What Are Gastrointestinal Neuroendocrine Tumours

Overview

Neuroendocrine cells play an important role in the digestion of food. They produce hormones and peptides, control the release of digestive enzymes to break down food, and coordinate the muscle activity that regulates food movement from the stomach to the intestines. Neuroendocrine cells are present in almost every organ in the body. They are found in the lungs and the respiratory tract; however, the majority of the neuroendocrine cells are found in the gastrointestinal tract (GIT).

When the DNA of the cells is damaged, they become abnormal and begin to multiply in large numbers, forming a mass or tumour. These tumours, which can be benign or malignant, grow very slowly and may spread to other parts of the body. Such tumours arising from abnormal neuroendocrine cells in the GIT are called gastrointestinal neuroendocrine (GI-NE) tumours.¹ Neuroendocrine cancer can affect the GIT and pancreas, with prevalence in regions spanning from the oesophagus to the anus. GI-NE tumours occur mostly in the small intestine, rectum, and appendix. Carcinoid syndrome, a rare neuroendocrine tumour, occurs in the GIT due to the high secretion of serotonin.

Cancer can be classified based on the origin and size of the tumour:^1,2

• Stage I: The cancer is localised within the GIT and has not spread to other organs. This primary cancer accounts for 70-80% of cases
• Stage II: The cancer spreads to the other parts of the body through tissues
• Stage III: The cancer spreads from its original site, travelling through the lymphatic vessels to other parts of the body
• Stage IV: The cancer spreads through the bloodstream to the other parts of the body. It is a rare and advanced stage of cancer that is characterised by the formation of metastatic tumours

Causes of gastrointestinal neuroendocrine tumour

The exact cause of GI-NE tumours is still unknown, with no avoidable risk factors identified. However, certain factors may predispose people to these tumors:^1,2 

1. Family history: Genetic alterations, such as mutations in the MEN1 gene associated with multiple endocrine neoplasia type 1 or NF1 gene linked to neurofibromatosis, can increase the risk of developing GI-NE tumours. Alterations in these genes may lead to foregut-origin carcinoma or duodenal neuroendocrine carcinoma, respectively³
2. Chronic atrophic gastritis: It is long-term inflammation of the stomach, which is considered a precursor for stomach cancer and may also be associated with the development of GI-NE tumours⁴
3. Age: While GI-NE tumours are rare in children, they are more commonly diagnosed in patients between 50 and 70 years
4. Race: GI-NETs are more frequently observed in white people compared to other racial groups
5. Gender: Women are more susceptible to GI-NETs than males

Signs and symptoms of gastrointestinal neuroendocrine tumour

Cancer patients often do not experience symptoms until the disease has progressed to an advanced stage. The appearance of signs and symptoms is usually influenced by factors such as the invasion of the primary tumour, spread to other organs, or the secretion of substances by neuroendocrine cancer cells in the GIT.

The following are the tumour-related symptoms:⁵

• Abdominal Pain
• Diarrhoea
• Bloating
• Rash
• Red blood in the stools or dark stools
• Constipation
• Nausea and vomiting
• Unexplained weight loss
• Rectal pain
• Jaundice
• Fatigue

Symptoms seen in patients with carcinoid syndrome include:

• Skin flushing
• Facial skin lesions
• Diarrhoea
• Difficulty in breathing
• Asthma-like symptoms
• Rapid heartbeat
• Fluctuations in blood pressure

Management and treatment of gastrointestinal neuroendocrine tumour

The treatment plan depends on several factors, including tumour size and location, the feasibility of complete removal, and whether the tumour has spread or recurred. A multidisciplinary approach involving different medical specialities allows for a comprehensive treatment strategy and aims at improving the quality of life for patients.^2,5

It's important to note that neuroendocrine tumours in the small intestine have a higher tendency to spread to other organs compared to those in the appendix, colon, or rectum.

• Surgery

Surgery is the primary approach, which aims to remove the tumour completely whenever possible. In most cases, surgery alone proves successful in removing the tumour. To ensure thorough removal of the tumour and minimise the risk of cancer recurrence, surgeons also remove the surrounding tissues, including margins or borders. Various surgical options are available, including local excision, partial gastrectomy, esophagectomy, small bowel resection, segmental colon resection, and appendectomy.

Liver metastasis is frequently observed in GI-NE tumours, making liver resection the first-choice treatment. Studies have shown that the removal of the affected parts of the liver controls the symptoms and extends the patient's life. In cases where cancerous tissue affects the entire liver, a liver transplantation is recommended. This treatment method is considered when the patient's condition worsens or fails to respond to other treatments.

• Symptomatic treatment

Interferon therapy is often prescribed to reduce symptoms such as flushing and diarrhoea. Interferons are natural substances that assist the immune system in fighting against infection and cancers. These substances are produced naturally by white blood cells and can also be made in the laboratory. In the case of cancer, interferon therapy helps to slow the tumour growth.

Treatment of carcinoid syndrome

• Hormonal therapy 

Somatostatin analogues and telotristat are commonly used to manage symptoms of carcinoid syndrome and prevent carcinoid crisis.⁶

• Chemotherapy

While chemotherapy is not usually the first-line treatment for GI-NE tumours, it may be recommended for advanced stages where tumours are unresponsive to other therapies. Some of the commonly utilised chemotherapeutic agents are Capecitabine (Xeloda), 5-fluorouracil (5-FU), and Doxorubicin (Adriamycin).

