NETs are a group of rare cancers that originate from neuroendocrine cells, which are found throughout the body. These cells are responsible for producing hormones, and as a result, NETs often have hormone-secreting capabilities.
Metastasis is the spread of cancer cells from their original site to other parts of the body. As the neuroendocrine system is spread throughout the body, this process can affect the progression and prognosis of neuroendocrine tumours (NETs).
While NETs can originate in various organs, they often metastasise to specific sites, making disease management more challenging. The likelihood of metastasis depends on the tumour’s grade, differentiation, and location, and metastatic disease significantly influences the treatment approach and overall prognosis for patients.
Metastasis occurs when cancerous NET cells break away from the primary tumour and spread to distant organs through the bloodstream or lymphatic system. This process leads to the formation of secondary tumours, known as metastases, in other parts of the body.
Neuroendocrine Cancer Australia (NECA), is dedicated to supporting individuals diagnosed with NETs, and their families. NECA offers a wealth of resources, educational programs, and advocacy efforts aimed at deepening the understanding of NETs, improving patient care, and encouraging research advancements. Patients diagnosed with NETs can engage with NECA’s comprehensive support and information by calling the NET nurse line.
The most common sites of metastasis for NETs include the liver, lungs, and bones. Among these, the liver is the most frequent site, with studies showing that up to 40-90% of patients with gastroenteropancreatic NETs (GEP-NETs) present with liver metastases at diagnosis.
Other common metastatic sites include:
The presence of metastasis significantly affects disease progression and prognosis. Metastatic NETs are typically more difficult to treat, and once the disease has spread to distant organs, curative treatment options may be limited.
Patients with metastatic disease often experience more severe symptoms due to the increased tumour burden, and some metastatic disease can also lead to hormone secretion, impacting both quality of life and long-term outcomes.
The exact pattern of metastasis depends on the type and origin of the NET. Let’s take a look at some of the most common patterns.
Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) originate in the gastrointestinal tract or pancreas and are the most common type of NETs.
Pancreatic NETs also have a high tendency to metastasise to the liver, followed by the lungs and bones. Metastatic GEP-NETs are often associated with increased hormonal activity, leading to symptoms such as flushing, diarrhoea, and abdominal pain.
Lung NETs, which include typical and atypical carcinoids as well as small-cell lung cancers, have a distinct pattern of metastasis. Lung NETs frequently metastasise to the lymph nodes, liver, and bones.
Studies show that between 20-30% of patients with lung NETs develop distant metastases, with bone metastases being particularly common in atypical carcinoids and small-cell neuroendocrine carcinomas (source: Journal of Thoracic Oncology).
The prognosis for lung NETs varies depending on the tumour grade and the extent of metastasis.
Other, less common types of NETs, such as pheochromocytomas (arising in the adrenal glands) and paragangliomas (occurring outside the adrenal glands), have unique patterns of metastasis. Pheochromocytomas often metastasise to the bones and lungs, while paragangliomas can spread to lymph nodes, liver, and bones. Though these tumours are rare, metastasis is often associated with more aggressive disease and poorer outcomes.
Detecting metastasis in NETs typically involves a range of advanced techniques, including imaging, biopsy and biomarker testing.
Computed tomography (CT) scans and magnetic resonance imaging (MRI) are commonly used to assess tumour size and location, particularly in the liver and other solid organs.
Positron emission tomography (PET)/CT with 68Ga-DOTATATE, a somatostatin receptor-based imaging technique, is considered one of the most sensitive methods for detecting metastasis in NETs.
This imaging modality allows for the visualisation of both primary and metastatic NETs by targeting somatostatin receptors, which are often overexpressed in these tumours.
While imaging is critical for detecting metastasis, biopsy remains preferable, but not always possible for confirming metastatic disease.
A biopsy of the metastatic lesion allows for histopathological examination and genetic testing, providing vital information about the tumour’s grade, differentiation, and potential treatment options.
In cases where metastases are suspected but not definitively diagnosed through imaging, a biopsy may be necessary to confirm the spread of the disease.
Blood tests for biomarkers such as chromogranin A (CgA) are frequently used to monitor the presence and progression of NETs, although these are not always reliable.
Elevated levels of this biomarker may indicate disease progression and metastasis, particularly in high-grade NETs.
Additionally, hormone levels such as serotonin or insulin can provide clues about metastatic activity, especially in hormone-secreting NETs. Testing such as 5HIAA can be valuable in monitoring serotonin levels.
Tumour grade and differentiation
The grade and differentiation of a NET are some of the most important prognostic factors.
The extent of metastasis at diagnosis is another key factor influencing prognosis. Patients with localised disease, where the tumour is confined to its primary site, tend to have better outcomes compared to those with distant metastases.
Patient-specific factors play an important role in prognosis, and include
Older patients or those with significant comorbidities may be less able to tolerate aggressive treatments such as surgery or chemotherapy, leading to a more conservative approach and potentially poorer outcomes.
Fortunately, there are a range of treatment options available for patients seeking treatment for metastatic NETs.
Surgical intervention remains one of the most effective treatments for metastatic NETs, particularly when the metastasis is confined to the liver.
Surgery is often combined with systemic therapies to maximise outcomes.
Systemic therapies, including somatostatin analogues (SSAs), chemotherapy, and peptide receptor radionuclide therapy (PRRT), are essential for managing metastatic NETs.
For patients with liver-dominant metastatic NETs, liver-directed therapies such as radiofrequency ablation (RFA) and transarterial embolisation (TAE) can be effective in controlling tumour growth and alleviating symptoms.
These minimally invasive procedures target the liver metastases directly, reducing the tumour burden and improving quality of life.
In cases where metastatic NETs are advanced and curative treatment is no longer possible, palliative care becomes essential.
The goal of palliative care is to manage symptoms, improve quality of life, and provide emotional and psychological support to both patients and their families.
The grade of the tumour has a significant impact on survival outcomes. Patients with low-grade, well-differentiated NETs tend to have much better survival rates than those with high-grade neuroendocrine carcinomas.
As previously mentioned, well-differentiated NETs have a 5-year survival rate of 60-80%, whereas poorly differentiated high-grade tumours have a much lower survival rate.
The site of metastasis also plays a critical role in prognosis. Here are some examples:
Survival rates for NETs are closely linked to the stage at diagnosis.
As mentioned earlier, patients with localised NETs have a 5-year survival rate of approximately 90%, while those with distant metastases have a survival rate of around 15-20%.
Early detection and intervention are key to improving these outcomes.
Long-term outcomes for patients with metastatic NETs are generally poorer than for those with non-metastatic disease.
However, with advances in systemic therapies and liver-directed treatments, patients with metastatic disease are living longer and experiencing improved quality of life.
Early diagnosis is critical for improving prognosis in NETs. Detecting the disease before metastasis occurs allows for more curative treatment options, such as surgery, and improves long-term survival rates.
Recent advances in treatment strategies, including PRRT, liver-directed therapies, and targeted systemic therapies, are helping to improve outcomes for patients with metastatic NETs. These therapies offer hope for better control of the disease and improved survival.
Research is ongoing to develop new therapies for metastatic NETs. Emerging treatments, such as immunotherapy and novel targeted therapies, are being tested in clinical trials and may offer new options for patients with advanced disease.
Personalised treatment approaches based on genetic profiling and prognostic biomarkers are a growing area of research. By identifying specific mutations and biomarkers, researchers hope to develop more targeted therapies that can improve outcomes for patients with metastatic NETs.
Further information and support for people diagnosed with NETs is available by calling the NECA NET nurse line.
