Neuroendocrine Tumors (NET): Complete Guide to Symptoms & Treatment

What Are Neuroendocrine Tumors?

Neuroendocrine tumors (NETs) are cancers that arise from neuroendocrine cells - specialized cells that receive signals from the nervous system and respond by producing hormones. These tumors can develop throughout the body but most commonly occur in the gastrointestinal tract (especially the small intestine) and lungs. NETs were previously called carcinoids.

Neuroendocrine cells are found throughout the body and serve as a bridge between the nervous and endocrine (hormonal) systems. When these cells become cancerous, they form neuroendocrine tumors that may continue producing hormones, sometimes in excess amounts that cause characteristic symptoms. The term "carcinoid" was historically used to describe these tumors because they were thought to be less aggressive than typical carcinomas, though we now know they represent a spectrum of malignancies with varying degrees of aggressiveness.

The World Health Organization (WHO) classifies neuroendocrine neoplasms into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Well-differentiated NETs tend to grow more slowly and have cells that still resemble normal neuroendocrine cells under the microscope. Poorly differentiated NECs are more aggressive and require different treatment approaches. This classification is essential for treatment planning and determining prognosis.

NETs are classified as rare cancers, affecting approximately 5-7 people per 100,000 annually. However, the incidence has been increasing over recent decades, partly due to improved diagnostic imaging that detects tumors that might have gone unnoticed in the past. Most patients are diagnosed around age 60, though NETs can occur at any age. Unlike many common cancers, there are no well-established lifestyle risk factors for most NETs, though certain inherited genetic syndromes do increase risk.

Where Do Neuroendocrine Tumors Develop?

Neuroendocrine tumors can develop wherever neuroendocrine cells exist in the body, but certain locations are more common than others. Understanding the primary site is important because it affects both symptoms and treatment approaches. The gastrointestinal tract accounts for the majority of NETs, with the small intestine being the most frequent site, followed by the rectum and appendix.

Gastroenteropancreatic NETs (GEP-NETs) comprise the largest category and include tumors arising in the stomach, small intestine (particularly the ileum), appendix, colon, rectum, and pancreas. Pancreatic NETs (pNETs) deserve special mention as they can produce various hormones leading to distinct clinical syndromes - insulinomas produce insulin causing low blood sugar, gastrinomas produce gastrin causing severe ulcers, and so forth.

Bronchopulmonary NETs arise in the lungs and airways and account for about 25% of all NETs. They range from typical carcinoids (slow-growing) to atypical carcinoids (intermediate behavior) to small cell and large cell neuroendocrine carcinomas (aggressive). Lung NETs may cause different symptoms including coughing, wheezing, and recurrent pneumonia.

Understanding Tumor Grade and Differentiation

The grade of a neuroendocrine tumor is one of the most important factors determining behavior and treatment. Grading is based on how quickly the tumor cells are dividing, measured by the Ki-67 index (percentage of cells actively dividing) and mitotic rate (number of dividing cells seen under the microscope). This grading system helps predict how aggressively a tumor might behave.

• Grade 1 (G1) NETs: Ki-67 less than 3%, mitotic rate less than 2 per 10 high-power fields. These are slow-growing tumors with the best prognosis.
• Grade 2 (G2) NETs: Ki-67 between 3-20%, mitotic rate 2-20 per 10 high-power fields. Intermediate behavior between G1 and G3.
• Grade 3 (G3) NETs: Ki-67 greater than 20%, mitotic rate greater than 20 per 10 high-power fields. More aggressive behavior requiring more intensive treatment.

What Are the Symptoms of Neuroendocrine Tumors?

Symptoms of neuroendocrine tumors depend on the tumor's location and whether it produces hormones. Many NETs cause no symptoms initially and are discovered incidentally. When symptoms occur, they may include flushing, diarrhea, abdominal pain, wheezing, and weight loss. The classic "carcinoid syndrome" with flushing and diarrhea typically occurs when tumors have spread to the liver.

One of the challenges in diagnosing neuroendocrine tumors is that they often grow silently for years before causing noticeable symptoms. In many cases, NETs are discovered incidentally during imaging studies or surgical procedures performed for other reasons. When symptoms do develop, they can be vague and easily attributed to more common conditions, which can delay diagnosis. The average time from symptom onset to NET diagnosis has historically been several years, though improved awareness is shortening this interval.

