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Neuroendocrine cancer of unknown primary (neuroendocrine CUP) is diagnosed when a neuroendocrine cancer is found in the body, but the place where it originally started (the primary site) cannot be identified despite specialist investigations. It can include both neuroendocrine tumours (NETs) and neuroendocrine carcinomas (NECs).
Sometimes the original tumour is very small and difficult to detect, even when cancer has been found elsewhere in the body. Finding the primary site can help guide treatment, but treatment decisions can still be made when it remains unknown, based on factors such as the type and grade of the cancer.
This page explains more about neuroendocrine CUP, including possible causes and symptoms, tests and scans, treatment and follow-up care. It also includes information about living with your diagnosis and where to find further information and support.
Use the links in the box to find the information that is most relevant to you.
What is neuroendocrine cancer of unknown primary?
Neuroendocrine cancer is a type of cancer that begins in the neuroendocrine cells, which are found throughout the body. These cells have the ability to release hormones that can regulate many body functions. When they become cancerous, their growth rate and normal function is disrupted.
There are two main types:
- Neuroendocrine tumours (NETs) – usually slower growing
- Neuroendocrine carcinomas (NECs) – less common and faster growing
Sometimes neuroendocrine cancer is found in the body, but despite specialist investigations, the place where it originally started cannot be identified. This is known as neuroendocrine cancer of unknown primary (CUP).
Treatment and outlook depend largely on the tumour grade, how differentiated the cells are, and the extent of disease.
About neuroendocrine CUP
Although it is usually possible to identify where a cancer started through symptoms, investigations and scans, this is not always possible with neuroendocrine cancers.
Neuroendocrine cancers can start as collections of cells so small they may be no larger than a grain of sand. These tiny tumours can remain hidden for months or years before becoming visible on scans.
Despite their small size, some neuroendocrine cancers may spread (metastasise) to other parts of the body such as:
- Lymph nodes
- Liver
- Lungs
- Bones
- Peritoneum
This does not necessarily mean the tumour is aggressive. It may simply indicate that the cancer has been present for a long time.
If the primary site cannot be identified, your specialist team may diagnose a neuroendocrine cancer of unknown primary (CUP).
Key facts
- CUP accounts for around 2 in 100 of all invasive cancers
- Neuroendocrine cancers make up less than 5 in 100 of all CUP diagnoses
- Up to 13 in 100 people metastatic neuroendocrine tumours have no identifiable primary site at diagnosis
- The most likely hidden primary sites include small bowel, pancreas, lung (bronchus), stomach, colon and rectum
Why finding the primary matters
Identifying the tumour’s origin can help guide treatment choices and predict behaviour. However, treatment can still be highly effective even when the primary site remains unknown.
Types of neuroendocrine CUP
Neuroendocrine CUP includes both:
- Neuroendocrine tumours (NETs)
- Neuroendocrine carcinomas (NECs)
Management is guided primarily by tumour grade, differentiation, somatostatin receptor status and overall disease burden, rather than simply by identifying the primary site.
Therefore knowing whether you have a NET or NEC is vitally important.
How does neuroendocrine CUP develop?
We do not yet fully understand what causes neuroendocrine cancers. Researchers are continuing to learn more about how the body works, how our environment may affect our health, and how genetic changes can lead to cancer. This growing knowledge is helping to improve diagnosis and treatment and may lead to better ways to prevent cancer in the future.
Most neuroendocrine cancers:
- Are not inherited
- Occur without any obvious cause
- Develop sporadically (no family history or obvious cause)
A small number may occur alongside rare inherited conditions including:
- Multiple endocrine neoplasia (e.g. MEN1) disorders
- Other rare familial cancer syndromes
If several family members have had cancer, particularly at a younger age (50 years or younger), tell your specialist team as genetic assessment may be helpful.
Many genetic changes found in neuroendocrine cancers occur only within tumour cells and are not inherited. These changes do not necessarily increase cancer risk for family members.
Signs and symptoms
Neuroendocrine CUP may or may not cause symptoms.
1. Symptoms caused by the tumour itself
Possible symptoms include:
- Unexplained weight loss
- Reduced appetite
- Fatigue
- Abdominal discomfort
- Pain related to metastatic disease
2. Symptoms caused by hormone changes
Hormone-producing tumours may cause specific syndromes that can sometimes provide clues about where the primary tumour originated.
Carcinoid syndrome is usually associated with metastatic well-differentiated NETs. Symptoms may include:
- Flushing
- Diarrhoea
- Wheezing
- Rapid heartbeat
- Sweating
- Abdominal discomfort
Other functional syndromes caused by specific hormone-producing tumours include:
- Zollinger-Ellison syndrome
- Insulinoma syndrome
- Glucagonoma syndrome
- Ectopic ACTH syndrome
These symptoms can sometimes help direct investigations towards a likely primary site.
