We’ve all heard the age-old question about the chicken and the egg? Scientists claimed to have ‘cracked’ the riddle of whether the chicken or the egg came first. The answer, they say, is the chicken. Researchers found that the formation of egg shells relies on a protein found only in a chicken’s ovaries. Therefore, an egg can exist only if it has been inside a chicken. There you have it!
On a similar subject, I’m often confused when someone says they have been diagnosed with ‘Carcinoid Syndrome‘ but not one of associated ‘Neuroendocrine Tumours’ – my instinct says that is impossible because the tumour is what causes the syndrome – i.e. chicken is the NET and the egg is the syndrome.
In terms of presentation, the syndrome might look like it comes first, particularly in cases of metastatic/advanced disease or other complex scenarios, i.e. the presence of the syndrome triggers further checks. Alternatively, a tumour may be found in an asymptomatic patient, quite often incidentally. However, on the basis that the widely accepted definition of Neuroendocrine Tumours would indicate that a syndrome is secondary to tumour growth, then the tumour must be the chicken. Without evidence of a tumour, it’s a second guess given that testing for hormonal syndromes is not 100% sensitive or specific. Evidence of a tumour helps confirm and tissue sampling to confirm NET is pretty conclusive along with the hormonal level evidence.
This is a very tricky situation, one where you really need a NET specialist to know how to diagnose NETs properly. They know stuff. For example, they would be able to pin down some of the presenting symptoms, know which tests to conduct and know which imaging devices to check for the locations of the tumours. They would also know that while most scenarios with carcinoid syndrome would indicate liver metastases are involved, they also know the rare exceptions to that rule and be able to look closer and tick off those possibilities; and perhaps find the culprit in the process. They also know about “pseudo carcinoid syndrome” where certain conditions can mimic it (i.e. differential diagnoses). They most likely also know that the small intestine is most common ‘occult’ location for unknown primaries in NET.
If I was a doctor sitting in front of such a case, here is what I would investigate:
This algorithm assumes the patient has symptoms compatible with carcinoid syndrome (flushing, diarrhoea, bronchospasm, pellagra‑like changes) but no tumour visible on CT/MRI/PET.
It reflects real‑world NET behaviour: biochemistry often becomes abnormal before radiology.
🟩 STEP 1 — Confirm the syndrome is truly serotonin‑driven
A. Biochemical testing
- 24‑hour urinary 5‑HIAA
- Plasma serotonin
- Plasma 5‑HIAA (if urine collection unreliable)
- Consider chromogranin A (with caveats)
B. Rule out mimics (“pseudo‑carcinoid syndrome”)
These can produce flushing/diarrhoea but are not serotonin‑driven:
- Mast cell activation disorders
- Medullary thyroid carcinoma
- Pheochromocytoma/paraganglioma
- VIPoma, glucagonoma, other functional NETs
- Menopause, rosacea, alcohol flushing
- Medication‑induced flushing (niacin, SSRIs, etc.)
If 5‑HIAA/serotonin are normal → not carcinoid syndrome. If elevated → proceed.
🟩 STEP 2 — Re‑examine the liver (most common source of occult disease)
Even with negative imaging, micrometastases may be present.
Recommended imaging
- MRI liver with hepatobiliary contrast (highest sensitivity for small lesions)
- Contrast‑enhanced multiphase CT
- DOTATATE PET/CT (or 64Cu‑DOTATATE if available)
If still negative
Assume biologically present but radiologically occult liver metastases remain possible.
🟩 STEP 3 — Search for primary tumours that bypass the liver
These can cause full carcinoid syndrome without liver metastases.
A. Bronchial NET
- CT chest (high‑resolution)
- DOTATATE PET/CT
- Bronchoscopy if suspicion persists
B. Ovarian NET (women)
- Pelvic MRI
- Transvaginal ultrasound
- DOTATATE PET/CT
C. Thymic NET
- CT chest with contrast
- DOTATATE PET/CT
D. Retroperitoneal NET
- CT/MRI abdomen
- DOTATATE PET/CT
🟩 STEP 4 — Investigate the small bowel (most common occult primary)
Small bowel NETs are submucosal, tiny, and easily missed.
Recommended sequence
- DOTATATE PET/CT (look for mesenteric nodes even if primary not seen)
- CT or MR enterography
- Capsule endoscopy
- Double‑balloon enteroscopy (targeted, if capsule suggests a lesion)
Why this matters
A patient can have:
- a 2–5 mm ileal primary
- microscopic liver mets
- full carcinoid syndrome
- normal CT, MRI, scopes, and even DOTATATE
This is a classic NET pattern.
🟩 STEP 5 — Repeat imaging over time
NETs grow slowly. Symptoms and biochemistry often appear years before a tumour becomes visible.
Recommended follow‑up
- Repeat DOTATATE PET/CT every 6–12 months
- Repeat MRI liver every 6–12 months
- Monitor 5‑HIAA/serotonin every 3–6 months
This is standard practice in high‑suspicion cases.
🟩 STEP 6 — Consider rare but real scenarios
A. Right‑to‑left cardiac shunt
Allows serotonin to bypass the lungs.
B. Non‑NET serotonin sources
Very rare and usually mild:
- Tryptophan‑rich diet
- Malabsorption
- Certain medications
These do not produce full carcinoid syndrome.
🟦 STEP 7 — If syndrome persists, assume tumour exists but is occult
This is the key clinical principle:
True carcinoid syndrome without a tumour is essentially impossible. If the syndrome is real, the tumour exists — it just hasn’t been found yet.
Management focuses on:
- controlling symptoms
- repeating imaging
- escalating to more sensitive modalities
- monitoring for eventual radiological emergence
Thanks for reading
Disclaimer
I am not a doctor or any form of medical professional, practitioner or counsellor. None of the information on my website, or linked to my website(s), or conveyed by me on any social media or presentation, should be interpreted as medical advice given or advised by me.
Neither should any post or comment made by a follower or member of my private group be assumed to be medical advice, even if that person is a healthcare professional.
Please also note that mention of a clinical service, trial/study or therapy does not constitute an endorsement of that service, trial/study or therapy by Ronny Allan, the information is provided for education and awareness purposes and/or related to Ronny Allan’s own patient experience. This element of the disclaimer includes any complementary medicine, non-prescription over the counter drugs and supplements such as vitamins and minerals.
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Thank you again for another interesting and informative blog! I so appreciate you sharing your research with all of us who need encouragement and information. My son is going into his third year since diagnosis, and gets the monthly injection. Things have remained stable. Boring appointments are good appointments for us!
I wish your son all the very best! Yes …. boring appointments normally mean good appointments!
Good one again Ronny!
Brilliant blog but Ronny how do you find the time to research and write all this.
A lot of the detail is in my head or in other posts. I just get ideas and build them into a blog. I have a certain set of skills 😀
Very interesting! Maybe we need to adopt the chicken as our symbol instead of the zebra. (Just kidding, of course!)
I’ll submit the idea to INCA 😄