• Radiotherapy

Various forms of radiotherapy are being used to kill cancer cells, including external beam radiation therapy (EBRT), peptide receptor radionuclide therapy (PRRT), and radioembolization. These techniques utilise high-energy rays or radioactive particles to target and destroy cancer cells.

• Targeted therapy

Clinical trials are often carried out to test new treatment modalities, including targeted therapy. This type of therapy identifies and attacks specific cancer cells using drugs designed to inhibit their growth or spread.

Diagnosis of gastrointestinal neuroendocrine tumour

Diagnosing GI-NE tumours poses significant challenges due to symptom overlap with other GI conditions. Cancer may be confirmed through various scenarios, such as abnormal hormonal release from neuroendocrine cells, symptoms developing due to tumour growth, or incidental discovery during surgery or diagnostic evaluations for unrelated GI conditions.

Various tests are available to confirm the diagnosis and assess the stage of the disease, whether it has spread, and the size of the tumour.^2,5

• Endoscopy

It involves the insertion of a flexible tube into the GIT to examine its internal structures. Capsule endoscopy is a specialised procedure where a capsule containing a camera is swallowed, allowing for visualisation of the intestine as the capsule moves through the digestive system and captures images.

• Biopsy

A diagnostic procedure to remove a sample of tissue for examination under a microscope. It assists in determining cell proliferation and differentiation, distinguishing between well-differentiated and poorly differentiated cells.

• Tumor marker test

This test involves the detection of a certain marker known as chromogranin A, which is seen in high levels in neuroendocrine tumours. This marker is usually detected in the blood, urine, or tissue samples.

• Nuclear medicine imaging

This involves the injection of a radioactive drug (a tracer) into the body, followed by a scan to visualise areas where the tracer accumulates and radioactivity builds up. Various traces are used, including gallium-68 (⁶⁸Ga) DOTATATE, copper-64 (⁶⁴Cu) DOTATATE, and (¹⁸F) fluorodeoxyglucose (FDG). The scans are usually performed using positron emission tomography (PET) combined with computed tomography (CT) scans.

FAQs

How can I prevent gastrointestinal neuroendocrine tumours?

While it may not be possible to prevent GI-NE tumours, we can take several steps to reduce the risk of the tumours. Some of the preventive measures include:

• Maintain a balanced diet and healthy weight
• Regular physical activity
• Be aware of the symptoms associated with GI-NE tumours 
• Avoid smoking and excessive alcohol consumption
• Regular screening and check-ups
• Genetic testing

If you have a family history of GI-NE tumours or experience persistent and concerning symptoms, consult your healthcare provider immediately for further evaluation.

How common is gastrointestinal neuroendocrine tumours?

GI-NE tumours are generally considered rare, but their incidence has increased due to advanced diagnostics and greater awareness in recent years. According to studies, the age-adjusted incidence rate was approximately 4.8 cases per 100,000 population annually.⁷

Who is at risk of gastrointestinal neuroendocrine tumours?

The exact cause of GI-NE tumours remains unknown; however, these factors are associated with an increased risk of developing GI-NE tumours:

• Patients with GI conditions
• People with a family history of GI-NE tumours
• Carriers of altered genes like MEN1 and NF1
• Adults over the age of 60 years  

What are the grades of neuroendocrine tumours?

World Health Organization system classifies neuroendocrine tumours into grads based on the speed of tumour growth and spread to the other organs:²

• Low-grade (Grade I): This is the most common subtype, in which the cells appear normal and multiply slowly
• Intermediate-grade (Grade II): The cells have features between a low- and high-grade tumour
• High-grade (Grade III): The cells multiply quickly and are of large and small cell types with a deeper level of invasion
• Grade IV: Rare and tends to be most aggressive

Grades I and II can be easily diagnosed due to their well-differentiated histology, while grades III and IV are aggressive tumours known as GI-NE carcinomas. The GI-NE carcinomas are poorly differentiated, showing metastasis with an increased risk of developing another cancer or spreading to other parts of the body. The growth and spread of these tumours are rapid.

When should I see a doctor?

Seeking medical attention is advisable if: 

• Your symptoms persist for more than a few weeks
• You have ongoing GI symptoms like blood in the stools, nausea, vomiting, constipation, or diarrhoea

Moreover, if you have a family history of GI-NE tumours, it is recommended to discuss your risks with a healthcare provider, even if you do not experience any symptoms.

Summary

Gastrointestinal neuroendocrine (GI-NE) tumours are rare cancers formed from cancerous neuroendocrine cells within the GIT. They can occur in various parts of the GIT, including the stomach, small intestine, colon, rectum, appendix, and other organs in the abdomen. Symptoms vary based on the location and size of the tumour, commonly including abdominal pain, nausea, vomiting, blood in stools, unexplained weight loss, and facial flushing. Treatment options include surgery, targeted therapies, chemotherapy, radiotherapy, and somatostatin analogues. Early detection and treatment generally offer a better quality of life for patients.