A Spotlight on Pancreatic Neuroendocrine Neoplasms

Disclaimer
The information in this Spotlight is for general education only. It cannot replace advice from your own medical team, who know your individual situation, test results, and treatment options. Neuroendocrine Neoplasms and related conditions are complex and research is evolving; guidance, classifications, and statistics may change over time. Always discuss any questions or concerns with your specialist team before making decisions about tests, treatments, or monitoring.

Pancreatic neuroendocrine neoplasms comprise Pancreatic NETs (well differentiated) and Pancreatic NEC (poorly differentiated)

1. What they are

Pancreatic NENs arise anywhere in the head, neck, body, or tail of the pancreas and include:

Well‑differentiated NETs (G1–G3)
Poorly differentiated NECs (small‑cell or large‑cell type)Well‑differentiated NETs (G1–G3)

Well‑differentiated NETs (G1–G3) may be non‑functional or functional, producing a range of hormones.

2. Epidemiology

United Kingdom (England, NCRAS 2018)

Pancreatic NETs: 1.00 per 100,000 per year
All NENs (NET + NEC): 8.61 per 100,000 per year

United States (SEER‑based, consensus values)

Pancreatic NETs: 1.20 per 100,000 per year
All NETs (all sites): 8.52 per 100,000 per year

Lung NEN under‑counting (UK + USA): Typical carcinoid, atypical carcinoid, and LCNEC are most liklely under‑reported in both NCRAS and SEER. This makes overall NEN incidence conservative, but if data was entered by hospitals correctly and extracted from cancer registries properly, pancreatic NET site‑specific rates may be considered reliable.

3. Functional pancreatic NETs (WHO 2019/2022)

Classic functional pNETs

Insulinoma: hypoglycaemia; usually small, often body/tail.
Gastrinoma: Zollinger–Ellison syndrome; pancreatic head/uncinate possible, but most gastrinomas are duodenal.
Glucagonoma: necrolytic migratory erythema, diabetes, weight loss; usually body/tail.
VIPoma: watery diarrhoea, hypokalaemia, achlorhydria; often tail‑favoured but can be anywhere.
Somatostatinoma: diabetes, gallstones, steatorrhoea; slight pancreatic head predominance, but most somatostatinomas are duodenal.

Rare/ultra‑rare functional pNETs

ACTH‑secreting NET (ectopic Cushing’s): pancreas possible; lung and thymus more common sources.
GRF‑secreting NET (acromegaly): pancreas possible; lung/thymus more frequent.
PTHrP‑secreting NET (hypercalcaemia): pancreas possible; lung more common.
Calcitonin‑secreting NET: pancreas possible; lung more common.
Ghrelinoma: pancreas (body/tail), stomach, duodenum.
Serotonin‑secreting pNET (i.e. carcinoid syndrome): extremely rare.
PPoma (pancreatic polypeptide): genuinely pancreatic, often head/uncinate; usually non‑syndromic but biochemically detectable.

Proportions

Non‑functional pNETs: ~70–80%
Functional pNETs: ~20–30%

4. Stage at diagnosis

Stage I–II: ~35–40%
Stage III: ~20–25%
Stage IV: ~35–40%

5. Diagnostic testing (notwithstanding test availability or local guidelines)

Biochemical

Chromogranin A (CgA)
Pancreatic polypeptide (PP)
- Helpful in CUP‑NEN: small intestine NETs do not raise PP, so elevated PP suggests pancreatic origin.
Hormone‑specific tests guided by symptoms: insulin, C‑peptide, proinsulin, gastrin, glucagon, VIP, somatostatin, ACTH, GRF, PTHrP, calcitonin, ghrelin.

Imaging

Contrast‑enhanced CT pancreas protocol
MRI pancreas/liver
Endoscopic ultrasound (EUS) with biopsy – highest sensitivity for small lesions and MEN1‑associated multifocal disease.
68Ga‑DOTATATE PET/CT – gold standard for well‑differentiated pNETs.
18F‑FDG PET/CT – for high‑grade NETs and all NECs.

Pathology and molecular

Distinguish NET vs NEC and assign grade (Ki‑67).
Immunohistochemistry: synaptophysin, chromogranin A, Ki‑67, hormone stains, DAXX/ATRX.
Molecular profiling (where done): MEN1, DAXX, ATRX, mTOR pathway genes.

