic acid (5-HIES) in a 24-hour urine sample: This marker is important when carcinoid syndrome caused by serotonin production is suspected.

  • Other hormones: Depending on the suspected tumor type, insulin, gastrin, glucagon, or other hormones may also be measured in the blood.

• Additional markers: If aggressive NEC is suspected, markers such as neuron-specific enolase (NSE) may also be relevant.

2. Imaging Procedures:

• Computed tomography (CT) and magnetic resonance imaging (MRI): These imaging techniques are essential for determining the tumor’s location, assessing its extent, and detecting possible metastases in organs such as the liver, lungs, or bones. They provide detailed cross-sectional images of the body. An MRI is often more advantageous for visualizing soft tissues such as the liver.

• PET/CT (positron emission tomography/computed tomography): This is a particularly sensitive method for visualizing NETs. 

  • Gallium-68-DOTATATE-PET/CT (also known as SSTR-PET/CT): This examination is the gold standard for detecting most NETs (G1–G3). It uses radioactively labeled substances that bind to specific receptors (somatostatin receptors) on the surface of NET cells. This allows even very small tumors and metastases to be visualized that might otherwise be overlooked by other imaging methods.

  • FDG-PET/CT: For more aggressive NETs, particularly NECs, an FDG-PET/CT is often used. This technique uses radioactively labeled glucose (a sugar molecule), which is taken up at a higher rate by rapidly growing cancer cells. This method is particularly useful when there are insufficient somatostatin receptors on the tumor cells or in cases of very aggressive tumors that exhibit high glucose metabolism.

The treatment of neuroendocrine neoplasms depends on several factors: tumor type (NET or NEC), tumor grade, Ki-67 score, tumor origin, extent of the disease, symptoms, hormonal activity, and the patient’s overall condition. In general, the treatment approaches differ significantly: NETs often grow more slowly and can be treated with hormonal, targeted, or nuclear medicine therapies. NECs are usually more aggressive and are more frequently treated with chemotherapy.

Somatostatin Analogs

Somatostatin analogs (SSAs) such as octreotide or lanreotide are among the most important medications for well-differentiated NETs. They resemble the body’s own hormone, somatostatin, and can bind to so-called somatostatin receptors on the tumor cells. This allows them to serve two purposes: On the one hand, they slow tumor growth in many NETs; on the other hand, they alleviate hormone-related symptoms, such as diarrhea or hot flashes associated with carcinoid syndrome. SSAs are usually administered as injections at regular intervals (typically every 4 weeks) and are generally well tolerated. In NEC, they generally do not play a central role, as these tumors often grow more rapidly and are less likely to express sufficient somatostatin receptors.

Targeted Therapy

Targeted therapies specifically interfere with signaling pathways that are important for tumor growth and blood vessel formation. Everolimus inhibits a growth pathway in the cell known as the mTOR signaling pathway and can be used primarily for advanced NETs of the pancreas, the gastrointestinal tract, or the lung. Sunitinib, among other things, inhibits the formation of new blood vessels and is particularly well-established for advanced pancreatic NETs. Cabozantinib is another tyrosine kinase inhibitor that also blocks signaling pathways involved in tumor and vascular development and may represent a therapeutic option for advanced NETs, especially when other treatments are no longer sufficiently effective. These medications are usually taken as tablets. Possible side effects include fatigue, mucositis, skin changes, high blood pressure, diarrhea, or changes in blood test results.

Chemotherapy

Chemotherapy is primarily used when the disease is growing rapidly, there is a high tumor burden, or other therapies are not suitable. For pancreatic NETs, a combination of streptozocin and 5-fluorouracil (STZ/5-FU) may be used. A commonly used alternative is temozolomide plus capecitabine (Tem/Cap), particularly for pancreatic NETs, but also in select other situations. This therapy is available in tablet form. FOLFOX, a combination of 5-fluorouracil, folinic acid, and oxaliplatin, may be considered for advanced or rapidly growing NETs. For NEC, chemotherapy is usually the primary treatment, often with platinum-based combinations, since NECs are biologically much more aggressive than NETs. The choice of regimen depends, among other factors, on Ki-67, tumor origin, prior treatments, and the patient’s general condition.

