Reviewed and edited 12th October 2026
The short answer
Neuroendocrine cancer is difficult to detect because many grow slowly, behave unpredictably, and often hide behind common, misleading symptoms. Even with modern imaging and pathology, many tumours remain invisible until they metastasise. That’s why NETs are often described as “a needle in a haystack.”
Why Neuroendocrine Cancer Is So Hard to Find
Neuroendocrine neoplasms (NENs) are uncommon, heterogeneous, and frequently misdiagnosed. They mimic everyday conditions such as IBS, asthma, menopause, anxiety, gallbladder disease, and acid reflux. This symptom overlap leads to long diagnostic delays — often 5–7 years from first symptoms to confirmed diagnosis.
Three factors drive this challenge:
- Slow growth: many NETs progress quietly for years.
- Functional vs non‑functional behaviour: hormone‑producing tumours behave differently from silent ones.
- Small, hidden primaries: especially in the small intestine, pancreas, and lung.
These characteristics make NETs fundamentally different from most solid tumours.
Cancer of Unknown Primary (CUP): When the Haystack Is Even Bigger
CUP occurs when metastatic cancer is found but the primary tumour cannot be identified. NETs are one of the most common cancers associated with CUP because:
- Small intestinal primaries can be microscopic.
- Pancreatic NETs may remain occult even with high‑resolution imaging.
- Lung NETs can be missed on standard CT.
- Liver metastases often appear before the primary is visible.
Older patients are disproportionately affected — over 60% of CUP cases occur in people aged 75+ — but NET‑related CUP can occur at any age.
For NET patients, CUP is not a failure of medicine; it’s a reflection of how stealthy these tumours can be. See 8 questions for CUP diagnoses below.
Imaging: Powerful, But Not Perfect
Modern imaging has transformed NET diagnosis, but limitations remain.
CT and MRI
Excellent for liver metastases, lymph nodes, and larger primaries — but small bowel NETs often evade detection.
Somatostatin receptor imaging (SSTR PET)
Ga‑68 DOTATATE and Cu‑64 DOTATATE PET/CT scans are now standard (but some countries lack the quantity needed). They detect many primaries, but not all:
- Very small lesions may not express enough receptor.
- High‑grade NECs often have low SSTR expression.
- Fibrotic mesenteric masses can obscure the true origin.
Endoscopy and capsule endoscopy
Useful for GI NETs, but still not guaranteed to find the primary.
Imaging is powerful — but NETs are often more powerful at hiding.
Biopsy and Immunohistochemistry (IHC): Clues, Not Certainty
Biopsy remains essential, but even IHC has limits.
Markers such as chromogranin A, synaptophysin, INSM1, Ki‑67, and site‑specific stains can suggest the tumour’s origin — but they cannot always confirm it 100% with certainty.
Most NET patients do eventually learn their primary site, but a small minority remain challenging. This is especially true for:
- Small intestinal NETs
- Pancreatic NETs
- Lung NETs
- High‑grade NECs
In these cases, treatment focuses on biology and behaviour rather than location.
Multiple Primaries: When There’s More Than One Needle
Some patients have more than one NET primary, especially in the small intestine. Surgeons often use the “Mark 1 eyeball” technique — manually inspecting the bowel during surgery — because imaging may miss additional tumours.
This is not rare. It’s a recognised feature of small bowel NET biology.
Metastasis Patterns: Where NETs Hide
NETs can spread to common and uncommon locations:
- Liver — the most frequent site
- Lymph nodes
- Bone
- Peritoneum
- Lung
- Brain (very rare)
- Breast (rare)
- Heart (extremely rare)
Unusual metastases do not necessarily indicate aggressive disease; they often reflect long‑standing, slow‑growing biology.
NEC vs NET: Why Grade Matters
The 2026 WHO classification emphasises the importance of tumour grade:
- NET G1–G2: well‑differentiated, slow‑growing
- NET G3: well‑differentiated but faster – equal to or less than 55% can often benefit from G2 treatments
- NEC: poorly differentiated, high‑grade, often Ki‑67 >55%
NEC behaves very differently from NET. It spreads faster, responds differently to treatment, and is more likely to present as CUP.