NETs are classified as functional or non-functional depending on whether they produce hormones that cause symptoms. Approximately 30-40% of GEP-NETs are functional, meaning they secrete hormones in quantities sufficient to cause clinical syndromes. Non-functional NETs may still produce hormones, but not enough to cause symptoms - their effects are mainly related to the tumor mass itself, such as obstruction or pain from local growth.

Carcinoid Syndrome

Carcinoid syndrome is a collection of symptoms caused by hormones released by neuroendocrine tumors, particularly serotonin, histamine, and other vasoactive substances. This syndrome typically occurs when NETs have metastasized to the liver, because the liver normally metabolizes these hormones before they reach the systemic circulation. When liver metastases are present, hormones can bypass this "first-pass" metabolism and cause widespread symptoms.

The classic symptoms of carcinoid syndrome include:

• Flushing: Sudden episodes of warmth and redness affecting the face and upper body. The skin may appear red in lighter-skinned individuals or darker in those with darker skin tones. Flushing can be triggered by stress, alcohol, certain foods (especially cheese, chocolate, and spicy foods), or physical exertion.
• Diarrhea: Watery, frequent bowel movements that can be severe and debilitating. This is caused by serotonin's effects on gut motility and can lead to significant fluid and electrolyte imbalances.
• Wheezing and breathing difficulties: Bronchospasm caused by hormone release can mimic asthma symptoms. This can be particularly concerning during surgery or other stressful procedures.
• Rapid heartbeat (tachycardia): Palpitations and racing heart during flushing episodes are common and can be alarming for patients.

Symptoms by Tumor Location

Different primary sites produce characteristic symptoms based on local effects and the specific hormones produced:

Small intestine NETs may cause intermittent abdominal pain, especially after meals, which can be mistaken for irritable bowel syndrome or other functional gut disorders. As they grow, they can cause partial or complete intestinal obstruction with severe cramping, bloating, and vomiting. Small intestine NETs are most likely to spread to the liver and cause carcinoid syndrome.

Rectal and colonic NETs may cause rectal bleeding, changes in bowel habits, or be discovered during routine colonoscopy. Many rectal NETs are small and found incidentally, with excellent prognosis when removed completely.

Lung NETs can cause coughing (sometimes with blood), wheezing, shortness of breath, and recurrent pneumonia. Some patients develop facial swelling and redness (different from carcinoid syndrome flushing) due to hormone effects specific to bronchial NETs.

Pancreatic NETs produce symptoms depending on the hormones they secrete. Insulinomas cause hypoglycemia with confusion, sweating, and tremors that improve with eating. Gastrinomas cause severe peptic ulcers (Zollinger-Ellison syndrome). Non-functional pancreatic NETs may present with abdominal pain, jaundice if blocking the bile duct, or weight loss.

What Causes Neuroendocrine Tumors?

The exact cause of most neuroendocrine tumors is unknown. Unlike many cancers, there are no well-established lifestyle risk factors for sporadic NETs. However, certain inherited genetic syndromes significantly increase NET risk, including Multiple Endocrine Neoplasia type 1 (MEN1), Von Hippel-Lindau disease (VHL), Neurofibromatosis type 1, and Tuberous Sclerosis Complex.

Research into the causes of neuroendocrine tumors continues to evolve, but for most patients, no specific cause can be identified. Unlike lung cancer with smoking or liver cancer with hepatitis, NETs lack clear environmental or lifestyle risk factors in most cases. This can be frustrating for patients who want to understand why they developed their disease, but it also means there is typically no reason to feel that personal choices led to the cancer.

Genetic mutations play a role in some NETs, even those that are not part of inherited syndromes. Researchers have identified mutations in genes like DAXX, ATRX, and MEN1 in sporadic (non-inherited) pancreatic NETs. These findings are helping scientists understand how NETs develop and may lead to new treatment approaches. Ongoing genomic research is expected to provide more insights into NET biology in coming years.

Hereditary Syndromes Associated with NETs

While most NETs occur sporadically, approximately 10-20% are associated with inherited genetic syndromes. Knowing about these associations is important for several reasons: patients with these syndromes benefit from surveillance programs to detect NETs early, and family members may benefit from genetic testing and monitoring.