Peptide Receptor Radionuclide Therapy (PRRT)

Peptide receptor radionuclide therapy (PRRT) is a targeted treatment method for patients with advanced, well-differentiated neuroendocrine tumors (NETs) that express specific somatostatin receptors (SSTRs) on their surface. These receptors can be detected beforehand using a gallium-68 DOTATATE PET/CT (SSTR-PET/CT), which confirms that the tumor is suitable for this therapy.

How does PRRT work?

In PRRT, a radioactive isotope (usually lutetium-177) is coupled to a somatostatin analog. This labeled peptide is administered intravenously to the patient. It circulates throughout the body and binds specifically to the somatostatin receptors on the surface of the tumor cells. This delivers the radioactive substance directly into the tumor cells or into their immediate vicinity. Lutetium-177 emits beta radiation, a short-range form of radiation that primarily damages and destroys the tumor cells. The surrounding healthy tissue is spared as much as possible.

Treatment of Carcinoid Syndrome

Carcinoid syndrome is a complex of symptoms that occurs in approximately 10–20% of NET patients, usually when tumors in the gastrointestinal tract have metastasized to the liver. It is caused by the excessive release of vasoactive substances, particularly serotonin, by the tumor cells. Typical symptoms include hot flashes (flushing), diarrhea, shortness of breath (similar to asthma), and, in advanced cases, heart valve damage (carcinoid heart).

• Somatostatin analogs (SSAs): These are the cornerstones of carcinoid syndrome treatment. By binding to the somatostatin receptors on tumor cells, they inhibit hormone release, which can significantly alleviate the symptoms of the syndrome.

• Telotristat: If SSAs alone are not sufficient to control the diarrhea associated with carcinoid syndrome, telotristat may be used. This medication inhibits serotonin production in the tumor cells, thereby reducing serotonin levels in the body. It is taken orally and can significantly reduce the frequency and severity of diarrhea.

• Locoregional Therapies for the Liver: In patients with liver metastases causing carcinoid syndrome, local treatments of the liver metastases can reduce hormone production. These include: 

  • Transarterial chemoembolization (TACE): In this procedure, a chemotherapy drug is injected directly into the arteries supplying the liver metastases via a catheter, and the blood supply to the metastasis is then blocked to concentrate the drug and starve the tumor cells.

  • Transarterial radioembolization (TARE, also known as SIRT): Similar to TACE, small beads containing radioactive substances are injected into the hepatic arteries, which then irradiate the metastases from within.

  • Ablation (e.g., radiofrequency ablation, microwave ablation): In cases of a few, smaller liver metastases, these can be selectively destroyed using heat.

  • Surgical removal: If there are a limited number of liver metastases, surgery may also be considered to reduce the hormone-producing tumor mass.

• Symptomatic therapies: In addition, medications may be used to provide supportive treatment for individual symptoms, such as antidiarrheals or bronchodilators for shortness of breath.

The choice of an appropriate treatment strategy is always an individualized decision made by an interdisciplinary team at a specialized center.

Multidisciplinary Tumor Board

An interdisciplinary tumor board offers a major advantage for patients with neuroendocrine neoplasms (NENs), as it brings together specialists from various fields to collaboratively plan the best possible treatment. Such a tumor board typically includes specialists from various fields, such as oncology, gastroenterology, surgery, radiology, nuclear medicine, and pathology. Each contributes their own perspective and experience. This ensures that all important test results—such as e e imaging, laboratory values, and histopathological findings—are discussed collectively and properly interpreted.

This close collaboration is particularly important for NETs, which can present in very different ways and often offer multiple treatment options. The tumor board helps identify a personalized treatment plan that is precisely tailored to the patient’s specific condition. For example, it helps determine whether medication, surgery, PRRT, or a combination of these approaches is most appropriate. The optimal timing for each treatment is also determined collectively.

For patients, this means they benefit from pooled expertise and a carefully coordinated treatment strategy without having to seek out different opinions themselves. This increases the likelihood of an effective and well-tolerated treatment while also providing greater peace of mind in managing the disease.