Neuroendocrine Tumour Liver Metastases (NETLMs)

Neuroendocrine tumours (NETs) are a group of rare, slow-growing neoplasms that arise from neuroendocrine cells, specialised cells found throughout the body that produce hormones in response to neural signals. While NETs can originate in various organs such as the gastrointestinal tract, pancreas, and lungs, they have a notable tendency to spread, or metastasise, to the liver. When this happens, it is referred to as neuroendocrine tumour liver metastases (NETLM). 

In many cases, liver metastases may be the first indication of an underlying NET, especially if the primary tumour is small or asymptomatic. The liver is the most common site for distant spread, with up to 75% of patients with gastrointestinal NETs eventually developing metastases in the liver. Fortunately resection of the liver metastases is often feasible and achieves prolonged survival.

Early detection and proper characterisation of NETLMs are critical for optimal treatment planning. A multidisciplinary approach, including surgery, interventional radiology, and oncology, is often needed to manage these patients effectively and improve both survival and quality of life.

What causes Neuroendocrine Tumour Liver Metastases (NETLMs)? 

Neuroendocrine tumour liver metastases (NETLMs) occur when cancerous neuroendocrine cells from a primary tumour spread to the liver. The exact mechanisms behind this metastatic spread are complex and depend on several biological and anatomical factors.

NETs most commonly arise in the gastrointestinal tract (especially the small intestine, appendix, and rectum) and the pancreas. These organs are connected to the liver through the portal venous system, which acts like a direct highway for tumour cells to travel from the gut to the liver. Once in the liver, these cells can implant and grow, forming secondary tumours known as metastases.

Several factors influence whether a NET is likely to spread to the liver:

• Tumour location — NETs in the midgut (small intestine and appendix) and pancreas have a higher likelihood of spreading to the liver due to their drainage into the portal vein.

• Tumour grade and differentiation — low-grade, well-differentiated NETs tend to spread more slowly, while high-grade or poorly differentiated tumours are more aggressive and prone to early metastasis.

• Lymphatic and vascular invasion — tumours that invade nearby blood vessels or lymphatic channels are more likely to spread to distant sites, including the liver.

• Delayed diagnosis — NETs often grow silently without symptoms, which causes the disease to spread before it is detected.

It is also worth noting that NETLMs are not always preventable, as even small and well-behaved tumours can sometimes metastasise unpredictably. 

What are the symptoms of Neuroendocrine Tumour Liver Metastases (NETLMs)? 

The symptoms of NETLMs can vary widely depending on the number, size, and hormone activity of the liver metastases. Some patients may remain symptom-free for years, while others may experience a range of physical or hormone-related symptoms. In some cases, symptoms of liver metastases are the first noticeable signs of an underlying neuroendocrine tumour.

The most common symptoms include:

• Abdominal pain or discomfort — often vague or located in the upper right side of the abdomen due to liver enlargement or stretching of the liver capsule.

• Unexplained weight loss — may occur due to tumour burden or chronic hormone secretion affecting metabolism.

• Fatigue — a common but non-specific symptom in patients with advanced disease.

• Bloating or a feeling of fullness — may result from liver enlargement or fluid accumulation in the abdomen (ascites).

• Jaundice (yellowing of the skin or eyes) — less common, but may occur if liver function is impaired or if a tumour compresses bile ducts.

• Changes in liver function tests — often detected during routine blood work, even before symptoms appear.

If the liver metastases originate from functioning NETs (those that secrete hormones), patients may also experience symptoms related to carcinoid syndrome, including:

• Flushing of the face and neck — sudden redness and warmth, often triggered by stress, alcohol, or certain foods.

• Watery diarrhoea — may be frequent and debilitating, caused by hormone overproduction such as serotonin.

• Wheezing or shortness of breath — due to bronchospasm triggered by hormone release.

• Heart valve problems — in long-standing cases, especially with elevated serotonin levels, fibrotic damage may affect the right-sided heart valves.

Because these symptoms can be subtle or overlap with other conditions, NETLMs are often diagnosed late. A high index of suspicion and appropriate imaging or biomarker testing are essential in patients presenting with these symptoms, especially if a neuroendocrine tumour has already been diagnosed elsewhere.

Who is at risk of Neuroendocrine Tumour Liver Metastases (NETLMs) in Singapore? 

Neuroendocrine tumour liver metastases often develop silently, and by the time they are diagnosed, many patients are already in the advanced stages of the disease. In Singapore, the incidence of NETs has been steadily rising, which makes awareness of risk factors all the more important.