• Multiple Endocrine Neoplasia Type 1 (MEN1): Caused by mutations in the MEN1 gene, this syndrome predisposes to pancreatic NETs, parathyroid tumors, and pituitary adenomas. Pancreatic NETs occur in 30-80% of MEN1 patients. Regular screening with imaging and hormone testing is recommended.
• Von Hippel-Lindau Disease (VHL): Associated with pancreatic NETs (occurring in 10-17% of patients), as well as kidney tumors, hemangioblastomas, and pheochromocytomas. The VHL gene normally functions as a tumor suppressor.
• Neurofibromatosis Type 1 (NF1): While primarily known for causing neurofibromas, NF1 also increases the risk of duodenal NETs, especially somatostatinomas near the ampulla of Vater.
• Tuberous Sclerosis Complex (TSC): This syndrome is associated with pancreatic NETs along with characteristic skin findings, kidney angiomyolipomas, and brain tubers.

How Are Neuroendocrine Tumors Diagnosed?

Diagnosis of neuroendocrine tumors involves blood and urine tests to detect tumor markers and hormones, imaging studies including CT, MRI, and specialized PET scans (particularly Gallium-68 DOTATATE PET/CT), and biopsy for histological confirmation and grading. The Ki-67 index from biopsy determines tumor grade, which is essential for treatment planning.

The diagnostic workup for neuroendocrine tumors is comprehensive and serves multiple purposes: confirming the diagnosis, determining the tumor grade, identifying the extent of disease (staging), and assessing whether the tumor is functional. This information guides treatment decisions and helps predict prognosis. The workup typically involves coordination between multiple specialists including oncologists, endocrinologists, gastroenterologists, and radiologists with NET expertise.

Many patients undergo multiple tests as part of their evaluation. While this can feel overwhelming, each test provides important information that contributes to optimal treatment planning. Understanding what each test measures can help patients feel more prepared for the diagnostic process.

Blood and Urine Tests

Several laboratory tests help in the diagnosis and monitoring of neuroendocrine tumors:

Chromogranin A (CgA) is a protein produced by most neuroendocrine cells and serves as a general tumor marker for NETs. Elevated CgA levels support the diagnosis and can be used to monitor treatment response. However, CgA can also be elevated by proton pump inhibitors (heartburn medications), kidney disease, and some other conditions, so results must be interpreted carefully.

24-hour urine 5-HIAA (5-hydroxyindoleacetic acid) measures a breakdown product of serotonin and is particularly useful for diagnosing and monitoring NETs associated with carcinoid syndrome. Patients need to avoid certain foods (bananas, avocados, plums, eggplant, tomatoes, pineapple, walnuts) and medications before collection to ensure accurate results.

Specific hormone tests may be ordered based on symptoms. These include insulin and C-peptide for suspected insulinoma, gastrin for suspected gastrinoma, glucagon, vasoactive intestinal peptide (VIP), and others depending on the clinical picture.

Imaging Studies

Modern imaging plays a crucial role in NET diagnosis and staging. Different imaging modalities provide complementary information:

CT (Computed Tomography) scans provide detailed anatomical images and are often the first imaging study performed. CT is excellent for detecting liver metastases and assessing tumor size. For pancreatic and small bowel NETs, multi-phase contrast-enhanced CT protocols improve detection.

MRI (Magnetic Resonance Imaging) is particularly useful for liver imaging and can detect small metastases that might be missed on CT. MRI is also valuable for evaluating pancreatic NETs and provides excellent soft tissue detail without radiation exposure.

Gallium-68 DOTATATE PET/CT is a specialized imaging study that has revolutionized NET diagnosis and staging. This scan uses a radioactive tracer that binds to somatostatin receptors, which are present on most well-differentiated NETs. It is highly sensitive for detecting primary tumors and metastases throughout the body and also helps predict response to certain treatments including peptide receptor radionuclide therapy (PRRT).

Octreoscan (Somatostatin Receptor Scintigraphy) is an older nuclear medicine study that also detects somatostatin receptors. While largely replaced by Gallium-68 DOTATATE PET/CT where available, octreoscan remains useful when PET/CT is not accessible.

Biopsy and Histological Grading

A biopsy is essential for confirming the diagnosis and determining the tumor grade. The pathologist examines the tissue under a microscope and performs special staining tests including:

• Synaptophysin and chromogranin immunostaining: These markers confirm neuroendocrine differentiation
• Ki-67 index: The percentage of cells staining positive for Ki-67 protein indicates proliferative activity and determines tumor grade
• Mitotic count: The number of dividing cells per 10 high-power fields contributes to grading

Biopsy can be obtained through various methods depending on tumor location: endoscopic biopsy for accessible gastrointestinal tumors, CT-guided needle biopsy for liver metastases or other sites, or surgical biopsy when other methods are not feasible. The biopsy procedure is generally well-tolerated, though there is a small theoretical concern about triggering hormone release in functional tumors - your medical team will take appropriate precautions.