Carcinoid crisis (rare) may occur in those who have carcinoid syndrome
Carcinoid crisis can happen during anaesthesia or tumour manipulation (biopsy, surgery or interventional radiology – e.g. embolisation or ablation treatments) or be triggered by mental/physical stress.
Symptoms may be similar to carcinoid syndrome but are much more severe. These include severe flushing – often accompanied by palpitations or a fast, irregular heart rate, low blood pressure, confusion and breathing difficulty – and can be life-threatening.
Specialist teams plan care to reduce this risk.
If you are at risk of carcinoid crisis, carry a Carcinoid Crisis Card so healthcare professionals know how to manage your care in an emergency. You can order one from us for free.
3. Rare symptoms (paraneoplastic syndromes)
Very rarely, cancer can trigger symptoms caused by the body’s immune response to cancer.
These are uncommon but can sometimes cause serious health problems.
Watch our video: Paraneoplastic Syndromes – Explained
4. Symptoms related to treatment
Treatments can cause side effects, but not everyone experiences them.
Your team will talk through possible side effects and how they can be managed.
Tests and scans
Investigations are guided by symptoms, tumour behaviour and potential primary sites. A comprehensive assessment usually includes:
- Clinical examination
- Blood and urine tests
- Cross-sectional imaging
- Functional imaging
- Endoscopy
- Histopathology
Blood and urine tests
Tests may include:
- Full blood count
- Liver function tests
- Kidney function tests
- Iron, ferritin, B12 and folate
- Calcium
- Thyroid function tests
- Chromogranin A (CgA) +/- chromogranin B (CgB)
- Gut hormone profile
- 5HIAA (urine or blood)
- More common tumour markers, e.g. CEA, CA19-9, CA125, AFP, Beta-HCG, LDH, PSA
- NT-ProBNP may be taken if you have a history of heart disease or carcinoid syndrome (NET only)
- Vitamin, mineral and trace element check
Other blood tests may include genetics and/or calcitonin, norepinephrine or adrenocorticotropic hormone (ACTH). But this will be decided on a case-by-case basis, guided by your symptoms and clinical expertise.
Scans and procedures
Structural imaging:
- CT chest, abdomen and pelvis
- MRI abdomen and pelvis
Functional imaging:
- Gallium-68 DOTATATE PET/CT
- Octreotide SPECT scan
- FDG-PET scan
Additional imaging:
- Bone scintigraphy (if bone disease is suspected)
- Echocardiogram where appropriate
Endoscopy: Depending on symptoms and test results, investigations may include:
- Gastroscopy
- Colonoscopy
- Bronchoscopy
- Endoscopic ultrasound
- Capsule endoscopy
Watch our video: Your Guide to Scans
Histopathology
This means looking at cells and tissues under a microscope to understand disease. It helps confirm whether cancer is present, where it started, what type of cells are involved, and how quickly the cells are growing.
Your doctor will explain which biopsy is best for you and why. You will also have time to ask questions and give consent before the procedure
A combination of these investigations may help identify the most likely primary site and guide treatment decisions.
Cancer gene changes and targeted treatments
Some neuroendocrine cancers (particularly NECs) may contain specific genetic alterations that can be targeted with treatment.
Examples include:
- PD-L1 expression
- DLL3 expression
- Other molecular alterations
Genomic testing may help identify targeted treatment options or eligibility for clinical trials.
Treatment options
Your care is individualised based on your tumour, health and preferences.
Treatment decisions are based on:
- NET or NEC diagnosis and stage.
- Tumour grade and Ki-67
- Symptoms
- Disease burden
- Somatostatin receptor status
- General health
- Your preferences
All patients should be discussed within a specialist neuroendocrine multidisciplinary team (MDT).
1. Monitoring (surveillance)
Monitoring may be used following treatment to check how well the treatment worked. It can also be used to monitor stable disease. When active treatment is not currently needed, monitoring is required.
This typically involves a clinical review, blood tests and further scans or investigations.
2. Surgery
Surgery may be appropriate when:
- Disease can be safely removed
- Symptoms can be improved
- A hidden primary site is suspected
- Diagnostic clarification is required
In selected patients, surgical exploration of the small bowel may identify previously undetected primary tumours.
3. NET treatment options
- Somatostatin analogues (SSAs): used to control hormone-related symptoms and/or tumour growth.
- Targeted medical therapy (e.g. the mTOR inhibitor everolimus): these are targeted treatments that block a protein that cancer cells use to grow and divide, helping to slow or stop tumour growth.
- Chemotherapy: rarely used as a first treatment for low grade (G1-2) NETs but may be considered in G2-3 or if other treatments are not suitable or have stopped working. It may be given as tablets or through a drip into a vein. For example CapTem (capecitabine + temozolomide) tablets or, rarely, Streptozocin/5FU via a drip.
- Radiotherapy: external beam radiation therapy (EBRT) may be used, following surgery or to treat symptomatic bone metastases.