Understanding grade is essential for prognosis and therapy.
MiNEN: When Two Cancers Co‑Exist
Mixed neuroendocrine–non‑neuroendocrine neoplasms (MiNENs) contain both NET/NEC and adenocarcinoma components. They are rare but important because:
- They can complicate diagnosis.
- Treatment may need to target both components.
- The non‑neuroendocrine part may drive behaviour.
MiNENs are another reason why NETs can be difficult to classify.
How We Improve Detection
Several tools help clinicians find the “needle” more reliably:
- High‑resolution SSTR PET
- Multiphasic liver MRI/CT
- Endoscopic ultrasound (EUS)
- Advanced pathology panels
- Genomic profiling
- Emerging molecular diagnostics
- More experienced NET centres
Specialist Knowledge – certain things are known about the behaviour of NENs
Early referral to a specialist centre remains one of the most important steps. Education and awareness is absolutely key – thus why I created the website RonnyAllan.NET
8 questions if told you have cancer of unknown primary (unknown primary NET or occult NET)
For a patient newly told they have a Cancer of Unknown Primary (CUP) or an Unknown Primary NET, the most useful questions are often the simplest ones. I’d suggest something like:
1. Understanding My Diagnosis
- What do you know for certain about my cancer so far?
- Is this definitely a neuroendocrine tumour (NET) or neuroendocrine carcinoma (NEC)?
- What grade is it and does that mean, does it help with locating the primary?
- Where has the cancer been found so far? Does that help with locating the primary?
- Do you have any clues yet about where the primary tumour started?
- What is the most important thing you know about my cancer so far?
2. Understanding the Tests
- What tests have I already had?
- What did the biopsy tell you?
- Did the pathology or immunohistochemistry (IHC) suggest a likely primary site?
- Which primary sites are currently most likely and which have been ruled out?
- Should I have a DOTATATE PET scan, FDG PET scan, CT, MRI, or another investigation?
- What are the chances that further tests will find the primary tumour?
3. If the Primary Cannot Be Found
- How common is it for the primary tumour never to be identified?
- If you never find the primary site, how will that affect my treatment?
- Can treatment still be effective even if the primary remains unknown?
- Will my treatment be based on the biopsy findings rather than the primary location?
4. Treatment Planning
- What treatment options are available right now?
- Do we need to find the primary before starting treatment?
- What is the goal of treatment in my situation?
- Would surgery ever be considered?
- Am I potentially suitable for treatments such as somatostatin analogues, PRRT, chemotherapy, targeted therapy or other options?
5. Expertise and Second Opinions
- Is my case being discussed at a specialist neuroendocrine multidisciplinary team (MDT)?
- Should I be referred to a specialist NET centre? (where applicable)
- Would a second pathology review be helpful, particularly by a pathologist who supports a NET MDT?
6. Prognosis
- What factors are most important in determining my outlook?
- Is knowing the grade and stage of the tumour more important than finding the primary?
- What should I expect over the next few months?
7. Practical Questions
- On the basis of a CUP initial diagnosis, what symptoms should I report urgently?
- Who should I contact if I have questions between appointments?
- Can I get a copy of my pathology report and scan reports?
8. One question I particularly like …..
“Based on everything you know so far, what do you think is the most likely primary site, and what evidence supports that view?” It is simple, non-confrontational, and often reveals a great deal about how confident your team is in the ‘working’ diagnosis.
Summary
Neuroendocrine cancer is difficult to detect because it very often grows slowly, hides in complex anatomy, and often produces misleading symptoms. Even with modern imaging and pathology, many primaries remain invisible. But with improved scans, better pathology, and increasing awareness, detection is steadily improving. NETs may be a needle in a haystack — but the haystack is gradually getting smaller.
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Very useful information, Ronny. Thank you!
This is a brilliant overview, Ronny. I’m between three-monthly CT scans as part of a surveillance regime (PNET primary, liver metastases, both ‘disappeared’ – for now) and your blog keeps me abreast of developments and progress in diagnostic tools and treatments.
Thank you thank you