How Are Neuroendocrine Tumors Treated?

Treatment of neuroendocrine tumors depends on tumor grade, location, extent of disease, and whether it is functional. Surgery is the primary treatment for localized NETs and offers the possibility of cure. For advanced disease, options include somatostatin analogs, targeted therapies like everolimus, peptide receptor radionuclide therapy (PRRT), and chemotherapy for aggressive tumors. Many patients can live for years with appropriate treatment.

The treatment approach for neuroendocrine tumors has evolved significantly over recent decades, with multiple effective options now available. Treatment decisions are best made by multidisciplinary teams that include medical oncologists, surgeons, interventional radiologists, nuclear medicine specialists, and endocrinologists with NET expertise. Treatment is individualized based on tumor characteristics, disease extent, symptoms, and patient preferences.

For many patients, especially those with low-grade tumors, treatment focuses on long-term disease control rather than aggressive intervention. The slow-growing nature of many NETs means that patients can often live well for many years with appropriate management. Quality of life considerations are important, and treatment side effects must be weighed against benefits.

Surgery

Surgery is the only potentially curative treatment for neuroendocrine tumors and is the treatment of choice for localized disease. Complete surgical removal of the primary tumor and any regional lymph node involvement offers the best chance of cure. For small intestine NETs, surgery typically involves removing the affected section of bowel along with associated lymph nodes and mesentery.

Even when cure is not possible, surgery may play an important role in management. Debulking surgery (removing as much tumor as possible while leaving some behind) can reduce hormone production and improve symptoms in functional NETs. This approach is particularly relevant for liver metastases, where removing the majority of tumor burden can significantly improve quality of life and potentially extend survival.

Before any surgery, patients with carcinoid syndrome or functional tumors require medical preparation to prevent carcinoid crisis. This typically involves treatment with octreotide before and during surgery. Your surgical and anesthesia teams will be aware of this requirement and take appropriate precautions.

Medical Therapies

Somatostatin analogs (octreotide LAR, lanreotide) are the backbone of medical treatment for most well-differentiated NETs. These medications mimic the natural hormone somatostatin and work in two ways: they reduce hormone secretion (controlling symptoms of carcinoid syndrome) and slow tumor growth. Large clinical trials have demonstrated that somatostatin analogs significantly delay tumor progression, even in patients without symptoms. They are typically given as monthly injections.

Targeted therapies offer additional options for progressive disease:

• Everolimus (Afinitor): An mTOR inhibitor approved for progressive GEP-NETs and lung NETs. It has been shown to significantly extend progression-free survival.
• Sunitinib (Sutent): A multi-kinase inhibitor approved for progressive pancreatic NETs.

Peptide Receptor Radionuclide Therapy (PRRT) represents a major advance in NET treatment. PRRT uses radioactive molecules (typically Lutetium-177) attached to somatostatin analogs that specifically target NET cells. The radioactivity is delivered directly to tumor cells while sparing normal tissue. The NETTER-1 trial demonstrated significant improvements in progression-free survival for patients with progressive midgut NETs, and PRRT is now an established treatment option for somatostatin receptor-positive tumors.

Chemotherapy has a more limited role in well-differentiated NETs compared to many other cancers, as these tumors are often less responsive to conventional chemotherapy. However, chemotherapy remains important for poorly differentiated neuroendocrine carcinomas (NECs), which typically require platinum-based regimens similar to small cell lung cancer. Some chemotherapy combinations (such as temozolomide-based regimens) show activity in pancreatic NETs.

Liver-Directed Therapies

Because the liver is the most common site of NET metastases and liver involvement drives many symptoms in carcinoid syndrome, several treatments specifically target liver tumors:

• Hepatic arterial embolization: Blocking blood flow to liver tumors can cause tumor death and symptom improvement
• Chemoembolization (TACE): Combines embolization with localized chemotherapy delivery
• Radioembolization (Y-90): Delivers radioactive microspheres directly to liver tumors through the hepatic artery
• Radiofrequency ablation (RFA) or microwave ablation: Uses heat to destroy smaller liver tumors

These liver-directed approaches can be particularly valuable for controlling symptoms and may be used in combination with systemic treatments.