• Patients with gastrointestinal or pancreatic NETs — tumours in the small intestine, rectum, or pancreas have a higher chance of spreading to the liver due to their direct drainage through the portal vein.

• Those with delayed diagnosis of NETs — because NETs often grow slowly and without obvious symptoms, they may remain undetected until they have already metastasised.

• Individuals with inherited cancer syndromes — genetic conditions like Multiple Endocrine Neoplasia (MEN 1 and MEN 2), Von Hippel-Lindau disease, and Neurofibromatosis type 1 are associated with a higher risk of NETs and potential liver spread.

• People with a strong family history of cancer — studies suggest a link between familial cancer history and a greater likelihood of developing neuroendocrine neoplasms.

• Those with metabolic conditions — individuals with obesity or type 2 diabetes may be more prone to certain types of NETs, especially those in the pancreas.

• Smokers and heavy alcohol users — lifestyle factors such as smoking and excessive alcohol consumption have been associated with increased risk in certain subtypes of neuroendocrine tumours.

How are Neuroendocrine Tumour Liver Metastases (NETLMs) diagnosed? 

Diagnosing NETLMs often requires a combination of blood tests, scans, and sometimes biopsy, as these tumours can be slow-growing and hard to detect early. 

• Blood tests and tumour markers — we check for specific biomarkers such as chromogranin A and serotonin levels, which may be elevated in patients with functioning NETs. Liver function tests are also done to assess overall liver health.

• Urine tests (24-hour urinary 5-HIAA) — this test measures the breakdown product of serotonin and is especially useful in detecting carcinoid syndrome in patients with functioning NETs.

• Cross-sectional imaging (CT or MRI scans) — we use high-resolution contrast-enhanced CT or MRI scans to visualise the liver and detect even small metastatic lesions. MRI is particularly helpful for identifying liver metastases that may not show clearly on CT.

• Nuclear medicine scans (e.g., Ga-68 DOTATATE PET/CT) — this highly sensitive scan helps us detect NETs and their metastases based on somatostatin receptor expression.

• Endoscopic procedures — in select cases, we collaborate with gastroenterologists to perform endoscopy or endoscopic ultrasound to locate the primary tumour, especially when it originates in the gastrointestinal tract.

• Biopsy — when needed, we arrange for image-guided liver biopsy to confirm the diagnosis and assess the tumour grade (based on Ki-67 index), which plays a critical role in treatment planning.

What are the treatment options for Neuroendocrine Tumour Liver Metastases (NETLMs) in Singapore? 

Treatment for NETLMs depends on the size, number, and behaviour of the tumours, as well as your overall health. 

• Surgical resection — when feasible, our doctors (link to ‘About Us’ page) may recommend liver surgery to remove metastatic lesions. This is one of the most effective options for long-term disease control in patients with limited and resectable liver metastases.

• Liver-directed therapies — for patients who are not candidates for surgery, we may recommend treatments such as:

• Radiofrequency ablation (RFA) — uses heat to destroy tumours.

• Transarterial chemoembolisation (TACE) — delivers chemotherapy directly into the liver tumour while blocking its blood supply.

• Selective internal radiation therapy (SIRT) — delivers targeted radiation through tiny beads injected into the liver’s arteries.

• Somatostatin analogues (SSAs) — these medications, such as octreotide or lanreotide, help slow tumour growth and control hormone-related symptoms in functioning NETs. We often start this treatment in collaboration with your oncologist.

• Peptide receptor radionuclide therapy (PRRT) — suitable for patients with somatostatin receptor-positive tumours. This targeted therapy delivers radiation directly to tumour cells, which helps with disease control and symptom relief.

• Targeted therapy and chemotherapy — in more aggressive or high-grade NETs, we may refer for systemic therapies such as everolimus or temozolomide-based chemotherapy, especially when disease burden is widespread.

• Supportive and symptomatic care — we also focus on improving quality of life by managing symptoms such as pain, diarrhoea, or hormonal imbalances, with careful monitoring and follow-up.

Summary 

Neuroendocrine tumour liver metastases (NETLMs) occur when neuroendocrine tumours — often originating in the gastrointestinal tract or pancreas — spread to the liver. These secondary tumours may grow silently for years or cause symptoms such as abdominal pain, flushing, or hormone-related syndromes. 

At Tan Siong San Surgery, we focus on early and accurate diagnosis using advanced imaging, lab tests, and biopsy when needed. Treatment is tailored to each patient, combining surgical and non-surgical approaches to manage tumour growth and maintain quality of life.

If you have been diagnosed with a neuroendocrine tumour or are concerned about possible liver metastases, schedule a consultation with us for a thorough evaluation and personalised treatment plan.