- Radioligand therapy (RLT, also known as PRRT or lutetium‑177): mainly used for metastatic or progressing disease. It is a targeted internal radiation treatment. It delivers radiation directly to cancer cells, usually given in four sessions spaced 8–12 weeks apart. RLT is not currently approved by National Institute for Health and Care Excellence (NICE) for CUP but may be accessible through clinical trial or other funding route. If your NET is a metastases from a suspected primary within the pancreas or digestive tract, you may be offered this treatment on the NHS.
- Symptom control and supportive care: includes any treatment or support that helps you feel better, even if it is not directly treating the cancer. This may include medicines, dietary advice and/or psychological support. Techniques such as mindfulness or relaxation may help with pain, fatigue, stress or anxiety.
- Clinical trial therapy: clinical trials are used to find out if new treatments and techniques are safer and more effective than the ones that already exist, or for discovering if existing treatments can be used in different, more effective, ways or combinations.
4. NEC treatment options
- Chemotherapy: is considered first line treatment for neuroendocrine carcinomas in inoperable disease. It may also be considered if surgery is not possible or after surgery – if it was incomplete or doctors think there is a high risk of recurrence. The main treatment is usually platinum-based chemotherapy, sometimes combined with etoposide (or irinotecan in certain cases). If the cancer comes back or grows, further treatment options may include reusing the first treatment or trying other forms of chemotherapy.
- Radiotherapy: external beam radiation therapy (EBRT) may be used to treat symptomatic bone metastases.
- Immunotherapy: clinical trials are looking promising in treating NECs, but it has yet to become a standard of care. Research is ongoing. Immunotherapy may be considered in NEC if available and accessible. Types of treatment may include immune checkpoint inhibitors, which help your immune system recognise and attack cancer by removing the ‘brakes’ that normally hold it back, and DLL3 inhibitors, which target the protein DLL3, frequently over-expressed in high-grade neuroendocrine cancers.
- Symptom control and supportive care: includes any treatment or support that helps you feel better, even if it is not directly treating the cancer. This may include medicines, dietary advice and/or psychological support. Techniques such as mindfulness or relaxation may help with pain, fatigue, stress or anxiety.
- Clinical trial therapy: clinical trials are used to find out if new treatments and techniques are safer and more effective than the ones that already exist, or for discovering if existing treatments can be used in different, more effective, ways or combinations.
Diagnosis and living with neuroendocrine CUP
A diagnosis of neuroendocrine cancer can bring questions, uncertainty and a range of emotions. Information and support are available to help you understand your diagnosis and navigate what happens next.
Just diagnosed with neuroendocrine cancer? Access information and support to help you navigate the early days after diagnosis.
Follow-up care
Follow-up is an important part of your ongoing care. It helps your healthcare team check how you are doing, spot any changes early, and support your physical and emotional wellbeing.
While expert guidelines offer a general plan for follow-up, your care will always be tailored to you and your specific type of neuroendocrine cancer.
At each appointment, your team will ask how you are feeling, review your symptoms and medications, and arrange blood tests if needed.
You may also be offered a holistic needs assessment (HNA). This is an opportunity to talk with your specialist nurse or doctor about any physical, emotional, practical, or social needs, so the right support can be put in place.
Guideline follow-up recommendations for CUP
For grade 1-2 NET (Ki-67 <20%):
- Follow-up according to specialist NET guidelines
- Typically includes regular imaging and biochemical monitoring
For grade 3 NET or NEC (Ki-67 >20%):
- Follow-up according to specialist NEC guidelines
- More frequent monitoring
- Imaging based on treatment response and disease activity
- Ongoing assessment for further treatment opportunities
How you can be part of your care
You are an important member of your healthcare team. You can help by:
- Reporting new symptoms or any changes in current symptoms or overall health promptly
- Attending scheduled appointments
- Asking questions
- Sharing your priorities and concerns
- Understanding your treatment plan
- Letting your team know if appointments are delayed or missed
Support and further information
We have worked with the International Neuroendocrine Cancer Alliance (INCA) to provide information resources in more than 10 different languages: these are available here.
Other sources of support including benefits/financial and general cancer advice:
- Cancer Research UK: Provides comprehensive guides on diagnosis and living with CUP, alongside a nurse-staffed helpline and online peer chat spaces.
- Maggie’s Centres: Run drop-in centres across the UK providing free practical, emotional and social support from professional specialists.
- Macmillan Cancer Support: Offers a free support line (0808 808 00 00), financial guidance, and a specialized online community forum for CUP patients.
Stories from our community
Hear from people connected to neuroendocrine cancer as they share their experiences, perspectives and insights – from living with the condition to caring for, treating and supporting those affected.
Remember
Every person’s experience of neuroendocrine CUP is different – there may be shared similarities, but each journey is unique.
Your healthcare team will support you every step of the way, guiding your treatment, care, and follow-up. We’re here alongside them, offering additional support and information whenever you need it.
The information on this page is based on available clinical expert guidelines and publications. It is for informational purposes only and should not be considered professional medical advice.