What Is the Prognosis for Neuroendocrine Tumors?

Prognosis for neuroendocrine tumors varies widely depending on tumor grade, stage, and location. Well-differentiated, localized NETs (Grade 1) have excellent prognosis with 5-year survival rates exceeding 90%. Even with metastatic disease, many patients with low-grade NETs live for many years with appropriate treatment. High-grade NECs have a more guarded prognosis similar to small cell lung cancer.

Understanding prognosis is important for patients and families, though it is essential to remember that statistics describe population averages and cannot predict individual outcomes. Many patients exceed statistical expectations, and advances in treatment continue to improve outcomes. The most relevant prognostic factors for NETs include tumor grade, disease stage at diagnosis, primary tumor location, and specific molecular features.

Grade is perhaps the most important prognostic factor. Grade 1 NETs have significantly better outcomes than Grade 2, which in turn have better outcomes than Grade 3. Even within the same grade, there can be variation based on other factors. Primary site also matters - pancreatic NETs and small bowel NETs may have different behaviors and outcomes.

Living with Metastatic NET

For patients with metastatic disease, it is important to understand that many well-differentiated NETs, even when spread to the liver and elsewhere, remain manageable for extended periods. Unlike some aggressive cancers where metastatic disease rapidly progresses, many NET patients live for years or even decades with good quality of life while receiving treatment.

Regular monitoring is important to track disease status and adjust treatment as needed. This typically involves periodic imaging (CT, MRI, or PET scans) and laboratory tests. The frequency of monitoring depends on tumor grade and treatment status - more aggressive tumors require more frequent surveillance.

How Does NET Affect Daily Life?

Living with NET involves managing treatment schedules, monitoring for symptoms, and making lifestyle adjustments. Patients with carcinoid syndrome may need to avoid triggers like alcohol and certain foods. Fatigue is common during treatment. Support from NET-specialized care teams, patient organizations, and mental health professionals can help patients maintain quality of life.

A diagnosis of neuroendocrine tumor affects life in many ways beyond the physical symptoms and treatments. Understanding what to expect and having strategies to cope can help patients navigate this journey. Many patients find that while NET changes their life, they can still pursue meaningful activities and maintain close relationships.

Managing Fatigue

Fatigue is one of the most common challenges faced by NET patients, both from the disease itself and from treatments. This isn't ordinary tiredness - cancer-related fatigue can be profound and isn't fully relieved by rest. However, there are strategies that can help:

• Prioritize activities that matter most to you
• Rest when needed, but keep rest periods short to avoid deconditioning
• Engage in regular gentle exercise - studies show this can actually improve cancer-related fatigue
• Discuss persistent fatigue with your medical team, as it may have treatable causes

Emotional and Psychological Support

A cancer diagnosis brings emotional challenges including anxiety, depression, uncertainty about the future, and changes in relationships and roles. These feelings are normal and deserve attention. Many cancer centers offer psychological support services, and patient organizations provide peer support programs where you can connect with others who understand the NET experience.

Family members and caregivers also need support. Watching a loved one face cancer is stressful, and caregivers often neglect their own needs. Encourage your loved ones to seek support for themselves - their wellbeing matters and helps them provide better support to you.

Diet and Lifestyle Considerations

Patients with carcinoid syndrome may need to modify their diet to avoid triggering flushing and other symptoms. Common triggers include alcohol, spicy foods, and certain amines found in aged cheeses, smoked meats, and fermented foods. However, dietary restrictions should be individualized - not everyone reacts to the same triggers, and overly restrictive diets can negatively impact nutrition and quality of life.

General healthy lifestyle practices benefit NET patients just as they benefit everyone: balanced nutrition, regular physical activity appropriate to your abilities, adequate sleep, and stress management. These won't cure NET but can improve overall wellbeing and tolerance of treatment.

When Should You Seek Medical Care?

Seek immediate medical attention if you experience severe abdominal pain (possible intestinal obstruction), severe flushing with low blood pressure or difficulty breathing (possible carcinoid crisis), or any new severe symptoms. Contact your NET care team for persistent diarrhea, new or worsening symptoms, or concerns about treatment side effects.

Knowing when to seek urgent care versus routine follow-up helps ensure appropriate management while avoiding unnecessary emergency visits. For patients with established NET, maintaining a relationship with your specialized care team provides access to expert guidance when concerns arise.

Frequently Asked Questions About Neuroendocrine Tumors