Germline testing Consider when:

Age < 40
Multifocal pNETs
Gastrinoma or insulinoma
Family history of endocrine tumours
Features of MEN1, VHL, TSC, NF1

Panels typically include MEN1, VHL, TSC1/2, NF1, sometimes RET if MEN2 is suspected.

6. Genetics Summary

Pancreatic NETs are the most genetically active types for inherited (germline) syndromes

MEN1: multiple pancreatic NETs (often non‑functional, gastrinomas, insulinomas).
VHL: non‑functional pNETs, often body/tail, sometimes multiple.
TSC1/TSC2: non‑functional pNETs, rare insulinomas.
NF1: more strongly linked to duodenal somatostatinomas, but pancreatic involvement can occur.

Somatic (tumour) genetics

MEN1 (~40–45%) – somatic is not hereditary see reassurance below.
DAXX (~20–25%) – loss of expression indicates a higher risk of tumour recurrence
ATRX (~15–20%) – loss of expression indicates a higher risk of tumour recurrence
mTOR pathway alterations (TSC2, PTEN, PIK3CA) – these alterations explain why some pancreatic NETs respond to mTOR inhibitors such as everolimus (Afinitor) — the drug directly blocks the overactive pathway. Not all patients have these mutations: Only a subset of NETs show TSC2, PTEN, or PIK3CA changes. Testing for them can help guide treatment decisions.

Reassurance about MEN1: When we say MEN1 is mutated in ~40–45% of pancreatic NETs, we are referring to somatic mutations in the tumour, not inherited mutations.

Somatic MEN1 mutation: present only in cancer cells; does not mean the patient has MEN1 syndrome or a familial condition.

Germline MEN1 mutation: present in every cell; this is what causes hereditary MEN1 syndrome, accounting for about 10% of pancreatic NETs.

NEC genetics

TP53 and RB1 inactivation – the hallmark of neuroendocrine carcinoma (NEC) rather than well‑differentiated NET. Studies show it occurs in >90% of small‑cell NECs and 30–40% of large‑cell NECs, but is rare (<10%) in NET G3. TP53 and RB1 inactivation is the hallmark of poorly differentiated NEC and is rare in well‑differentiated NETs, including NET G3. When one of these tumour‑suppressor genes is abnormal, it may indicate a more aggressive subtype. When both are lost, the tumour behaves as NEC rather than NET.
High mutational burden, biology similar to other high‑grade NECs and small‑cell carcinomas.

7. Grade 3 and NEC in the pancreas

Pancreatic NENs (NET + NEC)

Approximate distribution (WHO 2019/2022‑aligned):

NET G1–G2: ~70–80% of all pancreatic NENs
NET G3 (well‑differentiated, high‑grade):
- ~10–20% of pancreatic NETs
- ≈ 8–15% of all pancreatic NENs
NEC (poorly differentiated): ~10–15% of all pancreatic NENs

Classification update note: Before 2016, all Grade 3 pancreatic NENs were typically grouped as “NEC”. The WHO 2017 and WHO 2019 classifications introduced well‑differentiated NET G3 as a separate category from poorly differentiated NEC. Because registry coding (including SEER and NCRAS) has lagged behind this change, older datasets tend to over‑estimate NEC and under‑estimate NET G3. The proportions above reflect current WHO‑aligned practice rather than historical coding.

8. NECs in the pancreas

Pancreatic NECs are poorly differentiated, high‑grade tumours with aggressive behaviour. They normally require platinum‑based chemotherapy as first‑line treatment, rather than standard NET therapies (somatostatin analogues, targeted agents, PRRT). See most commonly used guidelines below.

9. Guideline anchors

ENETS pancreatic NET/NEC guidance
NANETS pancreatic NET guidance
NCCN Neuroendocrine & Adrenal Tumors
ESMO GEP‑NEN guidelines

10. Pancreatic Cancer vs Pancreatic Neuroendocrine Neoplasms

This article explains why pancreatic cancer and neuroendocrine neoplasms of pancreatic origin are not the same disease, why the confusion persists, and why accurate terminology matters for patients, clinicians, the media and the public. Click here or on the graphic below.

Ronny Allan’s Spotlight on NENs Series

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